RBCC

Full text data of CFTR

CFTR (ABCC7) [Confidence: low (only semi-automatic identification from reviews)]
Cystic fibrosis transmembrane conductance regulator; CFTR (ATP-binding cassette sub-family C member 7; Channel conductance-controlling ATPase; 3.6.3.49; cAMP-dependent chloride channel)

UniProt P13569
ID CFTR_HUMAN Reviewed; 1480 AA.
AC P13569; Q20BG8; Q20BH2; Q2I0A1; Q2I102;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-MAY-2007, sequence version 3.
DT 22-JAN-2014, entry version 189.
DE RecName: Full=Cystic fibrosis transmembrane conductance regulator;
DE Short=CFTR;
DE AltName: Full=ATP-binding cassette sub-family C member 7;
DE AltName: Full=Channel conductance-controlling ATPase;
DE EC=3.6.3.49;
DE AltName: Full=cAMP-dependent chloride channel;
GN Name=CFTR; Synonyms=ABCC7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT MET-470.
RX PubMed=2475911; DOI=10.1126/science.2475911;
RA Riordan J.R., Rommens J.M., Kerem B., Alon N., Rozmahel R.,
RA Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J.-L.,
RA Drumm M.L., Iannuzzi M.C., Collins F.S., Tsui L.-C.;
RT "Identification of the cystic fibrosis gene: cloning and
RT characterization of complementary DNA.";
RL Science 245:1066-1073(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MET-470.
RX PubMed=1710598; DOI=10.1016/0888-7543(91)90503-7;
RA Zielenski J., Rozmahel R., Bozon D., Kerem B., Grzelczak Z.,
RA Riordan J.R., Rommens J., Tsui L.-C.;
RT "Genomic DNA sequence of the cystic fibrosis transmembrane conductance
RT regulator (CFTR) gene.";
RL Genomics 10:214-228(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS MET-470 AND TRP-1453.
RA Stacy R., Subramanian S., Deodato C., Burkhardt P., Song Y.,
RA Paddock M., Chang J., Zhou Y., Haugen E., Waring D., Chapman P.,
RA Hayden H., Levy R., Wu Z., Rouse G., James R., Phelps K., Olson M.V.,
RA Kaul R.;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [6]
RP PHOSPHORYLATION AT SER-660; SER-686; SER-700; SER-737; SER-768;
RP SER-790; SER-795 AND SER-813.
RX PubMed=1377674;
RA Picciotto M.R., Cohn J.A., Bertuzzi G., Greenguard P., Nairn A.C.;
RT "Phosphorylation of the cystic fibrosis transmembrane conductance
RT regulator.";
RL J. Biol. Chem. 267:12742-12752(1992).
RN [7]
RP GLYCOSYLATION AT ASN-894 AND ASN-900, AND TOPOLOGY.
RX PubMed=7518437;
RA Chang X.-B., Hou Y.-X., Jensen T.J., Riordan J.R.;
RT "Mapping of cystic fibrosis transmembrane conductance regulator
RT membrane topology by glycosylation site insertion.";
RL J. Biol. Chem. 269:18572-18575(1994).
RN [8]
RP PHOSPHORYLATION AT SER-660; SER-700; SER-712; SER-737; SER-753;
RP SER-768; SER-795 AND SER-813.
RX PubMed=9385646;
RA Neville D.C.A., Rozanas C.R., Rice E.M., Gruis D.B., Verkman A.S.,
RA Townsend R.R.;
RT "Evidence for phosphorylation of serine 753 in CFTR using a novel
RT metal-ion affinity resin and matrix-assisted laser desorption mass
RT spectrometry.";
RL Protein Sci. 6:2436-2445(1997).
RN [9]
RP ALTERNATIVE SPLICING (ISOFORM 2).
RX PubMed=10766763; DOI=10.1074/jbc.M910165199;
RA Pagani F., Buratti E., Stuani C., Romano M., Zuccato E., Niksic M.,
RA Giglio L., Faraguna D., Baralle F.E.;
RT "Splicing factors induce cystic fibrosis transmembrane regulator exon
RT 9 skipping through a nonevolutionary conserved intronic element.";
RL J. Biol. Chem. 275:21041-21047(2000).
RN [10]
RP INTERACTION WITH GOPC.
RX PubMed=11707463; DOI=10.1074/jbc.M110177200;
RA Cheng J., Moyer B.D., Milewski M., Loffing J., Ikeda M., Mickle J.E.,
RA Cutting G.R., Li M., Stanton B.A., Guggino W.B.;
RT "A Golgi-associated PDZ domain protein modulates cystic fibrosis
RT transmembrane regulator plasma membrane expression.";
RL J. Biol. Chem. 277:3520-3529(2002).
RN [11]
RP INTERACTION WITH SC4A7 AND SLC9A3R1.
RX PubMed=12403779; DOI=10.1074/jbc.M201862200;
RA Park M., Ko S.B.H., Choi J.Y., Muallem G., Thomas P.J., Pushkin A.,
RA Lee M.-S., Kim J.Y., Lee M.G., Muallem S., Kurtz I.;
RT "The cystic fibrosis transmembrane conductance regulator interacts
RT with and regulates the activity of the HCO3- salvage transporter human
RT Na+-HCO3-cotransport isoform 3.";
RL J. Biol. Chem. 277:50503-50509(2002).
RN [12]
RP PHOSPHORYLATION BY AMPK.
RX PubMed=12519745; DOI=10.1152/ajpcell.00227.2002;
RA Hallows K.R., Kobinger G.P., Wilson J.M., Witters L.A., Foskett J.K.;
RT "Physiological modulation of CFTR activity by AMP-activated protein
RT kinase in polarized T84 cells.";
RL Am. J. Physiol. 284:C1297-C1308(2003).
RN [13]
RP INTERACTION WITH MYO6.
RX PubMed=15247260; DOI=10.1074/jbc.M403141200;
RA Swiatecka-Urban A., Boyd C., Coutermarsh B., Karlson K.H., Barnaby R.,
RA Aschenbrenner L., Langford G.M., Hasson T., Stanton B.A.;
RT "Myosin VI regulates endocytosis of the cystic fibrosis transmembrane
RT conductance regulator.";
RL J. Biol. Chem. 279:38025-38031(2004).
RN [14]
RP REVIEW.
RX PubMed=1378801;
RA McIntosh I., Cutting G.R.;
RT "Cystic fibrosis transmembrane conductance regulator and the etiology
RT and pathogenesis of cystic fibrosis.";
RL FASEB J. 6:2775-2782(1992).
RN [15]
RP ALTERNATIVE SPLICING (ISOFORM 3).
RX PubMed=12913074; DOI=10.1093/hmg/ddg215;
RA Aznarez I., Chan E.M., Zielenski J., Blencowe B.J., Tsui L.-C.;
RT "Characterization of disease-associated mutations affecting an exonic
RT splicing enhancer and two cryptic splice sites in exon 13 of the
RT cystic fibrosis transmembrane conductance regulator gene.";
RL Hum. Mol. Genet. 12:2031-2040(2003).
RN [16]
RP CHANNEL GATING REGULATION, AND PHOSPHORYLATION.
RX PubMed=12588899; DOI=10.1113/jphysiol.2002.035790;
RA Chappe V., Hinkson D.A., Zhu T., Chang X.B., Riordan J.R.,
RA Hanrahan J.W.;
RT "Phosphorylation of protein kinase C sites in NBD1 and the R domain
RT control CFTR channel activation by PKA.";
RL J. Physiol. (Lond.) 548:39-52(2003).
RN [17]
RP IDENTIFICATION IN A COMPLEX WITH RAB11A AND MYO5B.
RX PubMed=17462998; DOI=10.1074/jbc.M608531200;
RA Swiatecka-Urban A., Talebian L., Kanno E., Moreau-Marquis S.,
RA Coutermarsh B., Hansen K., Karlson K.H., Barnaby R., Cheney R.E.,
RA Langford G.M., Fukuda M., Stanton B.A.;
RT "Myosin Vb is required for trafficking of the cystic fibrosis
RT transmembrane conductance regulator in Rab11a-specific apical
RT recycling endosomes in polarized human airway epithelial cells.";
RL J. Biol. Chem. 282:23725-23736(2007).
RN [18]
RP UBIQUITINATION, AND SUBCELLULAR LOCATION.
RX PubMed=19398555; DOI=10.1074/jbc.M109.001685;
RA Bomberger J.M., Barnaby R.L., Stanton B.A.;
RT "The deubiquitinating enzyme USP10 regulates the post-endocytic
RT sorting of cystic fibrosis transmembrane conductance regulator in
RT airway epithelial cells.";
RL J. Biol. Chem. 284:18778-18789(2009).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-291 AND SER-549, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH ANO1.
RX PubMed=22178883; DOI=10.1159/000335765;
RA Ousingsawat J., Kongsuphol P., Schreiber R., Kunzelmann K.;
RT "CFTR and TMEM16A are separate but functionally related Cl-channels.";
RL Cell. Physiol. Biochem. 28:715-724(2011).
RN [21]
RP INTERACTION WITH SLC26A8.
RX PubMed=22121115; DOI=10.1093/hmg/ddr558;
RA Rode B., Dirami T., Bakouh N., Rizk-Rabin M., Norez C., Lhuillier P.,
RA Lores P., Jollivet M., Melin P., Zvetkova I., Bienvenu T., Becq F.,
RA Planelles G., Edelman A., Gacon G., Toure A.;
RT "The testis anion transporter TAT1 (SLC26A8) physically and
RT functionally interacts with the cystic fibrosis transmembrane
RT conductance regulator channel: a potential role during sperm
RT capacitation.";
RL Hum. Mol. Genet. 21:1287-1298(2012).
RN [22]
RP PHOSPHORYLATION AT SER-660; SER-686; SER-700; SER-712; THR-717;
RP SER-737; SER-795; SER-1444 AND SER-1456, UBIQUITINATION AT LYS-688,
RP PALMITOYLATION AT CYS-524 AND CYS-1395, AND MASS SPECTROMETRY.
RX PubMed=22119790; DOI=10.1093/protein/gzr054;
RA McClure M., Delucas L.J., Wilson L., Ray M., Rowe S.M., Wu X., Dai Q.,
RA Hong J.S., Sorscher E.J., Kappes J.C., Barnes S.;
RT "Purification of CFTR for mass spectrometry analysis: identification
RT of palmitoylation and other post-translational modifications.";
RL Protein Eng. Des. Sel. 25:7-14(2012).
RN [23]
RP 3D-STRUCTURE MODELING OF 425-638.
RX PubMed=9517543;
RX DOI=10.1002/(SICI)1097-0134(19980215)30:3<275::AID-PROT7>3.3.CO;2-L;
RA Hoedemaeker F.J., Davidson A.R., Rose D.R.;
RT "A model for the nucleotide-binding domains of ABC transporters based
RT on the large domain of aspartate aminotransferase.";
RL Proteins 30:275-286(1998).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 1476-1480 IN COMPLEX WITH
RP SLC9A3R1.
RX PubMed=11304524; DOI=10.1074/jbc.C100154200;
RA Karthikeyan S., Leung T., Ladias J.A.A.;
RT "Structural basis of the Na+/H+ exchanger regulatory factor PDZ1
RT interaction with the carboxyl-terminal region of the cystic fibrosis
RT transmembrane conductance regulator.";
RL J. Biol. Chem. 276:19683-19686(2001).
RN [25]
RP REVIEW ON VARIANTS.
RX PubMed=1284534; DOI=10.1002/humu.1380010304;
RA Tsui L.-C.;
RT "Mutations and sequence variations detected in the cystic fibrosis
RT transmembrane conductance regulator (CFTR) gene: a report from the
RT Cystic Fibrosis Genetic Analysis Consortium.";
RL Hum. Mutat. 1:197-203(1992).
RN [26]
RP VARIANTS CF.
RX PubMed=1695717; DOI=10.1038/346366a0;
RA Cutting G.R., Kasch L.M., Rosenstein B.J., Zielenski J., Tsui L.-C.,
RA Antonarakis S.E., Kazazian H.H. Jr.;
RT "A cluster of cystic fibrosis mutations in the first nucleotide-
RT binding fold of the cystic fibrosis conductance regulator protein.";
RL Nature 346:366-369(1990).
RN [27]
RP VARIANTS CF.
RX PubMed=2236053; DOI=10.1073/pnas.87.21.8447;
RA Kerem B.-S., Zielenski J., Markiewicz D., Bozon D., Gazit E.,
RA Yahav J., Kennedy D., Riordan J.R., Collins F.S., Rommens J.M.,
RA Tsui L.-C.;
RT "Identification of mutations in regions corresponding to the two
RT putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:8447-8451(1990).
RN [28]
RP VARIANTS CF.
RX PubMed=1710600; DOI=10.1016/0888-7543(91)90510-L;
RA White M.B., Krueger L.J., Holsclaw D.S. Jr., Gerrard B.C., Stewart C.,
RA Quittell L., Dolganov G., Baranov V., Ivaschenko T., Kapronov N.I.,
RA Sebastio G., Castiglione O., Dean M.;
RT "Detection of three rare frameshift mutations in the cystic fibrosis
RT gene in an African-American (CF444delA), an Italian (CF2522insC), and
RT a Soviet (CF3821delT).";
RL Genomics 10:266-269(1991).
RN [29]
RP VARIANTS CF PHE-520 AND HIS-1291.
RX PubMed=1284466; DOI=10.1093/hmg/1.1.11;
RA Jones C.T., McIntosh I., Keston M., Ferguson A., Brock D.J.H.;
RT "Three novel mutations in the cystic fibrosis gene detected by
RT chemical cleavage: analysis of variant splicing and a nonsense
RT mutation.";
RL Hum. Mol. Genet. 1:11-17(1992).
RN [30]
RP VARIANT CF MET-1283.
RX PubMed=1284468; DOI=10.1093/hmg/1.2.123;
RA Cheadle J.P., Meredith A.L., Al-Jader L.N.;
RT "A new missense mutation (R1283M) in exon 20 of the cystic fibrosis
RT transmembrane conductance regulator gene.";
RL Hum. Mol. Genet. 1:123-125(1992).
RN [31]
RP VARIANT CF PRO-1255.
RX PubMed=1284530; DOI=10.1093/hmg/1.6.441;
RA Lissens W., Bonduelle M., Malfroot A., Dab I., Liebaers I.;
RT "A serine to proline substitution (S1255P) in the second nucleotide
RT binding fold of the cystic fibrosis gene.";
RL Hum. Mol. Genet. 1:441-442(1992).
RN [32]
RP VARIANTS CF LYS-92 AND CYS-117.
RX PubMed=1284529; DOI=10.1093/hmg/1.6.439;
RA Shackleton S., Beards F., Harris A.;
RT "Detection of novel and rare mutations in exon 4 of the cystic
RT fibrosis gene by SSCP.";
RL Hum. Mol. Genet. 1:439-440(1992).
RN [33]
RP VARIANT CF LYS-1101.
RX PubMed=7680525;
RA Zielenski J., Fugiwara T.M., Markiewicz D., Paradis A.J.,
RA Anacleto A.I., Richards B., Schwartz R.H., Klinger K.W., Tsui L.-C.,
RA Morgan K.;
RT "Identification of the M1101K mutation in the cystic fibrosis
RT transmembrane conductance regulator (CFTR) gene and complete detection
RT of cystic fibrosis mutations in the Hutterite population.";
RL Am. J. Hum. Genet. 52:609-615(1993).
RN [34]
RP VARIANTS CF VAL-1052; ARG-1061; LEU-1066; GLN-1070; ARG-1085 AND
RP ARG-1101.
RX PubMed=7683628; DOI=10.1006/geno.1993.1183;
RA Mercier B., Lissens W., Novelli G., Kalaydjieva L., De Arce M.,
RA Kapranov N., Klain N.C., Lenoir G., Chauveau P., Lenaerts C.,
RA Rault G., Cashman S., Sangiuolo F., Audrezet M.-P., Dallapiccola B.,
RA Guillermit H., Bonduelle M., Liebaers I., Quere I., Verlingue C.,
RA Ferec C.;
RT "Identification of eight novel mutations in a collaborative analysis
RT of a part of the second transmembrane domain of the CFTR gene.";
RL Genomics 16:296-297(1993).
RN [35]
RP VARIANT CF LYS-92.
RX PubMed=7683954; DOI=10.1093/hmg/2.1.79;
RA Nunes V., Chillon M., Doerk T., Tuemmler B., Casals T., Estivill X.;
RT "A new missense mutation (E92K) in the first transmembrane domain of
RT the CFTR gene causes a benign cystic fibrosis phenotype.";
RL Hum. Mol. Genet. 2:79-80(1993).
RN [36]
RP VARIANT CF SER-205.
RX PubMed=7505694; DOI=10.1093/hmg/2.10.1741;
RA Chillon M., Casals T., Nunes V., Gimenez J., Ruiz E.P., Estivill X.;
RT "Identification of a new missense mutation (P205S) in the first
RT transmembrane domain of the CFTR gene associated with a mild cystic
RT fibrosis phenotype.";
RL Hum. Mol. Genet. 2:1741-1742(1993).
RN [37]
RP VARIANTS CF.
RX PubMed=7504969; DOI=10.1002/humu.1380020511;
RA Gasparini P., Marigo C., Bisceglia G., Nicolis E., Zelante L.,
RA Bombieri C., Borgo G., Pignatti P.F., Cabrini G.;
RT "Screening of 62 mutations in a cohort of cystic fibrosis patients
RT from north eastern Italy: their incidence and clinical features of
RT defined genotypes.";
RL Hum. Mutat. 2:389-394(1993).
RN [38]
RP VARIANTS CYS-31 AND ILE-1220, AND VARIANTS CF LEU-912; TYR-949;
RP PRO-1065 AND PRO-1071.
RX PubMed=7522211; DOI=10.1006/geno.1994.1290;
RA Ghaneb N., Costes B., Girodon E., Martin J., Fanen P., Goossens M.;
RT "Identification of eight mutations and three sequence variations in
RT the cystic fibrosis transmembrane conductance regulator (CFTR) gene.";
RL Genomics 21:434-436(1994).
RN [39]
RP VARIANT CF PRO-346.
RX PubMed=7513296; DOI=10.1007/BF00202817;
RA Boteva K., Papageorgiou E., Georgiou C., Angastiniotis M.,
RA Middleton L.T., Constantinou-Deltas C.D.;
RT "Novel cystic fibrosis mutation associated with mild disease in
RT Cypriot patients.";
RL Hum. Genet. 93:529-532(1994).
RN [40]
RP VARIANTS CF TYR-199; SER-619; ARG-1005 AND ARG-1291.
RX PubMed=7525450; DOI=10.1007/BF00211022;
RA Doerk T., Mekus F., Schmidt K., Bosshammer J., Fislage R., Heuer T.,
RA Dziadek V., Neumann T., Kaelin N., Wulbrand U., Wulf B.,
RA von der Hardt H., Maass G., Tuemmler B.;
RT "Detection of more than 50 different CFTR mutations in a large group
RT of German cystic fibrosis patients.";
RL Hum. Genet. 94:533-542(1994).
RN [41]
RP VARIANT CF GLU-1249.
RX PubMed=7520022;
RA Greil I., Wagner K., Rosenkranz W.;
RT "A new missense mutation G1249E in exon 20 of the cystic fibrosis
RT transmembrane conductance regulator (CFTR) gene.";
RL Hum. Hered. 44:238-240(1994).
RN [42]
RP VARIANT CF GLU-1397.
RX PubMed=7524913; DOI=10.1093/hmg/3.6.999;
RA Petreska L., Koceva S., Gordova-Muratovska A., Nestorov R.,
RA Efremov G.D.;
RT "Identification of two new mutations (711 +3A-->G and V1397E) in CF
RT chromosomes of Albanian and Macedonian origin.";
RL Hum. Mol. Genet. 3:999-1000(1994).
RN [43]
RP VARIANT CF CYS-109.
RX PubMed=7524909; DOI=10.1093/hmg/3.6.1001;
RA Schaedel C., Kristoffersson A.-C., Kornfaelt R., Holmberg L.;
RT "A novel cystic fibrosis mutation, Y109C, in the first transmembrane
RT domain of CFTR.";
RL Hum. Mol. Genet. 3:1001-1002(1994).
RN [44]
RP VARIANT CF THR-120.
RX PubMed=7517264; DOI=10.1002/humu.1380030308;
RA Chillon M., Casals T., Gimenez J., Nunes V., Estivill X.;
RT "Analysis of the CFTR gene in the Spanish population: SSCP-screening
RT for 60 known mutations and identification of four new mutations (Q30X,
RT A120T, 1812-1 G-->A, and 3667del4).";
RL Hum. Mutat. 3:223-230(1994).
RN [45]
RP VARIANT CF LEU-87.
RX PubMed=8081395; DOI=10.1002/humu.1380030412;
RA Bienvenu T., Petitpretz P., Beldjord C., Kaplan J.C.;
RT "A missense mutation (F87L) in exon 3 of the cystic fibrosis
RT transmembrane conductance regulator gene.";
RL Hum. Mutat. 3:395-396(1994).
RN [46]
RP VARIANTS CBAVD ARG-149; LYS-193; GLY-258 AND GLY-800.
RX PubMed=7529962;
RA Mercier B., Verlingue C., Lissens W., Silber S.J., Novelli G.,
RA Bonduelle M., Audrezet M.-P., Ferec C.;
RT "Is congenital bilateral absence of vas deferens a primary form of
RT cystic fibrosis? Analyses of the CFTR gene in 67 patients.";
RL Am. J. Hum. Genet. 56:272-277(1995).
RN [47]
RP VARIANTS CBAVD.
RX PubMed=7539342;
RA Jezequel P., Dorval I., Fergelot P., Chauvel B., Le Treut A.,
RA Le Gall J.-Y., Le Lannou D., Blayau M.;
RT "Structural analysis of CFTR gene in congenital bilateral absence of
RT vas deferens.";
RL Clin. Chem. 41:833-835(1995).
RN [48]
RP VARIANTS CF GLY-57; LYS-193 AND GLY-579.
RX PubMed=7544319; DOI=10.1007/BF00210414;
RA Brancolini V., Cremonesi L., Belloni E., Pappalardo E., Bordoni R.,
RA Seia M., Russo S., Padoan R., Giunta A., Ferrari M.;
RT "Search for mutations in pancreatic sufficient cystic fibrosis Italian
RT patients: detection of 90% of molecular defects and identification of
RT three novel mutations.";
RL Hum. Genet. 96:312-318(1995).
RN [49]
RP VARIANT CF TRP-206.
RX PubMed=8522333; DOI=10.1007/BF00210305;
RA Desgeorges M., Rodier M., Piot M., Demaille J., Claustres M.;
RT "Four adult patients with the missense mutation L206W and a mild
RT cystic fibrosis phenotype.";
RL Hum. Genet. 96:717-720(1995).
RN [50]
RP VARIANTS CF LEU-31 AND ARG-1098.
RX PubMed=7537150; DOI=10.1002/humu.1380050106;
RA Zielenski J., Markiewicz D., Chen H.S., Schappert K.T., Seller A.,
RA Durie P., Corey M., Tsui L.-C.;
RT "Identification of six mutations (R31L, 441delA, 681delC, 1461ins4,
RT W1089R, E1104X) in the cystic fibrosis transmembrane conductance
RT regulator (CFTR) gene.";
RL Hum. Mutat. 5:43-47(1995).
RN [51]
RP VARIANT CF ASN-572.
RX PubMed=7541273; DOI=10.1002/humu.1380050304;
RA Verlingue C., Kapranov N.I., Mercier B., Ginter E.K., Petrova N.V.,
RA Audrezet M.P., Ferec C.;
RT "Complete screening of mutations in the coding sequence of the CFTR
RT gene in a sample of CF patients from Russia: identification of three
RT novel alleles.";
RL Hum. Mutat. 5:205-209(1995).
RN [52]
RP VARIANT CF ARG-98.
RX PubMed=7581407; DOI=10.1002/humu.1380060216;
RA Romey M.-C., Desgeorges M., Ray P., Godard P., Demaille J.,
RA Claustres M.;
RT "Novel missense mutation in the first transmembrane segment of the
RT CFTR gene (Q98R) identified in a male adult.";
RL Hum. Mutat. 6:190-191(1995).
RN [53]
RP VARIANT CF ILE-338.
RX PubMed=7543567; DOI=10.1016/S0022-3476(95)70310-1;
RA Leoni G.B., Pitzalis S., Podda R., Zanda M., Silvetti M., Caocci L.,
RA Cao A., Rosatelli M.C.;
RT "A specific cystic fibrosis mutation (T338I) associated with the
RT phenotype of isolated hypotonic dehydration.";
RL J. Pediatr. 127:281-283(1995).
RN [54]
RP VARIANTS CF PHE-42; LEU-117; ARG-139 AND GLU-1006.
RX PubMed=7541510; DOI=10.1016/S0890-8508(95)80038-7;
RA Ferec C., Novelli G., Verlingue C., Quere I., Dallapiccola B.,
RA Audrezet M.P., Mercier B.;
RT "Identification of six novel CFTR mutations in a sample of Italian
RT cystic fibrosis patients.";
RL Mol. Cell. Probes 9:135-137(1995).
RN [55]
RP VARIANT CF SER-665.
RX PubMed=8800923;
RA Messaoud T., Verlingue C., Denamur E., Pascaud O., Quere I.,
RA Fattoum S., Elion J., Ferec C.;
RT "Distribution of CFTR mutations in cystic fibrosis patients of
RT Tunisian origin: identification of two novel mutations.";
RL Eur. J. Hum. Genet. 4:20-24(1996).
RN [56]
RP VARIANT CF ARG-314.
RX PubMed=8829633;
RX DOI=10.1002/(SICI)1098-1004(1996)7:2<151::AID-HUMU10>3.3.CO;2-U;
RA Nasr S.Z., Strong T.V., Mansoura M.K., Dawson D.C., Collins F.S.;
RT "Novel missense mutation (G314R) in a cystic fibrosis patient with
RT hepatic failure.";
RL Hum. Mutat. 7:151-154(1996).
RN [57]
RP VARIANT CF CYS-569.
RX PubMed=8723693;
RX DOI=10.1002/(SICI)1098-1004(1996)7:4<375::AID-HUMU17>3.3.CO;2-K;
RA Petreska L., Plaseska D., Koseva S., Stavljenic-Rukavina A.,
RA Efremov G.D.;
RT "A novel mutation in exon 12 (Y569C) of the CFTR gene identified in a
RT patient of Croatian origin.";
RL Hum. Mutat. 7:374-375(1996).
RN [58]
RP VARIANT CF ARG-1061.
RX PubMed=8723695;
RX DOI=10.1002/(SICI)1098-1004(1996)7:4<376::AID-HUMU18>3.3.CO;2-E;
RA Bienvenu T., Chertkoff L., Beldjord C., Segal E., Carniglia L.,
RA Barreiro C., Kaplan J.-C.;
RT "Identification of three novel mutations in the cystic fibrosis
RT transmembrane conductance regulator gene in Argentinian CF patients.";
RL Hum. Mutat. 7:376-377(1996).
RN [59]
RP VARIANT CF LEU-562.
RX PubMed=8956039;
RX DOI=10.1002/(SICI)1098-1004(1996)8:4<340::AID-HUMU7>3.3.CO;2-K;
RA Hughes D.J., Hill A.J.M., Macek M. Jr., Redmond A.O., Nevin N.C.,
RA Graham C.A.;
RT "Mutation characterization of CFTR gene in 206 Northern Irish CF
RT families: thirty mutations, including two novel, account for
RT approximately 94% of CF chromosomes.";
RL Hum. Mutat. 8:340-347(1996).
RN [60]
RP VARIANT CBAVD TYR-50.
RX PubMed=9067761;
RX DOI=10.1002/(SICI)1098-1004(1997)9:2<183::AID-HUMU13>3.3.CO;2-3;
RA Zielenski J., Patrizio P., Markiewicz D., Asch R.H., Tsui L.-C.;
RT "Identification of two mutations (S50Y and 4173delC) in the CFTR gene
RT from patients with congenital bilateral absence of vas deferens
RT (CBAVD).";
RL Hum. Mutat. 9:183-184(1997).
RN [61]
RP VARIANT CF MET-1140 DEL.
RX PubMed=9101301;
RX DOI=10.1002/(SICI)1098-1004(1997)9:4<368::AID-HUMU13>3.3.CO;2-F;
RA Clavel C., Pennaforte F., Pigeon F., Verlingue C., Birembaut P.,
RA Ferec C.;
RT "Identification of four novel mutations in the cystic fibrosis
RT transmembrane conductance regulator gene: E664X, 2113delA, 306delTAGA,
RT and delta M1140.";
RL Hum. Mutat. 9:368-369(1997).
RN [62]
RP VARIANT CF ASP-141.
RX PubMed=9222768;
RX DOI=10.1002/(SICI)1098-1004(1997)10:1<86::AID-HUMU15>3.3.CO;2-O;
RA Gouya L., Pascaud O., Munck A., Elion J., Denamur E.;
RT "Novel mutation (A141D) in exon 4 of the CFTR gene identified in an
RT Algerian patient.";
RL Hum. Mutat. 10:86-87(1997).
RN [63]
RP VARIANT CF CYS-1066.
RX PubMed=9375855;
RX DOI=10.1002/(SICI)1098-1004(1997)10:5<387::AID-HUMU9>3.3.CO;2-V;
RA Casals T., Pacheco P., Barreto C., Gimenez J., Ramos M.D., Pereira S.,
RA Pinheiro J.A., Cobos N., Curvelo A., Vazquez C., Rocha H.,
RA Seculi J.L., Perez E., Dapena J., Carrilho E., Duarte A.,
RA Palacio A.M., Nunes V., Lavinha J., Estivill X.;
RT "Missense mutation R1066C in the second transmembrane domain of CFTR
RT causes a severe cystic fibrosis phenotype: study of 19 heterozygous
RT and 2 homozygous patients.";
RL Hum. Mutat. 10:387-392(1997).
RN [64]
RP VARIANTS CF GLU-85; HIS-117; TYR-287; GLU-455; ASP-551; PRO-1070 AND
RP LYS-1303.
RX PubMed=9401006;
RX DOI=10.1002/(SICI)1098-1004(1997)10:6<436::AID-HUMU4>3.3.CO;2-N;
RA Shrimpton A.E., Borowitz D., Swender P.;
RT "Cystic fibrosis mutation frequencies in upstate New York.";
RL Hum. Mutat. 10:436-442(1997).
RN [65]
RP VARIANT CF PHE-311 DEL.
RX PubMed=9443874; DOI=10.1086/301681;
RA Friedman K.J., Leigh M.W., Czarnecki P., Feldman G.L.;
RT "Cystic fibrosis transmembrane-conductance regulator mutations among
RT African Americans.";
RL Am. J. Hum. Genet. 62:195-196(1998).
RN [66]
RP VARIANTS CF LEU-1013 AND ILE-1028.
RX PubMed=9521595; DOI=10.1007/s004390050683;
RA Onay T., Topaloglu O., Zielenski J., Gokgoz N., Kayserili H.,
RA Camcioglu Y., Cokugras H., Akcakaya N., Apak M., Tsui L.-C.,
RA Kirdar B.;
RT "Analysis of the CFTR gene in Turkish cystic fibrosis patients:
RT identification of three novel mutations (3172delAC, P1013L and
RT M1028I).";
RL Hum. Genet. 102:224-230(1998).
RN [67]
RP VARIANTS CF.
RX PubMed=9921909; DOI=10.1007/s004390050897;
RA Bombieri C., Benetazzo M., Saccomani A., Belpinati F., Gile L.S.,
RA Luisetti M., Pignatti P.F.;
RT "Complete mutational screening of the CFTR gene in 120 patients with
RT pulmonary disease.";
RL Hum. Genet. 103:718-722(1998).
RN [68]
RP VARIANTS CF.
RX PubMed=9736778; DOI=10.1093/hmg/7.11.1761;
RA Vankeerberghen A., Wei L., Jaspers M., Cassiman J.-J., Nilius B.,
RA Cuppens H.;
RT "Characterization of 19 disease-associated missense mutations in the
RT regulatory domain of the cystic fibrosis transmembrane conductance
RT regulator.";
RL Hum. Mol. Genet. 7:1761-1769(1998).
RN [69]
RP VARIANTS CF SER-560 AND ASP-569.
RX PubMed=9482579;
RX DOI=10.1002/(SICI)1098-1004(1998)11:2<152::AID-HUMU8>3.3.CO;2-C;
RA Malone G., Haworth A., Schwarz M.J., Cuppens H., Super M.;
RT "Detection of five novel mutations of the cystic fibrosis
RT transmembrane regulator (CFTR) gene in Pakistani patients with cystic
RT fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C).";
RL Hum. Mutat. 11:152-157(1998).
RN [70]
RP VARIANTS CF PHE-13 AND ILE-338.
RX PubMed=9554753;
RA Leoni G.B., Pitzalis S., Tonelli R., Cao A.;
RT "Identification of a novel mutation (S13F) in the CFTR gene in a CF
RT patient of Sardinian origin.";
RL Hum. Mutat. 11:337-337(1998).
RN [71]
RP VARIANTS CF PRO-117 AND ASP-192 DEL.
RX PubMed=9452048;
RA Feldmann D., Sardet A., Cougoureux E., Plouvier E., Fontaine J.-L.,
RA Tournier G., Aymard P.;
RT "Identification of three novel mutations in the CFTR gene, R117P,
RT deltaD192, and 3121+1G-->A in four French patients.";
RL Hum. Mutat. Suppl. 1:S78-S80(1998).
RN [72]
RP VARIANT CF ARG-1065.
RX PubMed=9452054;
RA Casals T., Ramos M.D., Gimenez J., Nadal M., Nunes V., Estivill X.;
RT "Paternal origin of a de novo novel CFTR mutation (L1065R) causing
RT cystic fibrosis.";
RL Hum. Mutat. Suppl. 1:S99-S102(1998).
RN [73]
RP VARIANT CF ASN-LYS-370 INS.
RX PubMed=9452073;
RA Shackleton S., Harris A.;
RT "A 2-amino acid insertion mutation (1243insACAAAA) in exon 7 of the
RT CFTR gene.";
RL Hum. Mutat. Suppl. 1:S156-S157(1998).
RN [74]
RP VARIANT CBAVD GLY-513, AND VARIANT MET-470.
RX PubMed=10651488;
RA Bienvenu T., Bousquet S., Vidaud D., Hubert D., Francoual C.,
RA Beldjord C., Kaplan J.-C.;
RT "A novel missense mutation D513G in exon 10 of the cystic fibrosis
RT transmembrane conductance regulator (CFTR) gene identified in a French
RT CBAVD patient.";
RL Hum. Mutat. 12:213-214(1998).
RN [75]
RP VARIANTS CBAVD LEU-111; LYS-244; VAL-544 AND VAL-1364.
RA de Meeus A., Guittard C., Desgeorges M., Carles S., Demaille J.,
RA Claustres M.;
RT "Genetic findings in congenital bilateral aplasia of vas deferens
RT patients and identification of six novel mutations.";
RL Hum. Mutat. 12:480-480(1998).
RN [76]
RP VARIANT CF GLY-579.
RX PubMed=10094564;
RX DOI=10.1002/(SICI)1098-1004(1999)13:2<173::AID-HUMU20>3.0.CO;2-3;
RA Picci L., Cameran M., Olante P., Zacchello F., Scarpa M.;
RT "Identification of a D579G homozygote cystic fibrosis patient with
RT pancreatic sufficiency and minor lung involvement.";
RL Hum. Mutat. 13:173-173(1999).
RN [77]
RP VARIANT [LARGE SCALE ANALYSIS] MET-470.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J.,
RA Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C.,
RA Graubert T.A., DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
CC -!- FUNCTION: Involved in the transport of chloride ions. May regulate
CC bicarbonate secretion and salvage in epithelial cells by
CC regulating the SLC4A7 transporter. Can inhibit the chloride
CC channel activity of ANO1. Plays a role in the chloride and
CC bicarbonate homeostasis during sperm epididymal maturation and
CC capacitation.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O = ADP + phosphate.
CC -!- SUBUNIT: Interacts with SLC26A3, SLC26A6 and SHANK2 (By
CC similarity). Interacts with SLC9A3R1, MYO6 and GOPC. Interacts
CC with SLC4A7 through SLC9A3R1. Found in a complex with MYO5B and
CC RAB11A. Interacts with ANO1. Interacts with SLC26A8.
CC -!- INTERACTION:
CC P51572:BCAP31; NbExp=3; IntAct=EBI-349854, EBI-77683;
CC P27824:CANX; NbExp=3; IntAct=EBI-349854, EBI-355947;
CC Q9BUN8:DERL1; NbExp=2; IntAct=EBI-349854, EBI-398977;
CC Q9H8Y8:GORASP2; NbExp=3; IntAct=EBI-349854, EBI-739467;
CC P19120:HSPA8 (xeno); NbExp=2; IntAct=EBI-349854, EBI-907802;
CC P05787:KRT8; NbExp=7; IntAct=EBI-349854, EBI-297852;
CC Q9HBW0:LPAR2; NbExp=4; IntAct=EBI-349854, EBI-765995;
CC Q5T2W1:PDZK1; NbExp=2; IntAct=EBI-349854, EBI-349819;
CC P30153:PPP2R1A; NbExp=3; IntAct=EBI-349854, EBI-302388;
CC Q99942:RNF5; NbExp=3; IntAct=EBI-349854, EBI-348482;
CC Q96RN1:SLC26A8; NbExp=2; IntAct=EBI-349854, EBI-1792052;
CC O14745:SLC9A3R1; NbExp=4; IntAct=EBI-349854, EBI-349787;
CC Q15599:SLC9A3R2; NbExp=7; IntAct=EBI-349854, EBI-1149760;
CC -!- SUBCELLULAR LOCATION: Early endosome membrane; Multi-pass membrane
CC protein. Cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P13569-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13569-2; Sequence=VSP_022123;
CC Note=Exon skipping favored by a high number of TG repeats and a
CC low number of T repeats at the intron-exon boundary. Causes
CC congenital bilateral absence of the vas deferens (CBAVD);
CC Name=3;
CC IsoId=P13569-3; Sequence=VSP_022124, VSP_022125;
CC Note=Alternative acceptor site favored by mutation in an exonic
CC splicing enhancer (ESE). Causes cystic fibrosis (CF);
CC -!- TISSUE SPECIFICITY: Found on the surface of the epithelial cells
CC that line the lungs and other organs.
CC -!- DOMAIN: The PDZ-binding motif mediates interactions with GOPC and
CC with the SLC4A7, SLC9A3R1/EBP50 complex.
CC -!- PTM: Phosphorylated; activates the channel. It is not clear
CC whether PKC phosphorylation itself activates the channel or
CC permits activation by phosphorylation at PKA sites. Phosphorylated
CC by AMPK.
CC -!- PTM: Ubiquitinated, leading to its degradation in the lysosome.
CC Deubiquitination by USP10 in early endosomes, enhances its
CC endocytic recycling.
CC -!- DISEASE: Cystic fibrosis (CF) [MIM:219700]: A common generalized
CC disorder of the exocrine glands which impairs clearance of
CC secretions in a variety of organs. It is characterized by the
CC triad of chronic bronchopulmonary disease (with recurrent
CC respiratory infections), pancreatic insufficiency (which leads to
CC malabsorption and growth retardation) and elevated sweat
CC electrolytes. It is the most common genetic disease in Caucasians,
CC with a prevalence of about 1 in 2'000 live births. Inheritance is
CC autosomal recessive. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Congenital bilateral absence of the vas deferens (CBAVD)
CC [MIM:277180]: Important cause of sterility in men and could
CC represent an incomplete form of cystic fibrosis, as the majority
CC of men suffering from cystic fibrosis lack the vas deferens.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCC
CC family. CFTR transporter (TC 3.A.1.202) subfamily.
CC -!- SIMILARITY: Contains 2 ABC transmembrane type-1 domains.
CC -!- SIMILARITY: Contains 2 ABC transporter domains.
CC -!- WEB RESOURCE: Name=CFTR; Note=Cystic fibrosis mutation db;
CC URL="http://www.genet.sickkids.on.ca/cftr/app";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CFTR";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CFTR entry;
CC URL="http://en.wikipedia.org/wiki/Cystic_fibrosis_transmembrane_conductance_regulator";
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC
CC proteins;
CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=P13569";
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DR EMBL; M28668; AAA35680.1; -; mRNA.
DR EMBL; M55131; AAC13657.1; -; Genomic_DNA.
DR EMBL; M55106; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55107; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55108; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55110; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55111; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55112; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55113; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55114; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55115; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55116; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55117; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55118; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55119; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55120; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55121; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55122; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55123; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55124; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55125; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55126; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55127; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55128; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55129; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; M55130; AAC13657.1; JOINED; Genomic_DNA.
DR EMBL; DQ354388; ABC79050.1; -; Genomic_DNA.
DR EMBL; DQ354389; ABC79052.1; -; Genomic_DNA.
DR EMBL; DQ354390; ABC79054.1; -; Genomic_DNA.
DR EMBL; DQ354391; ABC79056.1; -; Genomic_DNA.
DR EMBL; DQ356258; ABC87055.1; -; Genomic_DNA.
DR EMBL; DQ356259; ABC87057.1; -; Genomic_DNA.
DR EMBL; DQ356261; ABC87061.1; -; Genomic_DNA.
DR EMBL; DQ356262; ABC87063.1; -; Genomic_DNA.
DR EMBL; DQ356263; ABC87065.1; -; Genomic_DNA.
DR EMBL; DQ356264; ABC87067.1; -; Genomic_DNA.
DR EMBL; DQ388128; ABD72183.1; -; Genomic_DNA.
DR EMBL; DQ388129; ABD72185.1; -; Genomic_DNA.
DR EMBL; DQ388131; ABD72189.1; -; Genomic_DNA.
DR EMBL; DQ388132; ABD72191.1; -; Genomic_DNA.
DR EMBL; DQ388133; ABD72193.1; -; Genomic_DNA.
DR EMBL; DQ388134; ABD72195.1; -; Genomic_DNA.
DR EMBL; DQ388135; ABD72197.1; -; Genomic_DNA.
DR EMBL; DQ388138; ABD72203.1; -; Genomic_DNA.
DR EMBL; DQ388139; ABD72205.1; -; Genomic_DNA.
DR EMBL; DQ388140; ABD72207.1; -; Genomic_DNA.
DR EMBL; DQ388141; ABD72209.1; -; Genomic_DNA.
DR EMBL; DQ388142; ABD72211.1; -; Genomic_DNA.
DR EMBL; DQ388143; ABD72213.1; -; Genomic_DNA.
DR EMBL; DQ388145; ABD72217.1; -; Genomic_DNA.
DR EMBL; AC000061; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC000111; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236947; EAL24353.1; -; Genomic_DNA.
DR EMBL; M65196; AAA51979.1; -; Genomic_DNA.
DR EMBL; M65197; AAA51980.1; -; Genomic_DNA.
DR PIR; A39069; DVHUCF.
DR RefSeq; NP_000483.3; NM_000492.3.
DR UniGene; Hs.489786; -.
DR UniGene; Hs.621460; -.
DR UniGene; Hs.661104; -.
DR PDB; 1NBD; Model; -; A=425-638.
DR PDB; 1XMI; X-ray; 2.25 A; A/B/C/D/E=389-678.
DR PDB; 1XMJ; X-ray; 2.30 A; A=389-677.
DR PDB; 2BBO; X-ray; 2.55 A; A=389-678.
DR PDB; 2BBS; X-ray; 2.05 A; A/B=389-678.
DR PDB; 2BBT; X-ray; 2.30 A; A/B=389-678.
DR PDB; 2LOB; NMR; -; B=1473-1480.
DR PDB; 2PZE; X-ray; 1.70 A; A/B=387-646.
DR PDB; 2PZF; X-ray; 2.00 A; A/B=387-646.
DR PDB; 2PZG; X-ray; 1.80 A; A/B=375-646.
DR PDB; 3GD7; X-ray; 2.70 A; A/B/C/D=1193-1427.
DR PDB; 3ISW; X-ray; 2.80 A; C=5-20.
DR PDBsum; 1NBD; -.
DR PDBsum; 1XMI; -.
DR PDBsum; 1XMJ; -.
DR PDBsum; 2BBO; -.
DR PDBsum; 2BBS; -.
DR PDBsum; 2BBT; -.
DR PDBsum; 2LOB; -.
DR PDBsum; 2PZE; -.
DR PDBsum; 2PZF; -.
DR PDBsum; 2PZG; -.
DR PDBsum; 3GD7; -.
DR PDBsum; 3ISW; -.
DR DisProt; DP00012; -.
DR ProteinModelPortal; P13569; -.
DR SMR; P13569; 87-738, 948-1439.
DR DIP; DIP-32788N; -.
DR IntAct; P13569; 136.
DR MINT; MINT-148539; -.
DR STRING; 9606.ENSP00000003084; -.
DR BindingDB; P13569; -.
DR ChEMBL; CHEMBL4051; -.
DR DrugBank; DB00887; Bumetanide.
DR DrugBank; DB01016; Glibenclamide.
DR GuidetoPHARMACOLOGY; 707; -.
DR TCDB; 3.A.1.202.1; the atp-binding cassette (abc) superfamily.
DR PhosphoSite; P13569; -.
DR DMDM; 147744553; -.
DR PaxDb; P13569; -.
DR PRIDE; P13569; -.
DR DNASU; 1080; -.
DR Ensembl; ENST00000003084; ENSP00000003084; ENSG00000001626.
DR Ensembl; ENST00000454343; ENSP00000403677; ENSG00000001626.
DR GeneID; 1080; -.
DR KEGG; hsa:1080; -.
DR UCSC; uc003vjd.3; human.
DR CTD; 1080; -.
DR GeneCards; GC07P117119; -.
DR HGNC; HGNC:1884; CFTR.
DR HPA; CAB001951; -.
DR HPA; HPA021939; -.
DR MIM; 219700; phenotype.
DR MIM; 277180; phenotype.
DR MIM; 602421; gene.
DR neXtProt; NX_P13569; -.
DR Orphanet; 48; Congenital bilateral absence of vas deferens.
DR Orphanet; 586; Cystic fibrosis.
DR Orphanet; 676; Hereditary chronic pancreatitis.
DR Orphanet; 60033; Idiopathic bronchiectasis.
DR PharmGKB; PA109; -.
DR eggNOG; COG1132; -.
DR HOVERGEN; HBG004169; -.
DR InParanoid; P13569; -.
DR KO; K05031; -.
DR OMA; TLAMNIM; -.
DR OrthoDB; EOG7C2R0B; -.
DR PhylomeDB; P13569; -.
DR BioCyc; MetaCyc:HS00075-MONOMER; -.
DR BRENDA; 3.6.3.49; 2681.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR EvolutionaryTrace; P13569; -.
DR GenomeRNAi; 1080; -.
DR NextBio; 4500; -.
DR PRO; PR:P13569; -.
DR ArrayExpress; P13569; -.
DR Bgee; P13569; -.
DR CleanEx; HS_CFTR; -.
DR Genevestigator; P13569; -.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; NAS:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005902; C:microvillus; IEA:Ensembl.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; TAS:ProtInc.
DR GO; GO:0005224; F:ATP-binding and phosphorylation-dependent chloride channel activity; TAS:ProtInc.
DR GO; GO:0015106; F:bicarbonate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005260; F:channel-conductance-controlling ATPase activity; NAS:UniProtKB.
DR GO; GO:0019869; F:chloride channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0071320; P:cellular response to cAMP; ISS:UniProtKB.
DR GO; GO:0032870; P:cellular response to hormone stimulus; IEA:Ensembl.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:Ensembl.
DR GO; GO:0030301; P:cholesterol transport; IEA:Ensembl.
DR GO; GO:0051454; P:intracellular pH elevation; ISS:UniProtKB.
DR GO; GO:0015705; P:iodide transport; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0060081; P:membrane hyperpolarization; ISS:UniProtKB.
DR GO; GO:0045909; P:positive regulation of vasodilation; IEA:Ensembl.
DR GO; GO:0007585; P:respiratory gaseous exchange; TAS:ProtInc.
DR GO; GO:0034097; P:response to cytokine stimulus; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0043627; P:response to estrogen stimulus; IEA:Ensembl.
DR GO; GO:0043434; P:response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0048240; P:sperm capacitation; ISS:UniProtKB.
DR GO; GO:0030321; P:transepithelial chloride transport; IEA:Ensembl.
DR GO; GO:0042311; P:vasodilation; IEA:Ensembl.
DR GO; GO:0006833; P:water transport; IEA:Ensembl.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR003439; ABC_transporter-like.
DR InterPro; IPR017871; ABC_transporter_CS.
DR InterPro; IPR001140; ABC_transptr_TM_dom.
DR InterPro; IPR005291; cAMP_cl_channel.
DR InterPro; IPR025837; CFTR_reg_dom.
DR InterPro; IPR009147; CysFib_conduc_TM.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR Pfam; PF14396; CFTR_R; 1.
DR PRINTS; PR01851; CYSFIBREGLTR.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR TIGRFAMs; TIGR01271; CFTR_protein; 1.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 1.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Chloride; Chloride channel; Complete proteome; Disease mutation;
KW Endosome; Glycoprotein; Hydrolase; Ion channel; Ion transport;
KW Isopeptide bond; Lipoprotein; Membrane; Nucleotide-binding; Palmitate;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation.
FT CHAIN 1 1480 Cystic fibrosis transmembrane conductance
FT regulator.
FT /FTId=PRO_0000093419.
FT TOPO_DOM 1 80 Cytoplasmic (Potential).
FT TRANSMEM 81 103 Helical; Name=1; (Potential).
FT TOPO_DOM 104 117 Extracellular (Potential).
FT TRANSMEM 118 138 Helical; Name=2; (Potential).
FT TOPO_DOM 139 194 Cytoplasmic (Potential).
FT TRANSMEM 195 215 Helical; Name=3; (Potential).
FT TOPO_DOM 216 220 Extracellular (Potential).
FT TRANSMEM 221 241 Helical; Name=4; (Potential).
FT TOPO_DOM 242 307 Cytoplasmic (Potential).
FT TRANSMEM 308 328 Helical; Name=5; (Potential).
FT TOPO_DOM 329 330 Extracellular (Potential).
FT TRANSMEM 331 350 Helical; Name=6; (Potential).
FT TOPO_DOM 351 859 Cytoplasmic (Potential).
FT TRANSMEM 860 880 Helical; Name=7; (Potential).
FT TOPO_DOM 881 911 Extracellular (Potential).
FT TRANSMEM 912 932 Helical; Name=8; (Potential).
FT TOPO_DOM 933 990 Cytoplasmic (Potential).
FT TRANSMEM 991 1011 Helical; Name=9; (Potential).
FT TOPO_DOM 1012 1013 Extracellular (Potential).
FT TRANSMEM 1014 1034 Helical; Name=10; (Potential).
FT TOPO_DOM 1035 1102 Cytoplasmic (Potential).
FT TRANSMEM 1103 1123 Helical; Name=11; (Potential).
FT TOPO_DOM 1124 1128 Extracellular (Potential).
FT TRANSMEM 1129 1149 Helical; Name=12; (Potential).
FT TOPO_DOM 1150 1480 Cytoplasmic (Potential).
FT DOMAIN 81 365 ABC transmembrane type-1 1.
FT DOMAIN 423 646 ABC transporter 1.
FT DOMAIN 859 1155 ABC transmembrane type-1 2.
FT DOMAIN 1210 1443 ABC transporter 2.
FT NP_BIND 458 465 ATP 1 (Potential).
FT NP_BIND 1244 1251 ATP 2 (Potential).
FT MOTIF 1478 1480 PDZ-binding.
FT MOD_RES 291 291 Phosphothreonine.
FT MOD_RES 549 549 Phosphoserine.
FT MOD_RES 660 660 Phosphoserine; by PKA.
FT MOD_RES 686 686 Phosphoserine; by PKC.
FT MOD_RES 700 700 Phosphoserine; by PKA.
FT MOD_RES 712 712 Phosphoserine; by PKA.
FT MOD_RES 717 717 Phosphothreonine.
FT MOD_RES 737 737 Phosphoserine; by PKA.
FT MOD_RES 753 753 Phosphoserine; by PKA.
FT MOD_RES 768 768 Phosphoserine; by PKA.
FT MOD_RES 790 790 Phosphoserine; by PKC.
FT MOD_RES 795 795 Phosphoserine; by PKA.
FT MOD_RES 813 813 Phosphoserine; by PKA.
FT MOD_RES 1444 1444 Phosphoserine.
FT MOD_RES 1456 1456 Phosphoserine.
FT LIPID 524 524 S-palmitoyl cysteine.
FT LIPID 1395 1395 S-palmitoyl cysteine.
FT CARBOHYD 894 894 N-linked (GlcNAc...).
FT CARBOHYD 900 900 N-linked (GlcNAc...).
FT CROSSLNK 688 688 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 404 464 Missing (in isoform 2).
FT /FTId=VSP_022123.
FT VAR_SEQ 589 605 SCVCKLMANKTRILVTS -> RRRCSCLLDRNKKTIF (in
FT isoform 3).
FT /FTId=VSP_022124.
FT VAR_SEQ 606 1480 Missing (in isoform 3).
FT /FTId=VSP_022125.
FT VARIANT 13 13 S -> F (in CF).
FT /FTId=VAR_000101.
FT VARIANT 31 31 R -> C (in dbSNP:rs1800073).
FT /FTId=VAR_000102.
FT VARIANT 31 31 R -> L (in CF).
FT /FTId=VAR_000103.
FT VARIANT 42 42 S -> F (in CF).
FT /FTId=VAR_000104.
FT VARIANT 44 44 D -> G (in CF).
FT /FTId=VAR_000105.
FT VARIANT 44 44 D -> V (in dbSNP:rs1800074).
FT /FTId=VAR_000106.
FT VARIANT 50 50 S -> Y (in CBAVD).
FT /FTId=VAR_000107.
FT VARIANT 57 57 W -> G (in CF).
FT /FTId=VAR_000108.
FT VARIANT 67 67 P -> L (in CF).
FT /FTId=VAR_000109.
FT VARIANT 74 74 R -> W (in CF; dbSNP:rs115545701).
FT /FTId=VAR_000110.
FT VARIANT 75 75 R -> Q (in dbSNP:rs1800076).
FT /FTId=VAR_000111.
FT VARIANT 85 85 G -> E (in CF).
FT /FTId=VAR_000112.
FT VARIANT 87 87 F -> L (in CF).
FT /FTId=VAR_000113.
FT VARIANT 91 91 G -> R (in CF).
FT /FTId=VAR_000114.
FT VARIANT 92 92 E -> K (in CF).
FT /FTId=VAR_000115.
FT VARIANT 98 98 Q -> R (in CF).
FT /FTId=VAR_000116.
FT VARIANT 105 105 I -> S (in CF).
FT /FTId=VAR_000117.
FT VARIANT 109 109 Y -> C (in CF).
FT /FTId=VAR_000118.
FT VARIANT 110 110 D -> H (in CF).
FT /FTId=VAR_000119.
FT VARIANT 111 111 P -> L (in CBAVD).
FT /FTId=VAR_000120.
FT VARIANT 117 117 R -> C (in CF).
FT /FTId=VAR_000121.
FT VARIANT 117 117 R -> H (in CF and CBAVD).
FT /FTId=VAR_000122.
FT VARIANT 117 117 R -> L (in CF).
FT /FTId=VAR_000123.
FT VARIANT 117 117 R -> P (in CF).
FT /FTId=VAR_000124.
FT VARIANT 120 120 A -> T (in CF).
FT /FTId=VAR_000125.
FT VARIANT 138 138 L -> P (in dbSNP:rs1800078).
FT /FTId=VAR_009895.
FT VARIANT 139 139 H -> R (in CF).
FT /FTId=VAR_000126.
FT VARIANT 141 141 A -> D (in CF).
FT /FTId=VAR_000127.
FT VARIANT 148 148 I -> T (in CF; dbSNP:rs35516286).
FT /FTId=VAR_000128.
FT VARIANT 149 149 G -> R (in CBAVD).
FT /FTId=VAR_000129.
FT VARIANT 170 170 R -> H (in dbSNP:rs1800079).
FT /FTId=VAR_009896.
FT VARIANT 178 178 G -> R (in CF).
FT /FTId=VAR_000130.
FT VARIANT 182 182 S -> G (in dbSNP:rs1800080).
FT /FTId=VAR_009897.
FT VARIANT 192 192 Missing (in CF).
FT /FTId=VAR_000131.
FT VARIANT 193 193 E -> K (in CBAVD and CF).
FT /FTId=VAR_000132.
FT VARIANT 199 199 H -> Q (in CF).
FT /FTId=VAR_000133.
FT VARIANT 199 199 H -> Y (in CF).
FT /FTId=VAR_000134.
FT VARIANT 205 205 P -> S (in CF).
FT /FTId=VAR_000135.
FT VARIANT 206 206 L -> W (in CF).
FT /FTId=VAR_000136.
FT VARIANT 225 225 C -> R (in CF).
FT /FTId=VAR_000137.
FT VARIANT 244 244 M -> K (in CBAVD).
FT /FTId=VAR_000138.
FT VARIANT 258 258 R -> G (in CBAVD; dbSNP:rs191456345).
FT /FTId=VAR_000139.
FT VARIANT 287 287 N -> Y (in CF).
FT /FTId=VAR_000140.
FT VARIANT 297 297 R -> Q (in CF).
FT /FTId=VAR_000141.
FT VARIANT 301 301 Y -> C (in CF; dbSNP:rs150691494).
FT /FTId=VAR_000142.
FT VARIANT 307 307 S -> N (in CF).
FT /FTId=VAR_000143.
FT VARIANT 311 311 F -> L (in CF).
FT /FTId=VAR_000144.
FT VARIANT 311 311 Missing (in CF).
FT /FTId=VAR_000145.
FT VARIANT 314 314 G -> E (in CF).
FT /FTId=VAR_000146.
FT VARIANT 314 314 G -> R (in CF).
FT /FTId=VAR_000147.
FT VARIANT 322 322 V -> M (in dbSNP:rs1800085).
FT /FTId=VAR_009898.
FT VARIANT 334 334 R -> W (in CF; mild; dbSNP:rs121909011).
FT /FTId=VAR_000148.
FT VARIANT 336 336 I -> K (in CF).
FT /FTId=VAR_000150.
FT VARIANT 338 338 T -> I (in CF; mild; isolated hypotonic
FT dehydration).
FT /FTId=VAR_000151.
FT VARIANT 346 346 L -> P (in CF; dominant mutation but mild
FT phenotype).
FT /FTId=VAR_000152.
FT VARIANT 347 347 R -> H (in CF).
FT /FTId=VAR_000153.
FT VARIANT 347 347 R -> L (in CF).
FT /FTId=VAR_000154.
FT VARIANT 347 347 R -> P (in CF; MILD).
FT /FTId=VAR_000155.
FT VARIANT 351 351 T -> S (in dbSNP:rs1800086).
FT /FTId=VAR_009899.
FT VARIANT 352 352 R -> Q (in CF).
FT /FTId=VAR_000156.
FT VARIANT 353 353 Q -> H (in dbSNP:rs1800087).
FT /FTId=VAR_009900.
FT VARIANT 359 360 QT -> KK (in CF).
FT /FTId=VAR_000158.
FT VARIANT 359 359 Q -> K (in CF).
FT /FTId=VAR_000157.
FT VARIANT 370 370 K -> KNK (in CF).
FT /FTId=VAR_000159.
FT VARIANT 455 455 A -> E (in CF).
FT /FTId=VAR_000160.
FT VARIANT 456 456 V -> F (in CF).
FT /FTId=VAR_000161.
FT VARIANT 458 458 G -> V (in CF).
FT /FTId=VAR_000162.
FT VARIANT 467 467 L -> F (in dbSNP:rs1800089).
FT /FTId=VAR_000163.
FT VARIANT 470 470 V -> M (in dbSNP:rs213950).
FT /FTId=VAR_000164.
FT VARIANT 480 480 G -> C (in CF).
FT /FTId=VAR_000165.
FT VARIANT 492 492 S -> F (in CF).
FT /FTId=VAR_000166.
FT VARIANT 504 504 E -> Q (in CF).
FT /FTId=VAR_000167.
FT VARIANT 506 506 I -> M (in dbSNP:rs1800092).
FT /FTId=VAR_009901.
FT VARIANT 506 506 I -> V.
FT /FTId=VAR_000168.
FT VARIANT 507 507 I -> V (in dbSNP:rs1800091).
FT /FTId=VAR_000169.
FT VARIANT 507 507 Missing (in CF).
FT /FTId=VAR_000170.
FT VARIANT 508 508 F -> C (in dbSNP:rs1800093).
FT /FTId=VAR_000172.
FT VARIANT 508 508 Missing (in CF and CBAVD; most common
FT mutation; 72% of the population; CFTR
FT fails to be properly delivered to plasma
FT membrane).
FT /FTId=VAR_000171.
FT VARIANT 513 513 D -> G (in CBAVD).
FT /FTId=VAR_000173.
FT VARIANT 520 520 V -> F (in CF; dbSNP:rs77646904).
FT /FTId=VAR_000174.
FT VARIANT 532 532 K -> E (in dbSNP:rs35032490).
FT /FTId=VAR_048150.
FT VARIANT 544 544 G -> V (in CBAVD).
FT /FTId=VAR_000175.
FT VARIANT 549 549 S -> I (in CF).
FT /FTId=VAR_000177.
FT VARIANT 549 549 S -> N (in CF).
FT /FTId=VAR_000176.
FT VARIANT 549 549 S -> R (in CF).
FT /FTId=VAR_000178.
FT VARIANT 551 551 G -> D (in CF).
FT /FTId=VAR_000179.
FT VARIANT 551 551 G -> S (in CF).
FT /FTId=VAR_000180.
FT VARIANT 553 553 R -> Q (in CF).
FT /FTId=VAR_000181.
FT VARIANT 558 558 L -> S (in CF).
FT /FTId=VAR_000182.
FT VARIANT 559 559 A -> T (in CF).
FT /FTId=VAR_000183.
FT VARIANT 560 560 R -> K (in CF).
FT /FTId=VAR_000184.
FT VARIANT 560 560 R -> S (in CF).
FT /FTId=VAR_000185.
FT VARIANT 560 560 R -> T (in CF).
FT /FTId=VAR_000186.
FT VARIANT 562 562 V -> I (in dbSNP:rs1800097).
FT /FTId=VAR_000187.
FT VARIANT 562 562 V -> L (in CF; dbSNP:rs1800097).
FT /FTId=VAR_000188.
FT VARIANT 563 563 Y -> N (in CF).
FT /FTId=VAR_000189.
FT VARIANT 569 569 Y -> C (in CF).
FT /FTId=VAR_000190.
FT VARIANT 569 569 Y -> D (in CF).
FT /FTId=VAR_000191.
FT VARIANT 569 569 Y -> H (in CF).
FT /FTId=VAR_000192.
FT VARIANT 571 571 L -> S (in CF).
FT /FTId=VAR_000193.
FT VARIANT 572 572 D -> N (in CF).
FT /FTId=VAR_000194.
FT VARIANT 574 574 P -> H (in CF).
FT /FTId=VAR_000195.
FT VARIANT 576 576 G -> A (in dbSNP:rs1800098).
FT /FTId=VAR_000196.
FT VARIANT 579 579 D -> G (in CF).
FT /FTId=VAR_000197.
FT VARIANT 601 601 I -> F (in CF).
FT /FTId=VAR_000198.
FT VARIANT 605 605 S -> F (in dbSNP:rs766874).
FT /FTId=VAR_048151.
FT VARIANT 610 610 L -> S (in CF).
FT /FTId=VAR_000199.
FT VARIANT 613 613 A -> T (in CF; dbSNP:rs201978662).
FT /FTId=VAR_000200.
FT VARIANT 614 614 D -> G (in CF; dbSNP:rs201124247).
FT /FTId=VAR_000201.
FT VARIANT 618 618 I -> T (in CF).
FT /FTId=VAR_000202.
FT VARIANT 619 619 L -> S (in CF).
FT /FTId=VAR_000203.
FT VARIANT 620 620 H -> P (in CF).
FT /FTId=VAR_000204.
FT VARIANT 620 620 H -> Q (in CF).
FT /FTId=VAR_000205.
FT VARIANT 622 622 G -> D (in oligospermia).
FT /FTId=VAR_000206.
FT VARIANT 628 628 G -> R (in CF).
FT /FTId=VAR_000207.
FT VARIANT 633 633 L -> P (in CF).
FT /FTId=VAR_000208.
FT VARIANT 648 648 D -> V (in CF).
FT /FTId=VAR_000209.
FT VARIANT 651 651 D -> N (in CF).
FT /FTId=VAR_000210.
FT VARIANT 654 654 S -> G (in dbSNP:rs1800099).
FT /FTId=VAR_009902.
FT VARIANT 665 665 T -> S (in CF).
FT /FTId=VAR_000211.
FT VARIANT 668 668 R -> C (in dbSNP:rs1800100).
FT /FTId=VAR_000212.
FT VARIANT 693 693 F -> L (in dbSNP:rs1800101).
FT /FTId=VAR_000213.
FT VARIANT 754 754 V -> M (in CF; dbSNP:rs150157202).
FT /FTId=VAR_000214.
FT VARIANT 766 766 R -> M (in CBAVD).
FT /FTId=VAR_000215.
FT VARIANT 792 792 R -> G (in CBAVD).
FT /FTId=VAR_000216.
FT VARIANT 800 800 A -> G (in CBAVD).
FT /FTId=VAR_000217.
FT VARIANT 807 807 I -> M (in CBAVD; dbSNP:rs1800103).
FT /FTId=VAR_000218.
FT VARIANT 822 822 E -> K (in CF).
FT /FTId=VAR_000219.
FT VARIANT 826 826 E -> K (in thoracic sarcoidosis).
FT /FTId=VAR_000220.
FT VARIANT 866 866 C -> Y (in CF).
FT /FTId=VAR_000221.
FT VARIANT 903 903 Y -> H (in dbSNP:rs1800106).
FT /FTId=VAR_009903.
FT VARIANT 909 909 S -> I (in dbSNP:rs1800107).
FT /FTId=VAR_009904.
FT VARIANT 912 912 S -> L (in dbSNP:rs121909034).
FT /FTId=VAR_000222.
FT VARIANT 913 913 Y -> C (in CF).
FT /FTId=VAR_000223.
FT VARIANT 917 917 Y -> C (in CF).
FT /FTId=VAR_000224.
FT VARIANT 949 949 H -> Y (in CF).
FT /FTId=VAR_000225.
FT VARIANT 952 952 M -> I (in CF).
FT /FTId=VAR_000226.
FT VARIANT 967 967 L -> S (in dbSNP:rs1800110).
FT /FTId=VAR_009905.
FT VARIANT 997 997 L -> F (in CF; dbSNP:rs1800111).
FT /FTId=VAR_000227.
FT VARIANT 1005 1005 I -> R (in CF).
FT /FTId=VAR_000228.
FT VARIANT 1006 1006 A -> E (in CF).
FT /FTId=VAR_000229.
FT VARIANT 1013 1013 P -> L (in CF).
FT /FTId=VAR_000230.
FT VARIANT 1028 1028 M -> I (in CF).
FT /FTId=VAR_000231.
FT VARIANT 1052 1052 F -> V (in CF).
FT /FTId=VAR_000232.
FT VARIANT 1061 1061 G -> R (in CF; dbSNP:rs142394380).
FT /FTId=VAR_000233.
FT VARIANT 1065 1065 L -> P (in CF).
FT /FTId=VAR_000234.
FT VARIANT 1065 1065 L -> R (in CF).
FT /FTId=VAR_000235.
FT VARIANT 1066 1066 R -> C (in CF).
FT /FTId=VAR_000236.
FT VARIANT 1066 1066 R -> H (in CF).
FT /FTId=VAR_000237.
FT VARIANT 1066 1066 R -> L (in CF).
FT /FTId=VAR_000238.
FT VARIANT 1067 1067 A -> T (in CF).
FT /FTId=VAR_000239.
FT VARIANT 1067 1067 A -> V (in dbSNP:rs1800114).
FT /FTId=VAR_000240.
FT VARIANT 1070 1070 R -> P (in CF).
FT /FTId=VAR_000242.
FT VARIANT 1070 1070 R -> Q (in CF).
FT /FTId=VAR_000241.
FT VARIANT 1070 1070 R -> W (in CBAVD; dbSNP:rs202179988).
FT /FTId=VAR_011564.
FT VARIANT 1071 1071 Q -> P (in CF).
FT /FTId=VAR_000243.
FT VARIANT 1072 1072 P -> L (in CF).
FT /FTId=VAR_000244.
FT VARIANT 1077 1077 L -> P (in CF).
FT /FTId=VAR_000245.
FT VARIANT 1085 1085 H -> R (in CF).
FT /FTId=VAR_000246.
FT VARIANT 1098 1098 W -> R (in CF).
FT /FTId=VAR_000247.
FT VARIANT 1101 1101 M -> K (in CF; dbSNP:rs36210737).
FT /FTId=VAR_000248.
FT VARIANT 1101 1101 M -> R (in CF).
FT /FTId=VAR_011565.
FT VARIANT 1137 1137 M -> V (in CF).
FT /FTId=VAR_000249.
FT VARIANT 1140 1140 Missing (in CF).
FT /FTId=VAR_000250.
FT VARIANT 1152 1152 D -> H (in CF).
FT /FTId=VAR_000251.
FT VARIANT 1162 1162 R -> L (in dbSNP:rs1800120).
FT /FTId=VAR_000252.
FT VARIANT 1220 1220 T -> I (in dbSNP:rs1800123).
FT /FTId=VAR_000253.
FT VARIANT 1234 1234 I -> V (in CF).
FT /FTId=VAR_000254.
FT VARIANT 1235 1235 S -> R (in CF; dbSNP:rs34911792).
FT /FTId=VAR_000255.
FT VARIANT 1244 1244 G -> E (in CF).
FT /FTId=VAR_000256.
FT VARIANT 1249 1249 G -> E (in CF).
FT /FTId=VAR_000257.
FT VARIANT 1251 1251 S -> N (in CF).
FT /FTId=VAR_000258.
FT VARIANT 1255 1255 S -> P (in CF).
FT /FTId=VAR_000259.
FT VARIANT 1270 1270 D -> N (in CF; dbSNP:rs11971167).
FT /FTId=VAR_000260.
FT VARIANT 1282 1282 W -> R (in CF).
FT /FTId=VAR_000261.
FT VARIANT 1283 1283 R -> M (in CF).
FT /FTId=VAR_000262.
FT VARIANT 1286 1286 F -> S (in CF).
FT /FTId=VAR_000263.
FT VARIANT 1291 1291 Q -> H (in CF).
FT /FTId=VAR_000264.
FT VARIANT 1291 1291 Q -> R (in CF).
FT /FTId=VAR_000265.
FT VARIANT 1303 1303 N -> H (in CF).
FT /FTId=VAR_000266.
FT VARIANT 1303 1303 N -> K (in CF; dbSNP:rs80034486).
FT /FTId=VAR_000267.
FT VARIANT 1349 1349 G -> D (in CF).
FT /FTId=VAR_000268.
FT VARIANT 1364 1364 A -> V (in CBAVD).
FT /FTId=VAR_000269.
FT VARIANT 1397 1397 V -> E (in CF).
FT /FTId=VAR_000270.
FT VARIANT 1453 1453 R -> W (in dbSNP:rs4148725).
FT /FTId=VAR_048152.
FT CONFLICT 620 620 H -> N (in Ref. 1; AAA35680).
FT CONFLICT 833 833 F -> L (in Ref. 1; AAA35680).
FT STRAND 11 19
FT STRAND 390 399
FT HELIX 403 411
FT HELIX 433 436
FT STRAND 440 449
FT STRAND 453 457
FT HELIX 464 471
FT STRAND 478 484
FT STRAND 488 491
FT STRAND 499 501
FT HELIX 502 507
FT HELIX 514 523
FT HELIX 527 530
FT STRAND 533 535
FT HELIX 536 538
FT STRAND 540 542
FT HELIX 550 563
FT STRAND 567 573
FT TURN 574 577
FT HELIX 580 589
FT HELIX 590 594
FT TURN 595 597
FT STRAND 598 603
FT HELIX 607 612
FT STRAND 614 620
FT STRAND 623 628
FT HELIX 630 634
FT HELIX 640 644
FT HELIX 650 652
FT HELIX 655 669
FT STRAND 1204 1207
FT STRAND 1210 1223
FT STRAND 1226 1234
FT STRAND 1239 1245
FT HELIX 1250 1258
FT STRAND 1261 1271
FT HELIX 1279 1284
FT STRAND 1286 1290
FT STRAND 1297 1299
FT HELIX 1300 1304
FT HELIX 1312 1321
FT HELIX 1325 1328
FT HELIX 1334 1336
FT TURN 1341 1345
FT HELIX 1348 1361
FT STRAND 1366 1371
FT HELIX 1372 1375
FT HELIX 1378 1389
FT TURN 1390 1394
FT STRAND 1397 1400
FT STRAND 1402 1404
FT HELIX 1405 1407
FT STRAND 1411 1417
FT STRAND 1420 1426
FT STRAND 1478 1480
SQ SEQUENCE 1480 AA; 168142 MW; 8D082AA2E768C065 CRC64;
MQRSPLEKAS VVSKLFFSWT RPILRKGYRQ RLELSDIYQI PSVDSADNLS EKLEREWDRE
LASKKNPKLI NALRRCFFWR FMFYGIFLYL GEVTKAVQPL LLGRIIASYD PDNKEERSIA
IYLGIGLCLL FIVRTLLLHP AIFGLHHIGM QMRIAMFSLI YKKTLKLSSR VLDKISIGQL
VSLLSNNLNK FDEGLALAHF VWIAPLQVAL LMGLIWELLQ ASAFCGLGFL IVLALFQAGL
GRMMMKYRDQ RAGKISERLV ITSEMIENIQ SVKAYCWEEA MEKMIENLRQ TELKLTRKAA
YVRYFNSSAF FFSGFFVVFL SVLPYALIKG IILRKIFTTI SFCIVLRMAV TRQFPWAVQT
WYDSLGAINK IQDFLQKQEY KTLEYNLTTT EVVMENVTAF WEEGFGELFE KAKQNNNNRK
TSNGDDSLFF SNFSLLGTPV LKDINFKIER GQLLAVAGST GAGKTSLLMV IMGELEPSEG
KIKHSGRISF CSQFSWIMPG TIKENIIFGV SYDEYRYRSV IKACQLEEDI SKFAEKDNIV
LGEGGITLSG GQRARISLAR AVYKDADLYL LDSPFGYLDV LTEKEIFESC VCKLMANKTR
ILVTSKMEHL KKADKILILH EGSSYFYGTF SELQNLQPDF SSKLMGCDSF DQFSAERRNS
ILTETLHRFS LEGDAPVSWT ETKKQSFKQT GEFGEKRKNS ILNPINSIRK FSIVQKTPLQ
MNGIEEDSDE PLERRLSLVP DSEQGEAILP RISVISTGPT LQARRRQSVL NLMTHSVNQG
QNIHRKTTAS TRKVSLAPQA NLTELDIYSR RLSQETGLEI SEEINEEDLK ECFFDDMESI
PAVTTWNTYL RYITVHKSLI FVLIWCLVIF LAEVAASLVV LWLLGNTPLQ DKGNSTHSRN
NSYAVIITST SSYYVFYIYV GVADTLLAMG FFRGLPLVHT LITVSKILHH KMLHSVLQAP
MSTLNTLKAG GILNRFSKDI AILDDLLPLT IFDFIQLLLI VIGAIAVVAV LQPYIFVATV
PVIVAFIMLR AYFLQTSQQL KQLESEGRSP IFTHLVTSLK GLWTLRAFGR QPYFETLFHK
ALNLHTANWF LYLSTLRWFQ MRIEMIFVIF FIAVTFISIL TTGEGEGRVG IILTLAMNIM
STLQWAVNSS IDVDSLMRSV SRVFKFIDMP TEGKPTKSTK PYKNGQLSKV MIIENSHVKK
DDIWPSGGQM TVKDLTAKYT EGGNAILENI SFSISPGQRV GLLGRTGSGK STLLSAFLRL
LNTEGEIQID GVSWDSITLQ QWRKAFGVIP QKVFIFSGTF RKNLDPYEQW SDQEIWKVAD
EVGLRSVIEQ FPGKLDFVLV DGGCVLSHGH KQLMCLARSV LSKAKILLLD EPSAHLDPVT
YQIIRRTLKQ AFADCTVILC EHRIEAMLEC QQFLVIEENK VRQYDSIQKL LNERSLFRQA
ISPSDRVKLF PHRNSSKCKS KPQIAALKEE TEEEVQDTRL
//

MIM 219700
*RECORD*
*FIELD* NO
219700
*FIELD* TI
#219700 CYSTIC FIBROSIS; CF
;;MUCOVISCIDOSIS
*FIELD* TX
A number sign (#) is used with this entry because the disorder is caused
read moreby mutations in the cystic fibrosis conductance regulator gene (CFTR;
602421), located on chromosome 7.

DESCRIPTION

Formerly known as cystic fibrosis of the pancreas, this entity has
increasingly been labeled simply 'cystic fibrosis.' Manifestations
relate not only to the disruption of exocrine function of the pancreas
but also to intestinal glands (meconium ileus), biliary tree (biliary
cirrhosis), bronchial glands (chronic bronchopulmonary infection with
emphysema), and sweat glands (high sweat electrolyte with depletion in a
hot environment). Infertility occurs in males and females.

For discussion of a phenotype consisting of bronchiectasis with or
without elevated sweat chloride caused by mutation in the genes encoding
the 3 subunits of the epithelial sodium channel, see BESC1 (211400).

CLINICAL FEATURES

The mildest extreme of CF is represented by patients not diagnosed until
middle age (Scully et al., 1977). The phenotypic variability in CF was
analyzed by Sing et al. (1982). In an inbred kindred in North Carolina,
a mild form of cystic fibrosis was described by Knowles et al. (1989).
There was 1 instance of mother-daughter involvement, the mother being
related to her husband. One of the presumed homozygotes was a
62-year-old woman. Another was her 52-year-old sister, the mother of the
affected proposita. The daughter was an intensive care nurse, the mother
of a normal daughter. Manifestations in the family were predominantly
pulmonary; pancreatic exocrine insufficiency was not a conspicuous
feature, especially in the older patients.

The 2 subgroups defined by the A and C haplotypes of polymorphisms
closely linked to the CF locus on chromosome 7, reported by Estivill et
al. (1987), have clinical differences in terms of the frequency of
meconium ileus, pseudomonas infections, and pancreatic disease (Woo,
1988).

Gasparini et al. (1990) described a RFLP DNA marker closely linked to
the CF locus which showed an allelic correlation with severity of the
disorder: the genotype 2/2 was associated with severe disease; the
genotype 1/2 was overrepresented in patients with very mild clinical
manifestations, including pancreatic insufficiency, absence of meconium
ileus, and absence of Pseudomonas colonization.

- Meconium Ileus

Allan et al. (1981) showed that sibs tend to show recurrence of meconium
ileus as a feature of cystic fibrosis. The distal intestinal obstruction
syndrome is a 'meconium ileus equivalent' that occurs in adolescents and
adults with CF. It is the consequence of the abnormally viscid
mucofeculant material in the terminal ileum and right colon, where the
fecal stream is normally liquid.Typical features are recurrent episodes
of RLQ pain with palpable mass in the right iliac fossa. Symptoms are
exacerbated by eating.

Mornet et al. (1988) determined the haplotype associated with cystic
fibrosis in 41 families using 4 DNA probes, all of which are tightly
linked to the CF gene. In 17 of the families an affected child had
meconium ileus, and in the other 24 families there was a child without
meconium ileus. A different haplotype was associated with the 2 types of
families, suggesting that multiple allelism, i.e., different mutations
at the same locus, accounts for CF with or without meconium ileus.

- Liver Disease

Gaskin et al. (1988) found that 96% of patients with cystic fibrosis and
evidence of liver disease had biliary tract obstruction, usually a
stricture of the distal common bile duct. All patients without liver
disease had normal intrahepatic and common-duct excretion of tracer.

Bilton et al. (1990) described a case of cystic fibrosis complicated by
common bile duct stenosis.

Gabolde et al. (2001) showed that the presence of cirrhosis in patients
with cystic fibrosis is significantly associated with either homozygous
or compound heterozygous mutations in the MBL2 gene (154545), which
encodes mannose-binding lectin (MBL). The authors compared 216 patients
homozygous for the delta-F508 mutation (602421.0001) and found that 5.4%
of those homozygous or compound heterozygous for wildtype
mannose-binding lectin had cirrhosis, while 30.8% of those homozygous or
compound heterozygous for mutant alleles had cirrhosis (p = 0.008).

Approximately 3 to 5% of patients with cystic fibrosis develop severe
liver disease defined as cirrhosis with portal hypertension. Bartlett et
al. (2009) performed a 2-stage case control study enrolling patients
with CF and severe liver disease with portal hypertension from 63 CF
centers in the United States as well as 32 in Canada and 18 outside of
North America. In the first stage, 124 patients with CF and severe liver
disease, enrolled between January 1999 and December 2004, and 843
control patients without CF-related liver disease (all assessed at
greater than 15 years of age) were studied by genotyping 9 polymorphisms
in 5 genes previously studied as modifiers of liver disease in CF. In
the second stage, the 2 genes that were positive from the first stage
were tested in an additional 136 patients with CF-related liver disease,
enrolled between January 2005 and February 2007, and in 1,088 with no
CF-related liver disease. The combined analysis of the initial and
replication studies by logistic regression showed CF-related liver
disease to be associated with the SERPINA1 Z allele (107400.0011) (odds
ratio = 5.04; 95% confidence interval, 2.88-8.83; p = 1.5 x 10(-8)).
Bartlett et al. (2009) concluded that the SERPINA1 Z allele is a risk
factor for liver disease in CF. Patients carrying the Z allele are at
greater risk (odds ratio = approximately 5) of developing severe liver
disease with portal hypertension.

- Pancreatic Insufficiency

Approximately 15% of CF patients do not have pancreatic insufficiency,
i.e., are 'pancreatic sufficient.' Kerem et al. (1989) performed linkage
disequilibrium and haplotype association studies of patients in 2
clinical subgroups, one pancreatic insufficient (PI) and the other
pancreatic sufficient (PS). Significant differences were found in
allelic and haplotype distributions in the 2 groups. The data suggested
that most of the CF-PI patients were descendants of a single mutational
event at the CF locus, whereas the CF-PS patients resulted from
multiple, different mutations. Corey et al. (1989) commented on the
intrafamilial concordance for pancreatic insufficiency in CF.

Devoto et al. (1989) studied the allele and haplotype frequencies of 5
polymorphic DNA markers near the CF locus in 355 CF patients from
Belgium, the German Democratic Republic, Greece, and Italy who were
divided into 2 groups according to whether or not they were taking
supplementary pancreatic enzymes. The distributions of alleles and
haplotypes revealed by 2 of the probes were always different in patients
with or without pancreatic insufficiency in all the populations studied.
In the case of 1 haplotype that was present in 73% of all the CF
chromosomes in their sample, they found homozygosity in only 28% of
patients without pancreatic insufficiency as contrasted with 64% who
were homozygous and had pancreatic insufficiency. Like other workers,
they concluded that this indicated that pancreatic insufficiency and
sufficiency are associated with different mutations at the CF locus.

Ferrari et al. (1990) studied the distribution of haplotypes based on 8
polymorphic DNA markers linked to CF in 163 Italian patients and
correlated the findings with clinical presentation. Among 19 pancreatic
sufficient patients, 6 (31.6%) showed at least 1 copy of a rare
phenotype which was present in only 16 of 138 patients (11.6%) with
pancreatic insufficiency. In addition, only 5 pancreatic sufficient
patients were homozygous for the common 2,1 haplotype as compared with
88 patients (63.8%) with pancreatic insufficiency. Kristidis et al.
(1992) likewise found intrafamilial consistency of the pancreatic
phenotype, whether pancreatic sufficient or insufficient. Furthermore,
the PS phenotype occurred in patients who had 1 or 2 mild CFTR
mutations, such as arg117-to-his (602421.0005), arg334-to-trp
(602421.0034), arg347-to-pro (602421.0006), ala455-to-glu (602421.0007),
and pro574-to-his (602421.0018), whereas the PI phenotype occurred in
patients with 2 severe alleles, such as phe508-to-del (602421.0001),
ile507-to-del (602421.0002), gln493-to-ter (602421.0003), gly542-to-ter
(602421.0009), arg553-to-ter (602421.0014), and trp1282-to-ter
(602421.0022).

Borgo et al. (1993) commented on the phenotypic intrafamilial
heterogeneity displayed by an Italian family in which 3 sibs, 2 of whom
were dizygotic twins, were compound heterozygotes for the delF508
(602421.0001) and the 1717,-1,G-A splicing mutation (602421.0008). While
close intrafamilial concordance was found for exocrine pancreatic
phenotype, the pulmonary phenotype varied widely. They suggested that
interaction of the CFTR protein with tissue-specific proteins or the
action of modifier loci (which may be operationally identical
possibilities) plays a role in intrafamilial variability.

Barreto et al. (1991) concluded that the father of a girl with severe CF
also had CF but was mildly affected. The child was homozygous for the
delta-F508 mutation associated with haplotype B; the father was a
compound heterozygote for this mutation and a second CF mutation
associated with haplotype C. Perhaps it should not be surprising that
some patients with cystic fibrosis have no pancreatic lesions
(Oppenheimer, 1972).

Sharer et al. (1998) and Cohn et al. (1998) demonstrated that
heterozygosity for CFTR mutations can lead to 'idiopathic' chronic
pancreatitis, especially when the mutation is associated with the 5T
allele of the variable number of thymidines in intron 8 of the CFTR
gene.

- Pulmonary Disease

Pier et al. (1996) provided an experimental explanation for the
susceptibility of CF patients to chronic Pseudomonas aeruginosa lung
infections. They found that cultured human airway epithelial cells
expressing the delta-F508 allele of the CFTR gene were defective in
uptake of P. aeruginosa compared with cells expressing the wildtype
allele. P. aeruginosa lipopolysaccharide-core oligosaccharide was
identified as the bacterial ligand for epithelial cell ingestion;
exogenous oligosaccharide inhibited bacterial ingestion in a neonatal
mouse model, resulting in increased amounts of bacteria in the lungs.
The authors concluded that CFTR may normally contribute to a
host-defense mechanism that is important for clearance of P. aeruginosa
from the respiratory tract.

Ernst et al. (1999) identified unique lipopolysaccharide structures
synthesized by P. aeruginosa within CF patient airways. P. aeruginosa
synthesized lipopolysaccharide with specific lipid A structures,
indicating unique recognition of the CF airway environment. CF-specific
lipid A forms containing palmitate and aminoarabinose were associated
with resistance to cationic antimicrobial peptides and increased
inflammatory responses, indicating that they are likely to be involved
in airway disease.

Because mannose-binding lectin (MBL), encoded by the MBL2 gene (154545),
is a key factor in innate immunity, and lung infections are a leading
cause of morbidity and mortality in CF, Garred et al. (1999)
investigated whether MBL variant alleles, which are associated with
recurrent infections, might be risk factors for CF patients. In 149 CF
patients, different MBL genotypes were compared with respect to lung
function, microbiology, and survival to end-stage CF (death or lung
transplantation). The lung function was significantly reduced in
carriers of MBL variant alleles when compared with normal homozygotes.
The negative impact of variant alleles on lung function was especially
confined to patients with chronic Pseudomonas aeruginosa infection.
Burkholderia cepacia infection was significantly more frequent in
carriers of variant alleles than in homozygotes. The risk of end-stage
CF among carriers of variant alleles increased 3-fold, and the survival
time decreased over a 10-year follow-up period. Moreover, by using a
modified life table analysis, Garred et al. (1999) estimated that the
predicted age of survival was reduced by 8 years in variant allele
carriers when compared with normal homozygotes.

Davies et al. (2000) found that MBL binds to Burkholderia cepacia, an
important pathogen in patients with CF, and leads to complement
activation, but that this was not the case for Pseudomonas aeruginosa,
the more common colonizing organism in CF. Davies et al. (2000)
suggested that patients with CF and mannose-binding lectin deficiency
would be at a particularly high risk of B. cepacia colonization. The
lack of binding to P. aeruginosa suggests that the effect of this
organism on lung function in patients with MBL-deficient CF reflects a
role for MBL, either in intercurrent infections with other organisms, or
in the inflammatory process.

In an association study involving 112 patients with cystic fibrosis,
Yarden et al. (2004) found that patients with the MBL2 A/O or O/O
genotypes were more likely to have a more severe pulmonary phenotype
than patients with the A/A genotype (p = 0.002). No association was
found between the MBL2 genotype and the age at first infection with P.
aeruginosa. Yarden et al. (2004) concluded that it is very likely that
MBL2 is a modulating factor in cystic fibrosis.

Tarran et al. (2001) stated that there is controversy over whether
abnormalities in the salt concentration or volume of airway surface
liquid (ASL) initiate CF airway disease. Using CF mouse nasal epithelia,
they showed that an increase in goblet cell number was associated with
decreased ASL volume rather than abnormal Cl- concentration.
Aerosolization of osmolytes in vivo failed to raise ASL volume.
Osmolytes and pharmacologic agents were effective in producing isotonic
volume responses in human airway epithelia but were typically short
acting and less effective in CF cultures with prolonged volume
hyperabsorption and mucus accumulation. These data showed that therapies
can be designed to normalize ASL volume without producing deleterious
compositional changes in ASL, and that therapeutic efficacy will likely
depend on development of long-acting pharmacologic agents and/or an
increased efficiency of osmolyte delivery.

In 69 Italian patients with CF due to homozygosity for the delF508
mutation in the CFTR gene (F508del; 602421.0001), De Rose et al. (2005)
found that those who also carried the R131 allele of the immunoglobulin
Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold
increased risk of acquiring chronic Pseudomonas aeruginosa infection (p
= 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability
contributes to this infection susceptibility in CF patients.

Emond et al. (2012) used exome sequencing and an extreme phenotype study
design to discover genetic variants influencing Pseudomonas aeruginosa
infection in cystic fibrosis. Forty-three individuals with early age of
onset of chronic P. aeruginosa infection (all below the tenth percentile
of age at onset), and the 48 oldest individuals who had not reached
chronic P. aeruginosa infection (all past the mean age of onset) were
sequenced. After Bonferroni adjustment, a single gene, DCTN4, was
significantly associated with time to chronic P. aeruginosa infection
(naive P = 2.2 x 10(-6); adjusted P = 0.025). Twelve of the 43
individuals in the early extreme sample carried a missense variant in
DCTN4, 9 a phe349-to-leu substitution (F349L; dbSNP rs11954652) and 3 a
tyr270-to-cys substitution (Y270C; dbSNP rs35772018). None of the 48
individuals in the late P. aeruginosa extreme sample had either missense
variant. Subsequently, 696 individuals with varied CFTR genotypes were
studied. Seventy-eight participants were heterozygous and 9 were
homozygous for the F349L (614758.0001) mutation; 15 were heterozygous
for the Y270C (614758.0002) mutation; 1 individual was heterozygous for
both mutations. The presence of at least 1 DCTN4 missense variant was
significantly associated with both early age of first P.
aeruginosa-positive culture (p = 0.01, hazard ratio = 1.4) and with
early age of onset of chronic P. aeruginosa infection (p = 0.004, hazard
ratio = 1.9). The risk was highest in individuals with less selective
bias toward a P. aeruginosa-negative history, i.e., children enrolled
before 1.5 years of age and 103 enrollees who participated in the study
despite a history of P. aeruginosa-positive cultures. No significant
interaction was found between CFTR genotypes and DCTN4 mutations,
although power to detect such an interaction was low.

- Infertility

Oppenheimer et al. (1970) suggested that characteristics of cervical
mucus may account for infertility in females with cystic fibrosis.
Congenital bilateral absence of the vas deferens (CBAVD; 277180) is a
usual cause of male infertility in cystic fibrosis. It also occurs with
CFTR mutations in heterozygous state, especially when associated with
the polymorphic number of thymidines in intron 8, specifically the 5T
allele.

- Carcinoma

Siraganian et al. (1987) pointed to adenocarcinoma of the ileum in 3
males with cystic fibrosis. The diagnosis was made between ages 29 and
34 years.

From a pancreatic adenocarcinoma developing in a 26-year-old patient
with cystic fibrosis due to the phenylalanine-508 deletion, Schoumacher
et al. (1990) established a cell line in which the cells showed
morphologic and chemical characteristics typical of pancreatic duct
cells and showed physiologic properties of CF cells. Schoumacher et al.
(1990) suggested that the cell line, which had been stable through more
than 80 passages over a 2-year period, could serve as a continuous cell
line for studies of the CF defect. Bradbury et al. (1992) demonstrated
that the CFTR protein is involved in cAMP-dependent regulation of
endocytosis and exocytosis. In a study of pancreatic cancer cells
derived from a CF patient, they found that plasma membrane recycling did
not occur until normal CFTR was provided.

Neglia et al. (1995) performed a retrospective cohort study of the
occurrence of cancer in 28,511 patients with cystic fibrosis from 1985
through 1992 in the United States and Canada. The number of cases
observed was compared with the number expected, calculated from
population-based data on the incidence of cancer. They also analyzed
proportional incidence ratios to assess the association between specific
cancers and cystic fibrosis in Europe. The final results indicated that
although the overall risk of cancer in patients with cystic fibrosis is
similar to that of the general population, there is an increased risk of
digestive tract cancers. They recommended that persistent or unexplained
gastrointestinal symptoms in CF patients should be carefully
investigated.

Patients with cystic fibrosis have altered levels of plasma fatty acids.
Affected tissues from cystic fibrosis knockout mice show elevated levels
of arachidonic acid and decreased levels of docosahexaenoic acid.
Freedman et al. (2004) performed studies of fatty acids in nasal and
rectal biopsy specimens, nasal epithelial scrapings, and plasma from 38
patients with cystic fibrosis, and found alterations in fatty acids
similar to those in the knockout mice.

- Other Features

Delayed puberty is common among individuals with cystic fibrosis and is
usually attributed to chronic disease and/or poor nutrition. However,
delayed puberty has been reported as a feature of CF even in the setting
of good nutritional and clinical status (Johannesson et al., 1997).

INHERITANCE

Recessive inheritance of cystic fibrosis was first shown clearly by Lowe
et al. (1949). Roberts (1960) collected family data which appeared to
him inconsistent with the quarter ratio expected of a recessive trait.
Bulmer (1961) pointed out, however, that when proper correction is made
for ascertainment bias, the observed proportions may agree with those
expected for a recessive trait.

Rather than estimating the frequency of the CF gene from the square root
of the incidence figure, Danks et al. (1983) used the frequency of CF in
first cousins. The estimate of gene frequency was 0.0281 as contrasted
with 0.0198 (based on direct count). Danks et al. (1983) suggested that
the disparity between the 2 estimates might be the existence of 2 gene
loci, each with a frequency of 0.0140 for the CF gene and a heterozygote
frequency of 1 in 36. Thus, in Victoria, Australia, 1 in 18 persons
might be heterozygous at one or the other locus. Later, however, the
authors published a retraction and concluded that they had no evidence
of more than 1 locus.

For risk analysis in cystic fibrosis, Edwards and Miciak (1990) proposed
a simple procedure called the 'slash sheet.' They pointed out that the
various methods of estimating genetic risk fall into 2 main groups:
first, enumerating all possibilities and excluding those inconsistent
with the tests, a simple procedure in small families, and second, using
conditional arguments. The latter approach uses Bayes theorem. The
former approach, Edwards and Miciak (1990) pointed out, follows a
procedure advanced in 1654 by Pascal, following correspondence with
Fermat, on the problem of the Chevalier de Mere, now known as the
'problem of points.' Two noblemen were gambling, and, while one was
winning, the other was called away and the game was abandoned. How
should the stakes be divided? Edwards and Miciak (1990) noted that
'genetic risk is merely an unfinished game of chance.'

See Hodge et al. (1999) for a discussion of calculation of CF risk in a
fetus with 1 identified mutation in CFTR and echogenic bowel.

CYTOGENETICS

Park et al. (1987) concluded that CF is distal to and on the 5-prime
side of MET. They determined this by in situ hybridization on metaphase
and prometaphase chromosomes of normal lymphocytes as well as
lymphoblastoid cells containing a t(5;7)(q35;q22). Normal cells showed
clustering of MET grains to 7q31. Furthermore, in the lymphoblastoid
cell line, there was significant labeling within the 5q+ chromosome,
confirming that MET is located distal to 7q22 with most grains clustered
at 7q31. Somatic cell hybrids containing the derivative 7 showed on
Southern analysis that the 3-prime portion of the MET gene, but not the
5-prime portion, was located there; thus, MET is at the translocation
breakpoint. Studies in another cell line with a 7q32 translocation
breakpoint indicated that MET is located at or proximal to 7q32. A break
at this site was accompanied by loss of 3 markers within 1 cM of CF,
suggesting that if MET is at the breakpoint on 7q31, CF is located
distally.

In the course of studying a case of cystic fibrosis, Spence et al.
(1988) discovered what appeared to be a case of uniparental disomy: the
father did not contribute alleles to the propositus for markers near the
CF locus or for centromeric markers on chromosome 7. High-resolution
cytogenetic analysis was normal, and the result could not be explained
by nonpaternity or a submicroscopic deletion. Uniparental disomy could
be explained by various mechanisms such as monosomic conception with
subsequent chromosome gain, trisomic conception followed by chromosome
loss, postfertilization error, or gamete complementation. Patients with
more than one genetic disorder might be suspected of having isodisomy,
which should also be suspected in cases of an apparent new mutation
leading to a recessive disorder when only 1 parent is heterozygous, and
in cases of females affected with X-linked recessive disorders. Engel
(1980) appears to have originated the concept of uniparental disomy and
resulting isodisomy. Voss et al. (1988, 1989) also demonstrated
uniparental disomy for chromosome 7 in a patient with cystic fibrosis.

MAPPING

Mayo et al. (1980) attempted to map the cystic fibrosis gene by study of
CF x mouse cell hybrids and examination for production of the cystic
fibrosis mucociliary inhibitor. The strongest chance of assignment was
for chromosome 4. Scambler et al. (1985) found that the albumin locus
labeled by a DNA clone did not segregate with CF or with any of 6 other
chromosome 4 markers. They estimated that about half the length of
chromosome 4 was accounted for by the markers used. Eiberg et al. (1984)
found a hint of linkage to F13B (134580); the maximum lod score was 1.71
at a recombination fraction of 0.05 for males and females combined.
Linkage with 56 other genetic markers was negative (Eiberg et al.,
1984). Eiberg et al. (1985) showed that cystic fibrosis and paraoxonase
(PON; 168820) are linked; the maximum lod score was 3.70 at theta = 0.07
in males and 0.00 in females.

Tsui et al. (1985) found that the CF locus is linked to that of a DNA
marker which is also linked to the PON locus, which in turn by
independent evidence is linked to CF, thus closing the circle. The DNA
marker was provisionally called D0CRI-917. The interval between the
marker and PON was about 5 cM and the interval between it and CF about
15 cM. Whether the order is marker--PON--CF or PON--marker--CF was not
certain; the former order was favored by 9:5 odds. Knowlton et al.
(1985) reported that the anonymous probe D0CRI-917, linked to CF with
about 15% recombination, is located on chromosome 7. White et al. (1985)
showed very tight linkage to the MET oncogene (164860), which was
assigned to the midportion of 7q. Wainwright et al. (1985) reported
tight linkage also to the gene for another anonymous DNA probe, pJ3.11,
which was assigned to 7cen-7q22. The closely linked probes pJ3.11 and
MET are sufficiently informative to permit carrier detection in 80% of
families in which there is a living CF child and unaffected sibs
(Farrall et al., 1986). Scambler et al. (1985) showed that the COL1A2
gene (120160) is linked to CF (maximum lod for the sexes combined = 3.27
at a male recombination fraction of 0.08 and a female recombination
fraction of 0.15.) PON and CF show recombination frequency of about 10%.
CF is about 10 cM from both TCRB (see 186930) and COL1A2. TCRB and
COL1A2 are not closely linked; thus, CF lies between them in the
proximal part of 7q22. Wainwright et al. (1986) presented linkage data
for COL1A2 versus CF (lod = 3.58 at theta = 0.10), TCRB versus CF (lod =
2.20 at theta = 0.15) and TCRB versus PON (all lods negative). Based on
combined linkage data from 50 informative 2-generation families,
Buchwald et al. (1986) concluded that CF is 19 cM from COL1A2, which is
located at 7q21.3-q22.1. COL1A2 is closely linked to D7S15 and to PON.
The probable order is COL1A2--D7S15--PON--CF. The regional localization
of CF is 7q22.3-q23.1. Linkage of cystic fibrosis to various DNA markers
and/or classical markers was reported in a series of articles by Beaudet
et al. (1986), White et al. (1986), Bowcock et al. (1986), Farrall et
al. (1986), Tsui et al. (1986), Spence et al. (1986), and Watkins et al.
(1986). In Amish/Mennonite/Hutterite kindreds, Klinger et al. (1986) and
Watkins et al. (1986) found close linkage with markers on chromosome 7,
consistent with locus homogeneity for the defect causing CF in the
populations that had been examined to date.

Estivill et al. (1987) identified a candidate for the cystic fibrosis
locus by using a 'rare-cutter cosmid library.' They found a genomic
region with the characteristics of an HTF island in high linkage
disequilibrium with CF. The fact that the sequence was conserved
throughout mammalian evolution strengthens the view that this is the CF
gene. HTF islands, standing for HpaII tiny fragments, have a sequence
length of between 500 and 1000 bp and often include the first exons as
well as upstream sequences 5-prime to coding genes (Bird, 1986; Brown
and Bird, 1986). These HTF islands are regions of DNA rich in the
nonmethylated dinucleotide CpG and contain clusters of sites for
CpG-methylation-sensitive restriction enzymes. (There are about 30,000
HTF islands in the human genome.) Estivill et al. (1987) stated that 94%
of the chromosomes are of haplotype B, which is present in only 34% of
the chromosomes in the general population. In 127 Italian families,
Estivill et al. (1988) studied linkage disequilibrium of markers at the
locus containing the CpG-enriched methylation-free island designated
D7S23. In a search for deletions by means of field inversion gel
electrophoresis (FIGE), Morreau et al. (1988) analyzed DNA from 10
cystic fibrosis patients representing 19 different CF chromosomes. No
differences were detected after digestion of the samples with 2
different restriction enzymes and hybridization with 4 different probes.
The authors estimated that the percentage of deletions occurring within
the CF region is less than 15.2% (95% confidence interval, N = 19). The
fact that no patient with a combination of cystic fibrosis and a genetic
syndrome due to a second affected locus in close vicinity to the CF
locus has been described suggests that deletions are rare. Beaudet et
al. (1989) found strong linkage disequilibrium between the CF locus and
closely linked markers on chromosome 7. By in situ hybridization Duncan
et al. (1988) mapped 2 DNA sequences closely linked to the CF locus to
7q31.3-q32. This is a more distal location than had been inferred from
previous data.

Using cystic fibrosis and published CF haplotypes as the test bed,
Collins and Morton (1998) illustrated how allelic association can be
efficiently combined with linkage evidence to identify a region for
positional cloning of a disease gene.

MOLECULAR GENETICS

For an extensive discussion of the molecular genetics of cystic fibrosis
and a listing of allelic variants of the CFTR gene, see 602421.

Collins (1992) gave an update concerning the molecular biology of CF and
the therapeutic implications thereof.

O'Sullivan and Freedman (2009) reviewed the clinical features,
pathogenesis, diagnosis, molecular genetics, and current state of gene
therapy in CF.

HETEROGENEITY

Vitale et al. (1986) found close linkage of the CF gene and the MET
locus in 12 unrelated Italian cystic fibrosis families, thus supporting
their hypothesis of genetic homogeneity based on the analysis of
consanguineous marriages among 624 couples of CF parents. Lander and
Botstein (1986) and Romeo et al. (1986) discussed further the
consanguinity method for studying heterogeneity in cystic fibrosis.
Estivill et al. (1987) used their haplotype data to argue against
genetic heterogeneity at the CF locus. They proposed that the great
majority of CF mutations found in the population arose from an original
mutational event which occurred in the Caucasian population after racial
divergence in man.

Nonclassic forms of CF have been associated with mutations that reduce
but do not eliminate the function of the CFTR protein. Mekus et al.
(1998) described a patient with a nonclassic CF phenotype in whom no
CFTR mutations could be found. Groman et al. (2002) assessed whether
alteration in CFTR function is responsible for the entire spectrum of
nonclassic CF phenotypes. Extensive genetic analysis of the CFTR gene
was performed in 74 patients with nonclassic CF. Furthermore, they
evaluated 2 families that each included a proband without identified
CFTR mutations and a sib with nonclassic CF to determine whether there
was linkage to the CFTR locus and to measure the extent of CFTR function
in the sweat gland and nasal epithelium. Of the 74 patients studied,
Groman et al. (2002) found that 29 had 2 mutations in the CFTR gene
(i.e., were either homozygous or compound heterozygous at the CFTR
locus), 15 had 1 mutation, and 30 had no mutations. A genotype of 2
mutations was more common among patients who had been referred after
screening for a panel of common CF-causing mutations that had identified
1 mutation than among those who had been referred after screening had
identified no such mutations. Comparison of clinical features and sweat
chloride concentrations revealed no significant differences among
patients with 2, 1, or no CFTR mutations. Haplotype analysis in the 2
families in which 2 sibs had nonclassic CF showed no evidence of linkage
to CFTR. Although each of the affected sibs had elevated sweat chloride
concentrations, measurements of cAMP-mediated ion and fluid transport in
the sweat gland and nasal epithelium demonstrated the presence of
functional CFTR. Groman et al. (2002) concluded that factors other than
mutations in the CFTR gene can produce phenotypes clinically
indistinguishable from nonclassic CF caused by CFTR dysfunction.

Because proteinase-antiproteinase imbalances are common in both CF and
alpha-1-antitrypsin deficiency (613490), Meyer et al. (2002)
investigated the hypothesis that the common AAT deficiency alleles PI Z
(107400.0011) and PI S (107400.0013) contribute to pulmonary prognosis
in CF. In 269 CF patients from southern Germany, they determined the
serum concentrations of AAT (107400) and C-reactive protein (CRP;
123260) by nephelometry and screened for the common AAT deficiency
alleles by PCR and restriction enzyme digest. The onset of chronic
bacterial colonization by P. aeruginosa was correlated with the AAT
phenotypes PI MM, PI MS, and PI MZ. Only 3 of 9 (33%) CF patients
diagnosed with either PI MS or PI MZ had developed chronic P. aeruginosa
lung infection earlier in their lives; the remaining 6 PI MS or PI MZ
patients showed a later onset of chronic P. aeruginosa lung infection.
The results suggested that PI MS and PI MZ are not associated with a
worse pulmonary prognosis in CF.

Mekus et al. (2003) examined modifying factors in CF by studying 34
highly concordant and highly discordant delF508 homozygous sib pairs
selected from a group of 114 pairs for extreme disease phenotypes by
nutritional and pulmonary status. They were typed for SNPs and short
tandem repeat polymorphisms (STRPs) in a 24-cM CFTR-spanning region.
Allele frequencies differed significantly at D7S495, located within a
21-cM distance 3-prime of CFTR, comparing concordant mildly affected,
concordant severely affected, and discordant sib pairs. A rare haplotype
of 2 SNPs within the leptin gene promoter (LEP; 164160) was found
exclusively among the concordant mildly affected pairs. All concordant
sib pairs shared the paternal delF508 chromosome between CFTR and
D7S495, while the cohort of discordant sib pairs inherited equal
proportions of recombined and nonrecombined parental chromosomes. Mekus
et al. (2003) concluded that disease manifestation in CF is modulated by
loci in the partially imprinted region 3-prime of CFTR that determine
stature, food intake, and energy homeostasis, such as the Silver-Russell
syndrome (180860) candidate gene region and LEP.

There is great variability of pulmonary phenotype and survival in cystic
fibrosis, even among patients who are homozygous for the most prevalent
mutation, delF508 (602421.0001). Although environmental influences may
modify clinical disease, there is probably additional genetic variation
(i.e., modifier genes) that contribute to the expression of the final
phenotype. Drumm et al. (2005) studied variants of 10 genes previously
reported as modifiers in cystic fibrosis in 2 studies with different
patient samples. They first tested 808 patients who were homozygous for
the delF508 mutation and were classified as having either severe or mild
lung disease. Significant allelic and genotypic associations with
phenotype were seen only for TGFB1 (190180), the gene encoding
transforming growth factor beta-1, particularly the -509 and codon 10
polymorphisms. The odds ratio was about 2.2 for the highest-risk TGFB1
genotype (codon 10 CC; 190180.0007) in association with the phenotype of
severe lung disease. In the replication (second) study, Drumm et al.
(2005) tested 498 patients, with various CFTR genotypes and a range of
values for forced expiratory volume in 1 second (FEV1), for an
association of the TGFB1 codon 10 CC genotype with low FEV1. This
replication study confirmed the association of the TGFB1 codon 10 CC
genotype with more severe lung disease.

Buranawuti et al. (2007) determined the genotype of 4 variants of 3
putative CF modifier genes (TNF-alpha-238; TNF-alpha-308, 191160.0004;
TGF-beta-509; and MBL2 A/O) in 3 groups of CF patients: 101 children
under 17 years of age, 115 adults, and 38 nonsurviving adults (21
deceased and 17 lung transplant after 17 years of age). Genotype
frequencies among adults and children with CF differed for TNF-alpha-238
(G/G vs G/A, p = 0.022) and MBL2 (A/A vs O/O, p = 0.016), suggesting
that MBL2 O/O is associated with reduced survival beyond 17 years of
age, whereas TNF-alpha-238 G/A appears to be associated with an
increased chance of surviving beyond 17 years of age. When adults with
CF were compared to nonsurviving adults with CF, genotype frequencies of
both genes differed (TNF-alpha 238 G/G vs G/A, p = 0.0015; MBL2 A/A vs
O/O, p = 0.009); the hazard ratio for TNF-alpha-238 G/G versus G/A was
0.25 and for MLB2 O/O versus A/A or A/O was 2.5. Buranawuti et al.
(2007) concluded that TNF-alpha-238 G/A and MBL2 O/O genotypes appear to
be genetic modifiers of survival in patients with CF.

In a study of 1,019 Canadian pediatric CF patients, Dorfman et al.
(2008) found a significant association between earlier age of first P.
aeruginosa infection and MBL2 deficiency (onset at 4.4, 7.0, and 8.0
years for low, intermediate, and high MBL2 groups according to MBL2
genotype, respectively; p = 0.0003). This effect was amplified in
patients with the high-producing genotypes of TGFB1, including variant C
of codon 10. MBL2 deficiency was also associated with more rapid decline
of pulmonary function, most significantly in those homozygous for the
high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1
affected the modulation of age of onset by MBL2, there was no
significant direct impact of TGFB1 codon 10 genotypes alone. The
findings provided evidence for a gene-gene interaction in the
pathogenesis of CF lung disease, whereby high TGFB1 production enhances
the modulatory effect of MBL2 on the age of first bacterial infection
and the rate of decline of pulmonary function.

Using quantitative transmission disequilibrium testing of 472 CF
patient/parent trios, Bremer et al. (2008) found significant
transmission distortion of 2 TGFB1 SNPs, -509 (dbSNP rs1800469) and
codon 10 (dbSNP rs1982073), when patients were stratified by CFTR
genotype. Although lung function and nutritional status are correlated
in CF patients, there was no evidence of association between the TGFB1
SNPs and variation in nutritional status. A 3-SNP haplotype (CTC)
composed of the -509 SNP C allele, the codon 10 T allele, and a 3-prime
SNP dbSNP rs8179181 C allele was highly associated with increased lung
function in patients grouped by CFTR genotype. Bremer et al. (2008)
concluded that TGFB1 is a modifier of CF lung disease, with a beneficial
effect of certain variants on the pulmonary phenotype.

To identify genetic modifiers of lung disease severity in cystic
fibrosis, Gu et al. (2009) performed a genomewide single-nucleotide
polymorphism scan in 1 cohort of cystic fibrosis patients, replicating
top candidates in an independent cohort. This approach identified IFRD1
(603502) as a modifier of cystic fibrosis lung disease severity. IFRD1
is a histone deacetylase-dependent transcriptional coregulator expressed
during terminal neutrophil differentiation. Neutrophils, but not
macrophages, from Ifrd1-null mice showed blunted effector function,
associated with decreased NF-kappa-B p65 (RELA; 164014) transactivation.
In vivo, IFRD1 deficiency caused delayed bacterial clearance from the
airway, but also less inflammation and disease--a phenotype primarily
dependent on hematopoietic cell expression, or lack of expression, of
IFRD1. In humans, IFRD1 polymorphisms were significantly associated with
variation in neutrophil effector function. Gu et al. (2009) concluded
that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease
through the regulation of neutrophil effector function.

- Association with Epithelial Sodium Channel Subunits

Stanke et al. (2006) genotyped 37 delF508 homozygous sib pairs for
markers on chromosome 12p13, encompassing the epithelial sodium channel
(ENaC) subunit A (SCNN1A; 600228) and TNF-alpha receptor (TNFRSF1A;
191190) genes, and chromosome 16p12, encompassing the SCNN1B (600760)
and SCNN1G (600761) genes, as potential CF disease modifiers.
Transmission disequilibrium was observed at SCNN1G and association with
CF phenotype intrapair discordance was observed at SCNN1B. Family-based
and case-control analyses and sequencing uncovered an association of the
TNFRSF1A intron 1 haplotype with disease severity. Stanke et al. (2006)
suggested that the SCNN1B, SCNN1G, and TNFRSF1A genes may be modulators
of CF disease by affecting changes in airway surface liquids and host
inflammatory responses.

Fajac et al. (2008) screened the SCNN1B gene in 55 patients with
idiopathic bronchiectasis (see 211400) who had 1 or no mutations in the
CFTR gene and identified heterozygosity for 3 missense mutations in the
SCNN1B gene (see, e.g., 600760.0015) in 5 patients, 3 of whom also
carried a heterozygous mutation in CFTR (602421.0001 and 602421.0086).
Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious
for sodium channel function and lead to bronchiectasis, especially in
patients who also carry a mutation in the CFTR gene.

Viel et al. (2008) analyzed the SCNN1B and SCNN1G genes in 56 adult
patients with classic CF and discordance between their respiratory
phenotype and CFTR genotype, including 38 patients with a severe
genotype and an unexpectedly mild lung phenotype, and 18 patients with a
mild genotype and severe lung phenotype. Three patients carried at least
1 missense mutation in SCNN1B or SCNN1G, but analysis of sodium channel
function by nasal potential difference (PD) measurements did not support
that the variants were functional. Viel et al. (2008) concluded that
variation in SCNN1B and SCNN1G genes do not modulate disease severity in
the majority of CF patients.

Azad et al. (2009) identified several rare SCNN1A polymorphisms with an
increased incidence in patients with a cystic fibrosis-like phenotype
and 1 or no CFTR mutations versus controls, including several patients
with no CFTR mutation who were heterozygous for a hyperactive variant
(W493R; 600228.0007). The authors hypothesized that given the CF-carrier
(3.3%) and the W493R-carrier (3.1%) frequency in some populations, there
ma be a polygenic mechanism of disease involving CFTR and SCNN1A in some
patients.

Mutesa et al. (2009) analyzed the CFTR gene in 60 unrelated Rwandan
children who had CF-like symptoms and identified heterozygosity for a
CFTR mutation in 5 patients (none were homozygous). Sequencing of the
ENaC subunits revealed heterozygous mutations in the SCNN1A and SCNN1B
genes in 4 patients, respectively, whereas the remaining patient was
heterozygous for a mutation in both SCNN1B and SCNN1G. Among the 55
patients who were negative for mutation in CFTR, only polymorphisms were
found in the ENaC genes. Mutesa et al. (2009) concluded that some cases
of CF-like syndrome in Africa may be associated with mutations in CFTR
and ENaC genes.

PATHOGENESIS

Frizzell (1987) pointed out that cystic fibrosis is of interest to
neuroscientists because it appears to be a disease of ion channels. It
is apparently not the conduction properties of ion channels that are
affected, but rather their gating by chemical agonists. These
conductance pathways appear to be unique to epithelial cells in which
salt and water transport rates are governed by cyclic AMP and
calcium-dependent regulatory processes.

Decrease in fluid and salt secretion is responsible for the blockage of
exocrine outflow from the pancreas and the accumulation of heavy
dehydrated mucous in the airways. In sweat glands, salt reabsorption is
defective. This is the basis of the folkloric anecdote that the midwife
would lick the forehead of the newborn and, if the sweat tasted
abnormally salty, predict that the infant was destined to die of
pulmonary congestion and its side effects. Quinton (1983) and Knowles et
al. (1983) first suggested that the primary defect of cystic fibrosis
may be in chloride transport. Widdicombe et al. (1985) demonstrated a
cyclic AMP-dependent transepithelial chloride current in normal but not
CF epithelia. The pathophysiology of cystic fibrosis, specifically the
impermeability of epithelia to chloride ion, was reviewed by Welsh and
Fick (1987).

Landry et al. (1989) purified several proteins from kidney and trachea
that exhibit chloride channel activity when they are reconstituted into
artificial phospholipid bilayer membranes. One or more of these proteins
may turn out to be all or part of the secretory chloride channel that is
defective in CF. Using antibodies against CFTR peptides, Marino et al.
(1991) demonstrated that the CFTR molecule is located in and confined to
the apical domain of pancreatic centroacinar and intralobular duct
cells. From this they concluded that the proximal duct epithelial cells
play a key role in the early events leading to pancreatic insufficiency
in CF and that apical chloride transport by these cells is essential for
normal pancreatic secretory function. Jetten et al. (1989) created a
stable human airway epithelial cell line by retroviral transformation of
CF airway epithelium. They found that it maintains the defect in the
secretory chloride channel. Rich et al. (1990) expressed the CFTR gene
in cultured cystic fibrosis airway epithelial cells and assessed
chloride ion channel activation in single cells by means of a
fluorescence microscopic assay and a patch-clamp technique. In cells
from patients with CF, expression of the CFTR gene but not of the mutant
form corrected the chloride ion channel defect. Since there is no animal
model for CF, the authors viewed the cell line as very important in
studies of the basic defect and for screening of candidate genes which
would complement the defect and thus identify the site of the mutation.
Bradbury et al. (1992) raised the question as to whether there may be
more to the pathogenesis of cystic fibrosis than merely a defect in
chloride passage across cell membranes and the concomitant defect in
secretion of water.

Two hypotheses, 'hypotonic (low salt)/defensin' and 'isotonic volume
transport/mucus clearance,' attempt to link defects in cystic fibrosis
transmembrane conductance regulator-mediated ion transport to CF airways
disease. Matsui et al. (1998) tested these hypotheses with planar and
cylindrical culture models and found no evidence that the liquids lining
airway surfaces were hypotonic or that salt concentrations differed
between CF and normal cultures. In contrast, CF airway epithelia
exhibited abnormally high rates of airway surface liquid absorption,
which depleted the periciliary liquid layer and abolished mucus
transport. The failure to clear thickened mucus from airway surfaces
likely initiates CF airways infection. These data indicate that therapy
for CF lung disease should not be directed at modulation of ionic
composition, but rather at restoring volume (salt and water) on airway
surfaces.

Reddy et al. (1999) demonstrated that in freshly isolated normal sweat
ducts, epithelial sodium channel (ENaC; see 600228) activity is
dependent on, and increases with, CFTR activity. Reddy et al. (1999)
also found that the primary defect in chloride permeability in cystic
fibrosis is accompanied secondarily by a sodium conductance in this
tissue that cannot be activated. Thus, reduced salt absorption in cystic
fibrosis is due not only to poor chloride conductance but also to poor
sodium conductance.

Kravchenko et al. (2008) showed that a bacterial small molecule,
N-(3-oxo-dodecanoyl) homoserine lactone (C12), selectively impairs the
regulation of NF-kappa-B (see 164011) functions in activated mammalian
cells. The consequence is specific repression of stimulus-mediated
induction of NF-kappa-B-responsive genes encoding inflammatory cytokines
and other immune regulators. Kravchenko et al. (2008) concluded that
their findings uncovered a strategy by which C12-producing opportunistic
pathogens such as P. aeruginosa attenuate the innate immune system to
establish and maintain local persistent infection in humans, for
example, in cystic fibrosis patients.

DIAGNOSIS

Boue et al. (1986) reported on prenatal diagnostic studies in 200
pregnancies with a presumed 1-in-4 risk of recurrence of cystic
fibrosis. The method involved measurement of total enzymes and
isoenzymes of gamma-glutamyl-transpeptidase, aminopeptidase M, and
alkaline phosphatase in amniotic fluid in the second trimester. The
recurrence rate of cystic fibrosis was 22.5% in 147 cases in which the
index case had cystic fibrosis without meconium ileus at birth but was
47.5% when the index case had meconium ileus. The authors speculated on
the mechanism of the 50% recurrence rate and favored the view that 1
parent was in fact a homozygote for a mild allele. With use of their
method, the authors suggested 98% accuracy in prenatal diagnosis of
cystic fibrosis. Allan et al. (1981), Super (1987), and Boue et al.
(1986) found that in families in which a CF child did not have meconium
ileus the observed recurrence rate agreed with the expected 1-in-4 risk,
but that in families with a history of meconium ileus in the index case
the recurrence rate was much higher, 43.7% in the study of Boue et al.
(1986). Mornet et al. (1989) found different haplotype associations in
the 2 types of families. A distortion of the segregation ratio was
suggested to explain the high recurrence rate. Estivill et al. (1987)
pointed out that individuals with haplotypes A and C as determined by
their cosmid library, whether homozygous or heterozygous, have a
considerably reduced risk of being carriers as compared to the 1 in 20
average risk in the British population. On the other hand, a homozygote
for haplotype B had a risk of about 1 in 7 of being a carrier. It
appears that about 85% of cases of CF in northern Europeans have 1
particular haplotype and the rest a second haplotype. CF with or without
meconium ileus may be different entities. Baxter et al. (1988) stated
that the meconium ileus form of CF is often lethal so that families with
this form are underrepresented in linkage studies. On the other hand,
couples who seek prenatal diagnosis often have had children with this
problem. Harris et al. (1988) found that 30 of 37 British CF families
were sufficiently informative with 3 RFLP probes to enable prenatal
diagnosis. They also used linkage analysis to exclude CF in 2 cases in
which diagnosis of the disease was equivocal in the sib of an affected
child.

Strain et al. (1988), Krawczak et al. (1988), and Beaudet et al. (1989)
discussed the use of linkage disequilibrium between CF and DNA markers
in genetic risk calculation. Handyside et al. (1992) achieved
preimplantation diagnosis. In vitro fertilization techniques were used
to recover oocytes from each of 3 women and fertilize them with the
husband's sperm. Both members of the 3 couples carried the delF508
mutation. Three days after insemination, embryos in the cleavage stage
underwent biopsy with removal of 1 or 2 cells for DNA amplification and
analysis. In 2 of the women the oocytes produced noncarrier, carrier,
and affected embryos. Both couples chose to have 1 noncarrier embryo and
1 carrier embryo transferred. One woman became pregnant and gave birth
to a girl free of the deletion in both chromosomes. Curnow (1994) used
cystic fibrosis to illustrate how, in genetic counseling, one can
calculate carrier risk for recessive diseases when not all the mutant
alleles are detectable. Dean (1995) reviewed the 5 main methods used for
detecting mutations at the time.

Savov et al. (1995) demonstrated the presence of 2 different mutations
carried by the same CF allele in 4 out of 44 Bulgarian CF patients
during a systematic search of the entire coding sequence of the CFTR
gene. Two of the double mutant alleles include 1 nonsense and 1 missense
mutation, and although the nonsense mutation could be considered to be
the main defect, the amino acid substitutions are candidates for
disease-causing mutations as well. Savov et al. (1995) suggested that
double mutant alleles may be more common than expected and could account
for some of the problems in phenotype-genotype correlations. Stern
(1997) reviewed the diagnosis of cystic fibrosis. He presented a table
of conditions, all readily distinguishable from cystic fibrosis, that
can cause moderately elevated sweat electrolytes. With mutation
analysis, in approximately 1% of cases no abnormal gene can be found and
in about 18% more only 1 abnormal gene will be identified. Stern (1997)
pointed out, however, that even if both genes were abnormal, the patient
could have an ameliorating or neutralizing second mutation elsewhere.
For example, patients homozygous for delF508 (602421.0001) have normal
sweat electrolyte concentrations if a second mutation, R553Q
(602421.0121), is also present.

- Screening

Under the chairmanship of Beaudet and Kazazian (1990), a workshop at the
National Institutes of Health laid down guidelines concerning screening
for the cystic fibrosis gene. The following points were emphasized:
screening should be voluntary, and confidentiality must be assured;
screening requires informed consent; providers of screening services
have an obligation to ensure adequate education and counseling; quality
control in all aspects of testing is required; and there should be equal
access to testing.

Newborn babies with CF have abnormally high levels of immunoreactive
trypsin (IRT) in serum, which has been the basis for a screening test.
Hammond et al. (1991) reported on the results of a Colorado statewide
test of the feasibility and efficacy of measuring immunoreactive
trypsinogen in blood spots to screen for neonatal cystic fibrosis. They
found an incidence of cystic fibrosis of 1 in 3,827 (0.26 per 1,000),
with 3.2 newborns per 1,000 requiring repeat measurements. When adjusted
for race and compliance with testing, the incidence among the white
infants (1 in 2,521) was close to the expected incidence. They concluded
that screening was feasible and could be implemented with acceptable
rates of repeat testing and false positive and false negative results.
Laroche and Travert (1991) found 9 F508 deletion heterozygotes among 149
infants with neonatal transitory mild hypertrypsinemia. Dumur et al.
(1990) found an increased frequency of heterozygosity for the same
mutation in adults with chronic bronchial hypersecretion.

Observing that many patients with cystic fibrosis are malnourished by
the time the diagnosis is made, Farrell et al. (1997) sought to
determine whether newborn screening and early treatment might prevent
the development of nutritional deficiency. A total of 650,341 newborn
infants were screened by measuring immunoreactive trypsinogen on dried
blood spots (from April 1985 through June 1991) or by combining the
trypsinogen test with DNA analysis (from July 1991 through June 1994).
Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis
was diagnosed in 74 infants, including 5 with negative screening tests.
Excluding infants with meconium ileus, Farrell et al. (1997) evaluated
nutritional status for up to 10 years by anthropometric and biochemical
methods in 56 of the infants who received an early diagnosis and in 40
of the infants in whom the diagnosis was made by standard methods (the
control group). Pancreatic insufficiency was managed with nutritional
interventions that included high-calorie diets, pancreatic enzyme
therapy, and fat-soluble vitamin supplements. The diagnosis of cystic
fibrosis was confirmed by a positive sweat test at a younger age in the
early-diagnosis group than in the control group (mean age, 12 vs 72
weeks). At the time of diagnosis, the early-diagnosis group had
significantly higher height and weight percentiles and a higher head
circumference percentile. The early-diagnosis group also had
significantly higher anthropometric indices during the follow-up,
especially the children of pancreatic insufficiency and those who were
homozygous for the delta-F508 mutation. Dankert-Roelse and te Meerman
(1997) raised the question of whether the time had not arrived for
adoption of routine neonatal screening for cystic fibrosis.

Farrell et al. (2001) reported findings of the continuation of their
longitudinal study of children with CF detected by neonatal screening or
standard clinical methods (control). Because sequential analysis of
nutritional outcome measures revealed significantly better growth in
screened patients, the authors accelerated the unblinding of the control
group and identified 9 additional CF patients. After each member of this
cohort had been enrolled for at least 1 year, Farrell et al. (2001)
performed another statistical analysis of anthropometric indices. They
found that severe malnutrition persisted after delayed diagnosis of CF
and questioned whether catch-up growth is possible.

Muller et al. (1998) studied 209 fetuses with hyperechogenic bowel
diagnosed at routine ultrasonography and with no family history of
cystic fibrosis. Seven of the 209 fetuses (3.3%) were subsequently given
the diagnosis of cystic fibrosis. Muller et al. (1998) pointed out that
this incidence is 84 times the estimated risk of cystic fibrosis in the
general population, and concluded that screening for cystic fibrosis
should be offered to families in which fetal hyperechogenic bowel is
diagnosed at routine ultrasonography.

Boyne et al. (2000) demonstrated that of 88 neonates with transient
hypertrypsinemia shown to carry a delta-F508 mutation, 20 (22%) carried
a second CFTR mutation. In 45% of cases, the second mutation was R117H
(602421.0005). Forty-one percent of delta-F508 heterozygous neonates
with greater than 25 ng IRT/ml in the 27th day blood sample possessed a
second mutation, compared to approximately 6% of those with less than 25
ng/ml. Boyne et al. (2000) concluded that the IRT level at 27 days is a
useful marker to refine the risk of finding a second CFTR mutation in
delta-F508 heterozygotes with hypertrypsinemia.

Castellani et al. (2001) studied 47 neonates with hypertrypsinemia and
normal sweat chloride. Thirty-two of the newborns had 1 identified CFTR
mutation. Further analysis by DGGE identified additional mutations in 14
of the 32 babies in whom a mutation had previously been found. In 1
case, 2 more CFTR gene mutations were identified. Mutations were
identified in 8 of the 15 babies in whom a mutation had previously not
been identified. Castellani et al. (2001) pointed out that it is
impossible to predict the clinical outcome of these newborns and
suggested that in some cases these findings might represent CFTR-related
disease even in the presence of normal sweat chloride. They therefore
advocated close clinical follow-up of neonates in this group.

Scotet et al. (2002) evaluated the prenatal detection of CF by
ultrasound in more than 346,000 pregnancies in Brittany, France, where
the incidence of CF is very high. The authors found that the incidence
of CF in fetuses with echogenic bowel was 9.9%, significantly higher
than in the general population. Only severe mutations were identified in
these fetuses. The ultrasound examination enabled diagnosis of 11% of
affected fetuses. Scotet et al. (2002) concluded that CF screening based
on ultrasound examination is effective, particularly in populations
where the disease is frequent.

Dequeker et al. (2009) provided an update on the best practice
guidelines for the molecular genetic diagnosis of cystic fibrosis and
CFTR-related disorders, as established at a 2006 conference in
Manchester, U.K. The report included methods for CFTR mutation testing,
indications for CFTR testing, and guidelines for interpretation.

De Becdelievre et al. (2011) reported on an 18-year experience of
documenting comprehensive CFTR genotypes and correlations with
ultrasound patterns in a series of 694 cases of fetal bowel anomalies. A
total of 30 CF fetuses and 8 cases compatible with CFTR-related
disorders were identified. CFTR rearrangements were found in 5 of the 30
CF fetuses. A second rare mutation indicative of CF was found in 21.2%
of fetuses carrying a frequent mutation. The frequency of CF among
fetuses with no frequent mutation was 0.43%. Correlation with ultrasound
patterns revealed a significant frequency of multiple bowel anomalies in
CF fetuses. The association of at least 2 signs of bowel anomaly on
ultrasound, including hyperechogenic bowel, loop dilatation, and/or
nonvisualization of gallbladder, was observed in 14 of 30 CF fetuses
(46.7%) as compared with 61 of 422 (14.5%) non-CF fetuses (P less than
10(-3)). The rare triad of hyperechogenic bowel, loop dilatation, and
nonvisualization of the gallbladder was of the highest diagnostic value,
with a likelihood ratio of 31.40. Fetuses demonstrating this triad of
bowel anomalies should have extensive CFTR sequencing and a search for
rearrangements, even if no common mutation is detected.

CLINICAL MANAGEMENT

Cleghorn et al. (1986) obtained good results from oral administration of
a balanced solution rendered nonabsorbable by addition of polyethylene
glycol.

Hubbard et al. (1992) reported on the use of human deoxyribonuclease I
produced by recombinant DNA techniques for cleaving DNA in the sputum of
patients with cystic fibrosis and thereby reducing sputum viscosity.
Improvement of lung function was documented.

Rosenfeld et al. (1992) evaluated the direct transfer of the normal CFTR
gene to airway epithelium using a replication-deficient recombinant
adenovirus (Ad) vector containing normal human CFTR cDNA (Ad-CFTR). Two
days after in vivo intratracheal introduction of Ad-CFTR in cotton rats,
in situ analysis demonstrated human CFTR gene expression in lung
epithelium. Northern analysis of lung RNA revealed human CFTR
transcripts for up to 6 weeks. Human CFTR protein was detected in
epithelial cells using anti-human CFTR antibody 11 to 14 days after
infection. While the safety and effectiveness remained to be
demonstrated, these observations suggested the feasibility of in vivo
CFTR gene transfer as therapy for the pulmonary manifestations of CF.

Hyde et al. (1993) illustrated the feasibility of gene therapy for the
pulmonary aspects of CF in humans. They used liposomes to deliver a CFTR
expression plasmid to epithelia of the airway and to alveoli deep in the
lung, leading to the correction of the ion conductance defects found in
the trachea of transgenic (cf/cf) mice. Yang et al. (1993) described a
similar approach to the treatment of hepatobiliary disease of cystic
fibrosis. In situ hybridization and immunocytochemical analysis of rat
liver sections indicated that the endogenous CFTR gene is primarily
expressed in the intrahepatic biliary epithelial cells. To target
recombinant genes specifically to the biliary epithelium in vivo, Yang
et al. (1993) infused recombinant adenoviruses expressing lacZ or human
CFTR into the biliary tract through the common bile duct. Conditions
were established for achieving recombinant gene expression in virtually
all cells of the intrahepatic bile ducts in vivo. Expression persisted
in the smaller bile ducts for the duration of the experiment, which was
21 days.

Crystal et al. (1994) administered a recombinant adenovirus vector
containing the normal human CFTR cDNA to the nasal and bronchial
epithelium of 4 individuals with CF. They found that the vector can
express the CFTR cDNA in the CF respiratory epithelium in vivo. With
doses up to 2 x 10(9) pfu, there was no recombination/complementation or
shedding of the vector or rise of neutralizing antibody titers. At 2 x
10(9) pfu, a transient systemic and pulmonary syndrome was observed. The
syndrome was thought to have been caused by vector-induced inflammation
of the lower respiratory tract and was possibly induced by
interleukin-6, which was found at high levels in the serum of a patient.
Follow-up at 6 to 12 months demonstrated no long-term adverse effects.
Crystal et al. (1994) concluded that correction of the CF phenotype in
the airway epithelium might be achieved with this approach.

A controlled study of adenoviral-vector-mediated gene transfer in the
nasal epithelium of patients with cystic fibrosis by Knowles et al.
(1995) yielded less encouraging results than those predicted by Crystal
et al. (1994). Knowles et al. (1995) did not succeed in correcting the
functional defects in nasal epithelium and local inflammatory responses
limited the dose of adenovirus that could be administered to overcome
the inefficiency of gene transfer. Wilson (1995) reviewed gene therapy
for cystic fibrosis. Transplantation of ex vivo manipulated stem cells
was the concept of gene therapy used in ADA deficiency (102700). Wide
distribution of possible cellular targets for gene therapy in the CF
lung and the absence of a known lung epithelial stem cell suggested that
an ex vivo approach to gene therapy would not be feasible. Therefore
research focused on in vivo approaches for gene transfer that could
conveniently be delivered into the airway via aerosols.

Boucher (1999) reviewed the status of gene therapy for CF lung disease.

Smyth et al. (1994) described colonic strictures, later referred to as
fibrosing colonopathy, in children with cystic fibrosis. The patients
presented with intestinal obstruction and required surgical resection of
a thickened and narrowed area of the colon. The only aspect of these
children's management that had changed was a switch to new 'high
strength' pancreatic enzyme preparations about 12 months previously. It
was not clear whether the preparation was responsible for the problem or
whether this was a part of the pathology of cystic fibrosis. In some
instances, the clinical and radiologic features were suggestive of Crohn
disease or an inflammatory colitis, but the histologic findings were
strikingly different (Smyth, 1996). The stenoses, which are frequently
long segment, result from submucosal thickening by fibrous connective
tissue. This leads to intraluminal narrowing which occurs without a
significant reduction in the external diameter of the colon. The
epithelium is generally intact with very little inflammatory change in
the affected areas. FitzSimmons et al. (1997) studied 29 patients (mean
age, 5.0 years) with fibrosing colonopathy that required colectomy for
colonic strictures and compared the patients with 105 controls (mean age
5.2 years) who were other patients with cystic fibrosis matched for age
at the time of surgery and who did not have fibrosing colonopathy. They
found that the relative risk of fibrosing colonopathy that was
associated with a dose of 24,001 to 50,000 units of lipase per kilogram
per day, as compared with the dose of 0 to 24,000 units per kilogram per
day, was 10.9, and relative risk associated with a dose of more than
50,000 units per kilogram per day was 199.5. The findings were
considered to support the recommendation that the daily dose of
pancreatic enzymes for most patients should remain below 10,000 units of
lipase per kilogram.

In a multicenter, randomized, controlled, crossover trial of prepubertal
children with cystic fibrosis, Hardin et al. (2006) found that treatment
with recombinant human growth hormone (rhGH) improved height and weight,
decreased the number of hospitalizations, and improved quality of life
in 32 children who received the treatment compared to 29 children not
treated. These effects were sustained after rhGH was discontinued.

On January 31, 2012, the FDA approved Kalydeco, formerly VX-770
(ivacaftor), for use in cystic fibrosis patients with the G551D mutation
(602421.0013), as reported by Ledford (2012).

POPULATION GENETICS

Attempting total ascertainment of cases in white children born alive in
Ohio during the years 1950 through 1953, Steinberg and Brown (1960)
estimated the phenotype frequency to be about 1 in 3,700, a value only
about one-fourth that of some earlier estimates. Cystic fibrosis even at
this lower estimate is the most frequent lethal genetic disease of
childhood. The gene frequency was estimated to be about 0.016, and about
3% of white persons are heterozygotes.

Klinger (1983) found an incidence of 1 in 569 among 10,816 live births
in the Old Order Amish of Holmes County, Ohio. The gene frequency was
estimated to be at least 0.042. On the other hand, not a single case was
found among 4,448 live births in the Geauga County, Ohio, Amish. In
Connecticut, Honeyman and Siker (1965) arrived at higher phenotype
frequency estimates of 1 in 489 (maximal) and 1 in 1,863 (minimal).

Bois et al. (1978) reported a frequency of at least 1 in 377 births in
an area of Brittany, France. Scotet et al. (2002) retrospectively
registered all 520 CF patients born in Brittany since 1960. The
birthplace of the patients, the spectrum of CFTR mutations, and the
spatial distribution of the mutations across Brittany were determined.
The incidence of CF was 1 in 2,630, with a west/east gradient that was
confirmed over time (1 in 2,071 in the west, 1 in 3,286 in the east). At
the time of study, the incidence of CF was decreasing, mainly as a
result of prenatal diagnosis. A mutation detection rate of 99.7% was
obtained. Western Brittany presented a specific spectrum of mutations,
whereas the eastern region showed a spectrum more similar to the overall
picture in France.

In Italy, to estimate the incidence of CF, Romeo et al. (1985) used the
increase in first- and second-cousin parentage, as compared with the
general level of consanguinity indicated by the archive of
consanguineous marriages maintained by the Catholic Church. The
incidence was estimated to be about 1/2000. The data were consistent
with a single gene locus; consanguinity would have been higher if more
than one were present. The segregation ratio in 624 CF sibships was
0.252.

In Hutterite families with cystic fibrosis, Ober et al. (1987) found
close linkage to chromosome 7 markers as in non-Hutterite families.
Because 3 different chromosome 7 haplotypes carried the CF mutation in
these families, they suggested that the CF gene may have been introduced
into the Hutterite population by as many as 3 different ancestors.
Fujiwara et al. (1989) confirmed these observations.

From studies in Caucasian families in Utah, Jorde and Lathrop (1988)
concluded that fertility differences are unlikely to account for the
observed Caucasian CF gene frequency. They compared 143 grandparent
couples of Utah CF cases with 20 replicate sets of matched control
couples drawn from the Utah Genealogical Database. Before ascertainment
correction was applied, CF carriers appeared to manifest a significant
fertility advantage over controls. After the correction formula (not
used in previous studies) was applied, this difference disappeared.
Also, no differences were found between carriers and controls in the
length of intervals between births.

In the Hutterites, Klinger et al. (1990) demonstrated that 1 of the 3
previously identified CF haplotypes carries the phe508 deletion. The
other 2 Hutterite CF haplotypes are generally rare in Caucasian
populations and must carry different CF mutations. Thus, there must have
been at least 3 original carriers of CF mutations among the founders of
the Hutterite population. They found 1 Hutterite CF patient who had both
of the haplotypes that do not carry the phe508 deletion.

From a study in Northern Ireland, Hill et al. (1989) concluded that the
CF locus is in strong linkage disequilibrium with KM19 and Xv-2C, as it
is in other Caucasian populations. These findings indicate that CF in
northern European populations may have resulted from a single ancestral
mutation. A further finding was preferential inheritance of the paternal
CF allele (22 of 28) as opposed to the maternal CF allele (6 of 28) with
no significant difference in the sex of the children inheriting these
alleles. Cutting et al. (1989) concluded from the analysis of closely
linked DNA marker haplotypes that the majority of CF mutations in the
Caucasian population arose from a single mutational event. Similar
analysis in American black families suggested that multiple mutant
alleles are found in this population.

Although CF had been thought to be very rare in Arabs, Nazer et al.
(1989) documented CF in 13 children in Saudi Arabia. El-Harith et al.
(1998) reported that 6 mutations, detectable by PCR with subsequent
restriction enzyme digestion, would allow detection of 70% of Saudi CFTR
mutations.

Estivill et al. (1989) reported that in Spanish and Italian populations,
deletion of phe508 is present in only 46.2% of CF chromosomes. In all
cases, it occurred with haplotype 2, which accounts for about 75% of
southern European CF chromosomes; thus, at least 2 independent mutations
must have occurred on this haplotype. McIntosh et al. (1989) found a
frequency of 74.4% for the phe508 deletion in Scotland. Colten (1990)
indicated that one-third of the more than 15,000 patients listed in the
registry of the North American National Cystic Fibrosis Foundation are
older than 21 years.

Using PCR and hybridization with allele-specific oligonucleotides, Lemna
et al. (1990) found the phe508 deletion in 75.8% of 439 cystic fibrosis
chromosomes. The 3-base deletion was found in only 30.3% of cystic
fibrosis chromosomes from Ashkenazi families. In 5 southern European
populations (Albanian, Greek, Italian, Spanish, and Yugoslavian), Nunes
et al. (1991) found that, apart from delF508, the most frequent
mutations were G542X (602421.0009), 6.04%; R1162X (602421.0033), 3.61%;
and N1303K (602421.0032), 3.24%. Of the 14 mutations tested, 7 others
had frequencies of less than 1% and 4 mutations were not found at all.

Ten Kate et al. (1991) demonstrated that consanguinity, even if present,
may be irrelevant: a family with 2 brothers with cystic fibrosis whose
parents were consanguineous, being members of an isolated religious
group, were found to have inherited different mutations from the
parents. They presented a diagram relating the likelihood of
'autozygosity,' depending on gene frequency with consanguinity of
various degrees.

In a systematic study of 365 CF chromosomes in the Celtic population in
Brittany, Ferec et al. (1992) identified more than 98% of the cystic
fibrosis gene mutations. By use of the denaturing gradient gel
electrophoresis (DGGE) method, they detected 19 different CFTR mutations
located in 9 exons. Nine new mutations were found.

Kerem et al. (1995) reported that the incidence of CF and the frequency
of disease-causing mutations varies considerably among the Jewish ethnic
subgroups in Israel. Among Ashkenazi Jews, the frequency of CF is
1:3300, which is similar to the frequency in most Caucasian populations.
Among non-Ashkenazi Jews, the disease occurs at a similar frequency
among Jews from Libya (1:2700), Georgia (1:2700), Greece and Bulgaria
(1:2400), but is rare in Jews from Yemen (1:8800), Morocco, (1:15000),
Iraq (1:32000), and Iran (1:39000). To that point, only 12 mutations had
been identified in Israeli Jews, and this enabled the identification of
91% of the CF chromosomes in the entire Jewish CF population. However,
in each Jewish ethnic group, the disease is caused by a different
repertoire of mutations.

In a study in the Netherlands, de Vries et al. (1997) tested for the
carrier frequency of the delta-F508 mutation by analyzing mouthwashes
and matched blood samples from 11,654 blood donors from all over the
country. They detected a delF508 carrier frequency of 1 in 42 (95% CI
1/37-1/47). By assuming that the relative frequency of the delF508
mutation among carriers and patients is comparable in the Netherlands,
they estimated the overall CF carrier frequency as 1 in 32,
significantly less than 1 in 25, the usual figure cited. An increase in
carrier frequency with increasing distance from the northeastern region
of the country was observed, thus confirming that there is a gradient in
gene frequency with low frequencies in the northeastern part of the
country and high frequencies in the southern part.

Brock et al. (1998) studied a total of 27,161 women enrolled in prenatal
clinics in Scotland between 1990 and 1997. All 27,161 were screened for
the delta-F508 (602421.0001), G551D (602421.0013), and G542X
(602421.0009) mutations. In 14,360 women R117H was also measured. In
addition, 183 patients with cystic fibrosis were studied for the
presence of these mutations. Based on their data, the authors estimated
that the incidence of CF in the Scottish population is 1 in 1984, with
95% confidence intervals between 1 in 1,692 to 1 in 2,336.

Macek et al. (1997) reported a large-scale study for mutation
identification in African American CF patients. The entire coding and
flanking intronic sequence of the CFTR gene was analyzed by denaturing
gradient-gel electrophoresis (DGGE) and sequencing in 82 African
American CF chromosomes. One novel mutation, 3120+1G-A (602421.0120),
occurred with a frequency of 12.3% and was also detected in a native
African patient. To establish gene frequencies, an additional group of
66 African American CF chromosomes were screened for mutations
identified in 2 or more African American patients. Screening for 16
'common Caucasian' mutations identified 52% of CF alleles in African
Americans, while screening for 8 'common African' mutations accounted
for an additional 23%. The combined detection rate of 75% was comparable
to the sensitivity of mutation analysis in Caucasian CF patients. These
results indicated that African Americans have their own set of 'common'
CF mutations that originated from the native African population.

To examine whether the 3120+1G-A mutation has a common origin in the
diverse populations in which it has been observed or whether its
widespread distribution is the result of recurrent mutational events,
Dork et al. (1998) analyzed DNA samples obtained from 17 unrelated CF
patients in 4 different populations and from 8 unrelated African CF
carriers. They found identical extended CFTR haplotypes for the
3120+1G-A alleles in Arab, African, and African American patients,
strongly suggesting that the mutation had a common origin. This finding
was not surprising in the case of Africans and African Americans; it was
not as easy to explain the presence of the 3120+1G-A mutation in African
and Saudi Arab patients. Recent ethnic admixture accounts for a few
percent of Africans in Saudi Arabia; however, this was considered an
unlikely explanation of the finding, since none of the Saudi families
with the mutation had any anthropomorphologic signs of an African
descent. In the past, a continuous gene flow between Arab and African
populations probably persisted for many centuries, in association with
trading and with the spread of the Islamic religion. Thus far, the
Greeks are the only Caucasian population in which the 3120+1G-A mutation
has been identified. A recurrent mutational event seems to be unlikely,
because the Greek haplotype differs from the others in only minor
respects. Historical contacts, e.g., under Alexander the Great or during
the ancient Minoan civilization, may provide an explanation for the
common ancestry of the disease mutation in these ethnically diverse
populations. Dork et al. (1998) concluded that 3120+1G-A is an ancient
mutation that may be more common than previously thought in populations
of the tropical and subtropical belt, where CF probably is an
underdiagnosed disorder.

Padoa et al. (1999) screened 1,152 unrelated, healthy African blacks
from southern, western, and central Africa, and 9 black CF patients for
the 3120+1G-A mutation. The mutation was found to have a carrier
frequency of 1 in 91 for South African blacks, with a 95% confidence
interval of 1 in 46 to 1 in 197. A subset of those studied were also
screened for the A559T, S1255X, and 444delA mutations. These mutations
were not found in any of the patients or in over 373 healthy subjects
tested. Padoa et al. (1999) concluded that the corrected CF carrier
frequency in South African blacks would be between 1 in 14 and 1 in 59
and, hence, that the incidence of CF would be predicted to be between 1
in 784 and 1 in 13,924 in this population. Padoa et al. (1999)
speculated as to why the observed incidence in this population is lower
than that which they predicted.

Restrepo et al. (2000) used a reverse dot-blot detection kit to examine
the frequency of 16 CFTR mutations among 192 cystic fibrosis alleles in
Mexico, Colombia, and Venezuela. The detection efficacy of the panel
used was 47.9% in this population. The most prevalent CF allele was
delF508 (39.6%). The most common alleles among the others were G542X,
N1303K and 3849+10kbC-T (602421.0062). The authors compared their
results to population studies from Spain and concluded that an important
Spanish contribution is present in CFTR mutations in these 3 countries,
but that important regional differences in allele prevalence exist.

Kabra et al. (2000) analyzed CFTR mutations in 24 children with CF from
the Indian subcontinent. Of the mutant chromosomes, 33.3% had the
delF508 mutation. The authors screened 16 exons of the CFTR gene by SSCP
and heteroduplex analysis, but mutations were not identified in 46% of
chromosomes. The authors also reported novel mutations in their
population: 3622insT (602421.0125) and 3601-20T-C (602421.0126).

Wang et al. (2000) found that 7 of 29 Hispanic patients with CF were
heterozygous for a single-basepair deletion at nucleotide 3876 resulting
in a frameshift and termination at residue 1258 of the CFTR gene
(602421.0127). This mutation therefore accounted for 10.3% of mutant
alleles in this group. The patients with this mutation had a severe
phenotype as determined by age of diagnosis, high sweat chloride,
presence of allergic bronchopulmonary aspergillosis, pancreatic
insufficiency, liver disease, cor pulmonale, and early death. Wang et
al. (2000) also noted that this mutation had not been reported in any
other ethnic group.

Considering that the haplotype background of the mutations that most
often cause cystic fibrosis in Europe is different from that of non-CF
chromosomes, Mateu et al. (2002) reasoned that these haplotype
backgrounds might be found at high frequencies in populations in which
CF was currently not common; thus, such populations would be candidates
for the place of origin of CF mutations. In a worldwide survey of normal
chromosomes, they found a very low frequency or absence of the most
common CF haplotypes in all populations analyzed, and a strong genetic
variability and divergence, among various populations, of the
chromosomes that carry disease-causing mutations. They suggested that
the depth of the gene genealogy associated with disease-causing
mutations may be greater than that of the evolutionary process that gave
rise to the current human populations. The concept of 'population of
origin' lacks either spatial or temporal meaning for mutations that are
likely to have been present in Europeans before the ethnogenesis of the
current populations. Subsequent population processes may have erased the
traces of their geographic origin.

In Brittany, France, Scotet et al. (2003) reviewed the results of a
neonatal screening program for CF begun in 1989 to determine the
prevalence of CF at birth and to review data from prenatal diagnoses
carried out in the region, first in families related to a CF child and
also those made following the detection of an echogenic bowel upon
routine ultrasound examination performed during pregnancy. The
prevalence of CF at birth was estimated to be 1 in 2,838 in the region
from 1992 to 2001. By including the 54 CF-affected pregnancies that were
terminated during those 10 years, the corrected birth prevalence of CF
was 1 in 1,972. Prenatal diagnosis was therefore responsible for a
decrease in CF prevalence at birth of 30.5%.

Quint et al. (2005) described the mutation spectrum in Jewish CF
patients living in Israel. Using a panel of 12 CFTR mutations, they
identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews
of North African origin, and 75% in Jewish patients from Iraq.

In a survey of 495 blood samples of randomly selected healthy
individuals in Hanoi, Vietnam, Nam et al. (2005) found no instance of
the delta-F508 mutation.

Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States,
Chong et al. (2012) found 32 heterozygotes and no homozygotes for the
phe508del mutation in the CFTR gene (dbSNP rs113993960; 602421.0001),
for a frequency of 0.022, or 1 in 45.5. This frequency is lower than
that for the general population for this mutation, which is 1 in 30.
They identified the met1101-to-lys mutation (602421.0137) in 108
heterozygotes and 6 homozygotes among 1,473 screened, for a carrier
frequency of 0.073 (1 in 13.5).

Among 23,369 ethnically diverse individuals screened for cystic fibrosis
carrier status, Lazarin et al. (2013) identified 842 carriers (3.6%),
for an estimated carrier frequency of approximately 1 in 28.
Twenty-seven 'carrier couples' were identified. Nine individuals were
identified as homozygotes or compound heterozygotes. Among 12,870
individuals of northwestern European origin, the carrier frequency was 1
in 23. A carrier frequency of 1 in 40 was found among 1,122 south Asians
screened, supporting reports that cystic fibrosis is underreported in
this population.

EVOLUTION

Hansson (1988) speculated that if the defect in the control of apical
membrane chloride ion channels in CF extends to the intestine, a
resistance to bacterial toxin-mediated diarrhea might confer a selective
advantage on carriers for the CF gene. Baxter et al. (1988) presented
actual observations indicating that intestine in CF homozygotes fails to
exhibit a secretory response on exposure to bacterial toxins that would
normally induce a secretory diarrhea. They were proceeding to
investigate intestinal secretory responses of heterozygotes. The high
frequency of the CF gene might be explained by this mechanism. Romeo et
al. (1989) also suggested that a selective advantage consisting of high
resistance to chloride-ion-secreting diarrheas might have favored, in
the past, survival of infants heterozygous for the CF gene.

McMillan et al. (1989) demonstrated an apparent association between
heterozygosity at the cystic fibrosis locus and heterozygosity for a
RFLP near the constant region of the T-cell receptor beta chain
(186930). They suggested that this previously unreported disease
association might indicate some form of epistatic interaction between
the CF gene and the TCRB gene such that the double heterozygote is
immunologically advantaged.

Rodman and Zamudio (1991) suggested that resistance to cholera may have
been the environmental factor that selected CF heterozygotes over their
'normal' homozygote cohort. This suggestion obtained experimental
support from the observations of Gabriel et al. (1994). In a study of
the CFTR -/- mouse, created by disruption by the CFTR gene at exon 10 by
insertion of an in-frame stop codon to replace ser489, they found that
transgenic mice that expressed no CFTR protein did not secrete fluid in
response to cholera toxin. Heterozygotes expressed 50% of the normal
amount of CFTR protein in the intestinal epithelium and secreted 50% of
the normal fluid and chloride ion in response to cholera toxin. The
findings suggested that CF heterozygotes may possess a selective
advantage of resistance to cholera.

Pier et al. (1998) investigated whether increased resistance to typhoid
fever in the heterozygote could be a factor in maintaining mutant CFTR
alleles at high levels in selected populations. Typhoid fever is
initiated when Salmonella typhi enters gastrointestinal epithelial cells
for submucosal translocation. They found that S. typhi, but not the
related murine pathogen S. typhimurium, uses CFTR for entry into
epithelial cells. Cells expressing wildtype CFTR internalized more S.
typhi than isogenic cells expressing the most common CFTR mutation,
delF508 (602421.0001). Monoclonal antibodies and synthetic peptides
containing a sequence corresponding to the first predicted extracellular
domain of CFTR inhibited uptake of S. typhi. Heterozygous delF508 Cftr
mice translocated 86% fewer S. typhi into the gastrointestinal submucosa
than did wildtype Cftr mice; no translocation occurred in delF508 Cftr
homozygous mice. The Cftr genotype had no effect on the translocation of
S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound
S. typhi in the submucosa of Cftr wildtype mice than in delF508
heterozygous mice. Pier et al. (1998) concluded that diminished levels
of CFTR in heterozygotes decreases susceptibility to typhoid fever.

Van de Vosse et al. (2005) tested the hypothesis that CFTR heterozygotes
have a selective advantage against typhoid, which may be conferred
through reduced attachment of S. typhi to the intestinal mucosa. They
genotyped patients and controls in a typhoid endemic area in Indonesia
for 2 highly polymorphic markers in CFTR and the most common CF
mutation, F508del. Consistent with the apparently very low incidence of
CF in Indonesia, the F508del mutation was not present in any patients or
controls. However, they found significant association between a common
polymorphism in intron 8 (16 or 17 CA repeats) and selective advantage
against typhoid.

Hogenauer et al. (2000) used an intestinal perfusion technique to
measure in vivo basal and prostaglandin-stimulated jejunal chloride
secretion in normal subjects, CF heterozygotes, and patients with CF.
Patients with CF had essentially no active chloride secretion in the
basal state, and secretion was not stimulated by a prostaglandin analog.
However, CF heterozygotes secreted chloride at the same rate as did
people without a CF mutation. If heterozygotes are assumed to have less
than normal intestinal CFTR function, these results mean that CFTR
expression is not rate limiting for active chloride secretion in
heterozygotes. The results did not support the theory that the very high
frequency of CF mutations is due to a survival advantage that is
conferred on heterozygotes who contract diarrheal diseases mediated by
intestinal hypersecretion of chloride, such as infection with Vibrio
cholerae or E. coli.

GENOTYPE/PHENOTYPE CORRELATIONS

Wine (1992) pointed out that CFTR mutations associated with pancreatic
sufficiency, milder pulmonary disease, and improved sweat gland function
are associated with residual CFTR chloride-ion channel function. He
questioned the disruptive effects proposed for the delF508 mutation
because variation in homozygotes for this mutation is very large. At the
same time, those homozygous for stop codons have been severely affected,
showing pancreatic insufficiency and pulmonary function values (FEV1) in
the same range as those of delF508 subjects. Disruptive effects of
delF508 would be expected to give rise to a dominant pattern of
inheritance. Wine (1992) concluded that the observations are consistent
with the recessive nature of CF and with the likelihood that gene or
protein replacement therapy for CF will be effective on their own,
without requiring concomitant silencing of the delF508 gene. Sheppard et
al. (1993) found that some CFTR mutations, such as delF508, which
disrupt normal processing and hence are missing from the apical
membrane, generate no chloride current and are associated with severe
disease. Other mutants, such as R117H (602421.0005), R334W
(602421.0034), and R347P (602421.0006), which are correctly processed
and retain significant apical chloride channel function, are associated
with a milder form of the disease. Thus, the CF genotype determines the
biochemical abnormality, which determines the clinical phenotype.
Because these 3 'mild' mutants have normal regulation, interventions
designed to increase the activity of mutant CFTR may have therapeutic
efficacy in patients with these mutations. Studying 267 children and
adolescents with CF who were regularly seen at the same center, Kubesch
et al. (1993) found that the age-specific colonization rates with
Pseudomonas aeruginosa were significantly lower in pancreatic sufficient
than in pancreatic insufficient patients. The missense and splice site
mutations that were 'mild' CF alleles with respect to exocrine
pancreatic function were also 'low risk' alleles for the acquisition of
P. aeruginosa. On the other hand, the proportion of P.
aeruginosa-positive patients increased most rapidly in the pancreatic
insufficient delF508 compound heterozygotes who were carrying a
termination mutation in the nucleotide binding fold-encoding exons.

Kulczycki et al. (2003) stated that their oldest patient was a
71-year-old white male who was diagnosed with CF at the age of 27 years
because of recurrent nasal polyposis, elevated sweat sodium and
chloride, and a history of CF in his 20-year-old sister. The man was
married but childless, and practiced as an attorney. Urologic
examination revealed CBAVD. Nutritional and pulmonary status were almost
normal. At the age of 60 years, genetic testing indicated 2 mutations in
the CFTR gene: his1282 to ter (H1282X; 602421.0129), which is associated
with severe CF, and ala445 to glu (A445E; 602421.0130), which is
associated with mild CF.

ANIMAL MODEL

Because the pulmonary complications of CF are the most morbid aspects of
the disease, a potential therapeutic strategy is to reconstitute
expression of the normal CFTR gene in airway epithelia by somatic gene
transfer. Engelhardt et al. (1992) developed an animal model of the
human airway, using bronchial xenografts engrafted on rat tracheas and
implanted into nude mice, and tested the efficiency of in vivo
retroviral gene transfer. They found that in undifferentiated
regenerating epithelium, 5 to 10% retroviral gene transfer was obtained,
whereas in fully differentiated epithelium, no gene transfer was noted.
These findings suggested that retroviral-mediated gene transfer to the
airways in vivo may be feasible if the proper regenerative state can be
induced.

Several groups succeeded in constructing a transgenic mouse model of
cystic fibrosis (Clarke et al., 1992; Colledge et al., 1992; Dorin et
al., 1992; Snouwaert et al., 1992). Unlike the HPRT-deficient mouse,
constructed as a model for the Lesch-Nyhan syndrome (308000), the
CFTR-deficient homozygote showed measurable defects in ion permeability
of airway and intestinal epithelia, similar to those demonstrable in
human CF tissues. Furthermore, most of the deficient mice had intestinal
pathology similar to that of meconium ileus. Also, there appeared to be
no prenatal loss from litters produced from crosses between
heterozygotes. Most of the mice, however, died soon after birth as a
consequence of intestinal blockage. Unlike the human male, the
homozygous mouse male in at least one instance was fertile. In a
transgenic mouse model of CF created by Dorin et al. (1994) through
insertion in exon 10, only a low incidence of meconium ileus was
observed. In contrast to the very high level of fatal intestinal
obstruction in 3 other CF mouse models, they showed that the partial
duplication consequent upon insertional gene targeting allowed exon
skipping and aberrant splicing to produce normal Cftr mRNA, but at
levels greatly reduced compared with wildtype mice. Instead of the
predicted mutant Cftr transcript, a novel mRNA was produced that
utilized cryptic splice sites in the disrupting plasmid sequence.
Although residual wildtype mRNA in the exon 10 insertional mutant mouse
seems to ameliorate the severity of the intestinal phenotype observed in
the absolute 'null' CF mice, the presence of low-level residual wildtype
Cftr mRNA does not correct the CF ion transport defect. The long-term
survival of this insertional mutant mouse provides the opportunity to
address factors important in the development of lung disease. To correct
the lethal intestinal abnormalities that occur in the transgenic
CFTR-null mouse, Zhou et al. (1994) used the human CFTR gene under the
control of the rat intestinal fatty acid binding protein (134640) gene
promoter. The mice survived and showed functional correction of ileal
goblet cell and crypt cell hyperplasia and cAMP-stimulated chloride
secretion. The results supported the concept that transfer of the human
CFTR gene may be a useful strategy for correcting physiologic defects in
patients with CF.

Mice homozygous for disruption of the Cftr gene, unlike the human
disease, fail to show any gross lung pathology (Rozmahel et al. (1996)).
It was proposed that a calcium-activated Cl(-) conductance could
compensate for the lack of the Cftr-encoded Cl(-) channel function in
these mice. The absence of this alternative chloride transport mechanism
in the intestinal epithelial cells was believed to be responsible for
the severe intestinal pathology observed in the same mice. Prolonged
survival in these mice was demonstrated among backcross and intercross
progeny with different inbred strains, suggesting that modulation of
disease severity was genetically determined. A genome scan showed that
the major modifier locus mapped near the centromere of mouse chromosome
7 in a region of conserved synteny with human chromosome 19q13.
Candidate genes in that region include the gamma-subunit of protein
kinase C (176980), the alpha-3 subunit of the type 1 Na(+)/K(+)
exchanging ATPase (182350), and the sodium channel, type 1,
beta-polypeptide (600235).

In connection with the design of a large-animal model for cystic
fibrosis, Tebbutt et al. (1995) cloned and sequenced the CFTR cDNA of
sheep. It showed a high degree of conservation at the DNA coding and
predicted polypeptide levels with human CFTR; at the nucleotide level,
there was a 90% conservation (compared with 80% between human and
mouse). At the polypeptide level, the degree of similarity was 95%
(compared with 88% between human and mouse). Northern blot analysis and
reverse transcription-PCR showed that the patterns of expression of the
ovine CFTR gene are very similar to those seen in humans. Further, the
developmental expression of CFTR in the sheep is equivalent to that
observed in humans.

Harris (1997) pointed out that the generation of cloned sheep (Campbell
et al., 1996; Wilmut et al., 1997) establishes the practicality of
creating an ovine model of CF. The failure of mice with disruption of
the Cftr gene to reproduce the pulmonary and pancreatic features of CF
may be due, in the case of the lung at least, in part to considerable
differences in submucosal gland distribution in mouse and human. Mice
have very few of these glands and they are restricted to the tracheal
submucosa. The CFTR chloride ion channel is not expressed at high levels
in the mouse pancreas, in contrast to humans where the pancreas is the
site of most abundant CFTR expression. Sheep and human CFTR show greater
identity and similarity than do human and mouse. Furthermore, Harris
(1997) noted that the tissue-specific pattern of expression of the ovine
CFTR gene and the developmental expression of CFTR in the sheep are very
similar to that in humans. CF pathology commences in utero; for example,
obstruction of CF pancreatic ducts by deposits of secreted material
commences in the midtrimester of human gestation and by term the
pancreas is structurally and functionally destroyed. Thus, in utero
therapy might be necessary.

Kent et al. (1997) described the phenotype of an inbred congenic strain
of CFTR-knockout mouse that developed spontaneous and progressive lung
disease of early onset. The major features of the lung disease included
failure of effective mucociliary transport, postbronchiolar
overinflation of alveoli, and parenchymal interstitial thickening, with
evidence of fibrosis and inflammatory cell recruitment. Kent et al.
(1997) speculated that the basis for development of lung disease in the
congenic CFTR-knockout mice is their observed lack of a non-CFTR
chloride channel normally found in CFTR-knockout mice of mixed genetic
background.

Using an intact human CFTR gene, Manson et al. (1997) generated
transgenic mice carrying a 320-kb YAC. Mice that only expressed the
human transgene were obtained by breeding with Cambridge-null CF mice.
One line had approximately 2 copies of the intact YAC. Mice carrying
this transgene and expressing no CFTR appeared normal and bred well, in
marked contrast to the null mice, where 50% died by approximately 5 days
of age. The chloride secretory responses in mice carrying the transgene
were as large as or larger than those in the wildtype tissues.
Expression of the transgene was highly cell-type specific and matched
that of the endogenous mouse gene in the crypt epithelia throughout the
gut and in salivary gland tissue. However, there was no transgene
expression in some tissues, such as the Brunner glands, where it would
be expected. Where there were differences between the mouse and human
pattern of expression, the transgene followed the mouse pattern.

Coleman et al. (2003) found that under proper conditions, transgenic CF
mice are hypersusceptible to P. aeruginosa colonization and infection
and can be used for evaluation of lung pathophysiology, bacterial
virulence, and development of therapies for CF lung disease.

The delta-F508 CFTR mutation results in the production of a misfolded
CFTR protein that is retained in the endoplasmic reticulum and targeted
for degradation. Curcumin, a major component of the curry spice
turmeric, is a nontoxic calcium-adenosine triphosphatase pump inhibitor
that can be administered to humans safely. Oral administration of
curcumin to homozygous delta-F508 Cftr mice in doses comparable, on a
weight-per-weight basis, to those well tolerated by humans corrected
these animals' characteristic nasal potential difference defect. These
effects were not observed in mice homozygous for a complete knockout of
the CFTR gene. Curcumin also induced the functional appearance of
delta-F508 CFTR protein in the plasma membranes of transfected baby
hamster kidney cells. Thus, Egan et al. (2004) concluded that curcumin
treatment may be able to correct defects associated with the homozygous
expression of the delta-F508 CFTR gene, as it allows for dissociation
from ER chaperone proteins and transfer to the cell membrane.

To test the hypothesis that accelerated sodium transport can produce
cystic fibrosis-like lung disease, Mall et al. (2004) generated mice
with airway-specific overexpression of epithelial sodium channels. Mall
et al. (2004) used the airway-specific Clara cell secretory protein
promoter to target expression of individual SCNN1 subunit (see 600760)
transgenes to lower airway epithelia. They demonstrated that increased
airway sodium absorption in vivo caused airway surface liquid volume
depletion, increased mucus concentration, delayed mucus transport, and
mucus adhesion to airway surfaces. Defective mucus transport caused a
severe spontaneous lung disease sharing features with cystic fibrosis,
including mucus obstruction, goblet cell metaplasia, neutrophilic
inflammation, and poor bacterial clearance. Mall et al. (2004) concluded
that increasing airway sodium absorption initiates cystic fibrosis-like
lung disease and produces a model for the study of the pathogenesis and
therapy of this disease.

Harmon et al. (2010) found that colonic epithelial cells and whole lung
tissue from Cftr-null mice show a defect in peroxisome
proliferator-activated receptor-gamma (PPAR-gamma; 601487) function that
contributes to a pathologic program of gene expression. Lipidomic
analysis of colonic epithelial cells suggested that this defect results
in part from reduced amounts of the endogenous PPAR-gamma ligand
15-keto-prostaglandin E2. Treatment of Cftr-deficient mice with the
synthetic PPAR-gamma ligand rosiglitazone partially normalized the
altered gene expression pattern associated with Cftr deficiency and
reduced disease severity. Rosiglitazone has no effect on chloride
secretion in the colon, but it increases expression of the genes
encoding carbonic anhydrase IV (CA4; 114750) and carbonic anhydrase II
(CA2; 611492), increases bicarbonate secretion, and reduces mucous
retention. Harmon et al. (2010) concluded that their studies revealed a
reversible defect in PPAR-gamma signaling in Cftr-deficient cells that
can be pharmacologically corrected to ameliorate the severity of the
cystic fibrosis phenotype in mice.

Rogers et al. (2008) generated pigs with a targeted disruption of both
CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride
transport and developed meconium ileus, exocrine pancreatic destruction,
and focal biliary cirrhosis, replicating abnormalities seen in newborn
humans with CF. The lungs of newborn CFTR-null piglets appeared normal.

Chen et al. (2010) reviewed features of the pig model of CF, which
closely resembles the human disease. At birth, Cftr -/- pigs manifest
pancreatic destruction, meconium ileus, early focal biliary cirrhosis,
and microgallbladder. Within hours of birth, Cftr -/- pigs show reduced
ability to eliminate bacteria from the lungs, but no inflammation. The
inability to eliminate bacteria results in spontaneous lung disease
within a few months of birth, including inflammation, infection, mucous
accumulation, tissue remodeling, and airway obstruction. Chen et al.
(2010) studied ion transport in newborn Cftr -/- pig nasal and
tracheal/bronchial epithelia in tissues and cultures and in vivo, prior
to the onset of airway inflammation. Cftr -/- epithelia showed markedly
reduced Cl- and HCO3- transport, but there was no increase in
transepithelial Na+ or liquid absorption or reduction in periciliary
liquid depth. Like human CF, Cftr -/- pigs showed increased
amiloride-sensitive voltage and current, but this was due to lack of Cl-
conductance rather than increased Na+ transport.

HISTORY

Atresia of the ileum was reported by Blanck et al. (1965) in 2 brothers
with cystic fibrosis; 2 other sibs had cystic fibrosis without
intestinal atresia.

Spock et al. (1967) observed that patients have a factor in serum that
inhibits the action of cilia in explants of rabbit tracheal mucosa.
Serum from heterozygotes contained an amount of the factor intermediate
between none (the normal situation) and the level in patients.

Smith et al. (1968) found cystic fibrosis in a child with cri-du-chat
syndrome (123450). Only the mother was heterozygous by Spock test. They
suggested that loss of part of the short arm of the chromosome 5 derived
from the father had occurred and that the deleted portion carried the
cystic fibrosis locus. Danes and Bearn (1968) found vesicular
metachromasia in the fibroblasts of both parents suggesting that the
reported experience cannot be taken as evidence of localization of the
CF gene on the short arm of chromosome 5.

Edwards et al. (1984) reported a family in which deficiency at the tip
of 13q was associated with cystic fibrosis. Weak evidence supporting
assignment to 13q was provided by a boy with both cystic fibrosis and
hemophilia A; no translocation was visualized but the authors postulated
a telomeric translocation that disrupted both loci at the tip of the X
chromosome and chromosome 13. They cited 2 other observations of cystic
fibrosis with chromosome 13 abnormality.

Williamson (1984) excluded cystic fibrosis from chromosome 13; none of
the DNA probes that were monosomic in the case of Edwards et al. (1984)
were linked to cystic fibrosis in studies of affected sibs.

In skin fibroblasts from both homozygotes and heterozygotes, Danes and
Bearn (1968) found cytoplasmic intravesicular metachromasia of a type
readily distinguished from that of mucopolysaccharidoses. Danes and
Bearn (1969) described a morphologic change in the fibroblasts and
furthermore suggested that homozygosity at either of two different loci
can produce cystic fibrosis. In type I, the fibroblasts show discrete
metachromatic cytoplasmic vesicles and normal mucopolysaccharide
content. In type II, fibroblast metachromasia is present in both
vesicles and granules and is evenly distributed through the cytoplasm;
mucopolysaccharide content of the cells is markedly increased. On the
basis of cell culture phenotype, Danes et al. (1978) identified 3
classes of cystic fibrosis and concluded that there is a prognostic
difference between classes. They also suggested that their Class III
represents the genetic compound. A deficiency of arginine esterase has
been suggested by Rao and Nadler (1974), who reported absence of 1 of 3
isozymes in various cases of cystic fibrosis. Their hypothesis is that
the ciliary factor and related substances are present because of failure
of degradation when the enzyme is deficient. Stern et al. (1978)
described a cystic fibrosis variant with little pancreatic abnormality.
Hosli and Vogt (1979) claimed the successful discrimination of cystic
fibrosis patients, obligatory heterozygotes (parents), and normal
controls by heat inactivation of acid phosphatase and alpha-mannosidase
in plasma. In this test, normals retain 80 to 100% activity,
heterozygotes 40 to 60%, and CF patients almost none. There was no
overlap between groups. Katznelson et al. (1983) did a stringently
blinded trial of the reliability of the test of Hosli and Vogt (1979),
submitting doubly coded samples to Dr. Hosli. The genotype was correctly
identified in each of 45 cases. Shapiro and Lam (1982) found that the
usual increase in intracellular calcium in fibroblasts with successive
time (passages) in culture is exaggerated in cystic fibrosis
fibroblasts. In kidney specimens obtained at autopsy from patients with
cystic fibrosis, Katz et al. (1988) documented microscopic
nephrocalcinosis in 35 of 38 specimens. Hypercalciuria was present in 5
of 14 patients studied. The presence of microscopic nephrocalcinosis in
3 patients less than 1 year of age suggested to these authors that the
mutation in cystic fibrosis involves a primary abnormality of renal
calcium metabolism. Shapiro et al. (1982) reported anomalous kinetics of
mitochondrial NADH dehydrogenase in cystic fibrosis homozygotes and
heterozygotes. Studying white cells, Sanguinetti-Briceno and Brock
(1982) could not identify a correlation between NADH dehydrogenase and
CF genotype. Shepherd et al. (1988) found that cystic fibrosis infants
had 25% higher rates of total energy expenditure compared to healthy
infants matched for age and body weight. The authors suggested that the
data point to an energy-requiring basic defect.

*FIELD* SA
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Bearn (1969); Danes et al. (1977); Danks et al. (1965); Devoto et
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(1976); Di Sant'Agnese and Talamo (1967); Dork et al. (1991); Eiberg
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235. Shepherd, R. W.; Holt, T. L.; Vasques-Velasquez, L.; Coward,
W. A.; Prentice, A.; Lucas, A.: Increased energy expenditure in young
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Originally Volume 1.

236. Sheppard, D. N.; Rich, D. P.; Ostedgaard, L. S.; Gregory, R.
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237. Sheridan, M. B.; Fong, P.; Groman, J. D.; Conrad, C.; Flume,
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238. Shier, W. T.: Increased resistance to influenza as a possible
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239. Shwachman, H.; Kowalski, M.; Khaw, K.-T.: Cystic fibrosis: a
new outlook: 70 patients above 25 years of age. Medicine 56: 129-149,
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240. Sing, C. F.; Risser, D. R.; Howatt, W. F.; Erickson, R. P.:
Phenotypic heterogeneity in cystic fibrosis. Am. J. Med. Genet. 13:
179-195, 1982.

241. Siraganian, P. A.; Miller, R. W.; Swender, P. T.: Cystic fibrosis
and ileal carcinoma. (Letter) Lancet 330: 1158 only, 1987. Note:
Originally Volume 2.

242. Smith, D. W.; Docter, J. M.; Ferrier, P. E.; Frias, J. L.; Spock,
A.: Possible localisation of the gene for cystic fibrosis of the
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1968. Note: Originally Volume 2.

243. Smyth, R. L.: Fibrosing colonopathy in cystic fibrosis. Arch.
Child. Dis. 74: 464-466, 1996.

244. Smyth, R. L.; van Velzen, D.; Smyth, A. R.; Lloyd, D. A.; Heaf,
D. P.: Strictures of ascending colon in cystic fibrosis and high-strength
pancreatic enzymes. Lancet 343: 85-86, 1994.

245. Snouwaert, J. N.; Brigman, K. K.; Latour, A. M.; Malouf, N. N.;
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1992.

246. Spence, J. E.; Perciaccante, R. G.; Greig, G. M.; Willard, H.
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genetic disease. Am. J. Hum. Genet. 42: 217-226, 1988.

247. Spence, J. E.; Rosenbloom, C. L.; O'Brien, W. E.; Seilheimer,
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of DNA markers to cystic fibrosis in 26 families. Am. J. Hum. Genet. 39:
729-734, 1986.

248. Spock, A.; Heick, H. M. C.; Cress, H.; Logan, W. S.: Abnormal
serum factor in patients with cystic fibrosis of the pancreas. Pediat.
Res. 1: 173-177, 1967.

249. Stanke, F.; Becker, T.; Cuppens, H.; Kumar, V.; Cassiman, J.-J.;
Jansen, S.; Radojkovic, D.; Siebert, B.; Yarden, J.; Ussery, D. W.;
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250. Steinberg, A. G.; Brown, D. C.: On the incidence of cystic fibrosis
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Med. 336: 487-491, 1997.

252. Stern, R. C.; Boat, T. F.; Abramowsky, C. R.; Matthews, L. W.;
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253. Stern, R. C.; Boat, T. F.; Doershuk, C. F.: Obstructive azoospermia
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1401-1404, 1982. Note: Originally Volume 1.

254. Strain, L.; Curtis, A.; Mennie, M.; Holloway, S.; Brock, D. J.
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255. Super, M.: Genetic counselling and antenatal diagnosis of cystic
fibrosis. J. Roy. Soc. Med. 80: 13-15, 1987.

256. Tarran, R.; Grubb, B. R.; Parsons, D.; Picher, M.; Hirsh, A.
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observations and therapeutic approaches. Molec. Cell 8: 149-158,
2001.

257. Tebbutt, S. J.; Wardle, C. J. C.; Hill, D. F.; Harris, A.: Molecular
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258. Ten Kate, L. P.; Scheffer, H.; Cornel, M. C.; vanLookeren Campagne,
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260. Tsui, L.-C.; Buchwald, M.; Barker, D.; Braman, J. C.; Knowlton,
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261. Tsui, L.-C.; Buetow, K.; Buchwald, M.: Genetic analysis of cystic
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263. Viel, M.; Leroy, C.; Hubert, D.; Fajac, I.; Bienvenu, T.: ENaC-beta
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266. Voss, R.; Ben-Simon, E.; Zlotogora, Y.; Dagan, J.; Godfry, S.;
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269. Wang, J.; Bowman, M. C.; Hsu, E.; Wertz, K.; Wong, L.-J. C.:
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283. Yang, Y.; Devor, D. C.; Engelhardt, J. F.; Ernst, S. A.; Strong,
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284. Yang, Y.; Raper, S. E.; Cohn, J. A.; Engelhardt, J. F.; Wilson,
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286. Zhou, L.; Dey, C. R.; Wert, S. E.; DuVall, M. D.; Frizzell, R.
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1994.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

CARDIOVASCULAR:
[Heart];
Cor pulmonale

RESPIRATORY:
[Airways];
Chronic bronchopulmonary infection;
Bronchiectasis;
Asthma;
Pulmonary blebs;
Pseudomonas colonization

ABDOMEN:
[Pancreas];
Pancreatic insufficiency in 80%;
[Biliary tract];
Biliary cirrhosis;
[Gastrointestinal];
Meconium ileus in neonates (10-15%);
Distal intestinal obstruction syndrome;
Rectal prolapse;
Adenocarcinoma of the ileum

GENITOURINARY:
[Internal genitalia, male];
Male infertility (98%) due to congenital bilateral absence of the
vas deferens (CBAVD);
[Internal genitalia, female];
Female decreased fertility due to thickened cervical secretions and
chronic lung disease

LABORATORY ABNORMALITIES:
High sweat sodium and chloride;
Hyponatremic dehydration, rarely;
Hypercalciuria;
Abnormal nasal potential differences;
High newborn serum levels of immunoreactive trypsinogen

MISCELLANEOUS:
Delta-F508 present in 70% of alleles

MOLECULAR BASIS:
Caused by mutations in the cystic fibrosis transmembrane conductance
regulator gene (CFTR, 602421.0001)

*FIELD* CN
Ada Hamosh - updated: 7/13/1999
Michael J. Wright - revised: 6/17/1999
Ada Hamosh - revised: 6/17/1999
Ada Hamosh - updated: 5/12/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 09/23/2004
joanna: 10/3/2001
joanna: 7/15/1999
joanna: 7/13/1999
root: 6/24/1999
kayiaros: 6/21/1999
carol: 6/17/1999
kayiaros: 6/17/1999
joanna: 5/12/1999
carol: 5/10/1999

*FIELD* CN
Anne M. Stumpf - updated: 4/18/2013
Ada Hamosh - updated: 3/4/2013
Ada Hamosh - updated: 2/13/2013
Ada Hamosh - updated: 9/7/2011
Ada Hamosh - updated: 5/23/2011
Patricia A. Hartz - updated: 3/17/2011
Ada Hamosh - updated: 5/27/2010
Marla J. F. O'Neill - updated: 10/5/2009
Marla J. F. O'Neill - updated: 10/1/2009
Cassandra L. Kniffin - updated: 5/18/2009
Ada Hamosh - updated: 5/11/2009
Ada Hamosh - updated: 10/22/2008
Ada Hamosh - updated: 7/25/2008
Cassandra L. Kniffin - updated: 6/2/2008
John A. Phillips, III - updated: 9/28/2007
Marla J. F. O'Neill - updated: 6/7/2007
Cassandra L. Kniffin - updated: 5/12/2006
Paul J. Converse - updated: 2/8/2006
Victor A. McKusick - updated: 10/17/2005
Victor A. McKusick - updated: 10/14/2005
Marla J. F. O'Neill - updated: 4/20/2005
Marla J. F. O'Neill - updated: 12/9/2004
Ada Hamosh - updated: 6/2/2004
Ada Hamosh - updated: 4/30/2004
Victor A. McKusick - updated: 2/24/2004
Victor A. McKusick - updated: 8/13/2003
Victor A. McKusick - updated: 3/27/2003
Victor A. McKusick - updated: 2/4/2003
Victor A. McKusick - updated: 12/30/2002
Victor A. McKusick - updated: 11/6/2002
Victor A. McKusick - updated: 10/16/2002
Victor A. McKusick - updated: 8/21/2002
Michael J. Wright - updated: 6/28/2002
Deborah L. Stone - updated: 4/11/2002
Victor A. McKusick - updated: 1/22/2002
Stylianos E. Antonarakis - updated: 8/3/2001
Michael J. Wright - updated: 7/24/2001
Michael J. Wright - updated: 6/5/2001
Michael J. Wright - updated: 1/10/2001
Sonja A. Rasmussen - updated: 9/21/2000
Sonja A. Rasmussen - updated: 9/18/2000
Ada Hamosh - updated: 9/13/2000
Ada Hamosh - updated: 7/20/2000
Ada Hamosh - updated: 2/9/2000
Ada Hamosh - updated: 11/22/1999
Victor A. McKusick - updated: 10/11/1999
Ada Hamosh - updated: 4/7/1999
Victor A. McKusick - updated: 3/16/1999
Michael J. Wright - updated: 2/12/1999
Stylianos E. Antonarakis - updated: 2/4/1999
Michael J. Wright - updated: 11/16/1998
Victor A. McKusick - updated: 9/18/1998
Victor A. McKusick - updated: 9/14/1998
Ada Hamosh - updated: 5/18/1998
Victor A. McKusick - updated: 5/9/1998
Clair A. Francomano - updated: 5/7/1998
Victor A. McKusick - updated: 4/23/1998
John F. Jackson - reorganized: 3/7/1998
Victor A. McKusick - updated: 12/19/1997
Victor A. McKusick - updated: 11/10/1997
Victor A. McKusick - updated: 10/10/1997
Victor A. McKusick - updated: 6/26/1997
Victor A. McKusick - updated: 6/16/1997
Victor A. McKusick - updated: 6/5/1997
Victor A. McKusick - updated: 5/15/1997
Victor A. McKusick - updated: 3/16/1997
Victor A. McKusick - updated: 3/6/1997
Victor A. McKusick - updated: 2/28/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
mgross: 10/07/2013
carol: 5/29/2013
alopez: 4/19/2013
alopez: 4/18/2013
alopez: 3/4/2013
alopez: 2/13/2013
terry: 9/14/2012
alopez: 9/12/2012
terry: 8/8/2012
terry: 7/3/2012
alopez: 6/21/2012
terry: 6/4/2012
carol: 5/10/2012
alopez: 9/8/2011
terry: 9/7/2011
alopez: 5/24/2011
terry: 5/23/2011
terry: 3/18/2011
mgross: 3/17/2011
terry: 10/12/2010
carol: 8/13/2010
alopez: 6/2/2010
terry: 5/27/2010
carol: 4/29/2010
wwang: 10/29/2009
wwang: 10/28/2009
wwang: 10/12/2009
wwang: 10/7/2009
terry: 10/5/2009
wwang: 10/1/2009
wwang: 9/18/2009
terry: 9/3/2009
wwang: 6/12/2009
terry: 6/4/2009
terry: 6/3/2009
ckniffin: 5/18/2009
alopez: 5/13/2009
terry: 5/11/2009
terry: 4/9/2009
alopez: 10/22/2008
alopez: 7/30/2008
terry: 7/25/2008
wwang: 6/17/2008
ckniffin: 6/2/2008
carol: 10/10/2007
alopez: 9/28/2007
wwang: 6/13/2007
terry: 6/7/2007
terry: 11/15/2006
carol: 6/29/2006
wwang: 5/17/2006
ckniffin: 5/12/2006
carol: 2/8/2006
carol: 1/19/2006
alopez: 10/27/2005
alopez: 10/24/2005
terry: 10/17/2005
terry: 10/14/2005
wwang: 10/11/2005
wwang: 5/23/2005
wwang: 4/28/2005
wwang: 4/26/2005
terry: 4/20/2005
tkritzer: 12/9/2004
alopez: 6/2/2004
terry: 6/2/2004
alopez: 5/3/2004
terry: 4/30/2004
tkritzer: 2/27/2004
terry: 2/24/2004
carol: 2/19/2004
tkritzer: 11/7/2003
ckniffin: 11/3/2003
tkritzer: 8/19/2003
terry: 8/13/2003
cwells: 4/2/2003
terry: 3/27/2003
carol: 2/28/2003
tkritzer: 2/19/2003
terry: 2/4/2003
carol: 1/7/2003
tkritzer: 1/2/2003
terry: 12/30/2002
terry: 11/22/2002
carol: 11/13/2002
tkritzer: 11/12/2002
terry: 11/6/2002
carol: 10/17/2002
tkritzer: 10/16/2002
mgross: 10/14/2002
terry: 8/21/2002
alopez: 6/28/2002
terry: 6/28/2002
carol: 4/11/2002
carol: 2/4/2002
terry: 1/22/2002
carol: 9/10/2001
mgross: 8/3/2001
alopez: 8/2/2001
terry: 7/24/2001
alopez: 6/5/2001
alopez: 1/10/2001
mcapotos: 1/9/2001
terry: 12/13/2000
alopez: 10/3/2000
carol: 9/22/2000
mcapotos: 9/22/2000
mcapotos: 9/21/2000
mcapotos: 9/18/2000
terry: 9/13/2000
mcapotos: 8/1/2000
mcapotos: 7/28/2000
terry: 7/20/2000
alopez: 2/9/2000
alopez: 11/22/1999
terry: 11/22/1999
mgross: 10/11/1999
mgross: 7/14/1999
alopez: 4/7/1999
terry: 3/16/1999
mgross: 3/3/1999
mgross: 3/1/1999
terry: 2/12/1999
carol: 2/4/1999
dkim: 12/10/1998
alopez: 12/8/1998
terry: 11/16/1998
carol: 9/28/1998
terry: 9/18/1998
carol: 9/17/1998
terry: 9/14/1998
dkim: 7/24/1998
terry: 6/4/1998
alopez: 5/18/1998
alopez: 5/9/1998
dholmes: 5/7/1998
alopez: 4/23/1998
carol: 4/17/1998
carol: 3/30/1998
carol: 3/28/1998
carol: 3/7/1998
terry: 1/8/1998
mark: 1/2/1998
dholmes: 12/31/1997
terry: 12/19/1997
terry: 11/14/1997
terry: 11/10/1997
jenny: 10/17/1997
terry: 10/10/1997
joanna: 8/12/1997
terry: 7/25/1997
terry: 7/10/1997
terry: 7/9/1997
terry: 6/26/1997
mark: 6/20/1997
mark: 6/18/1997
terry: 6/16/1997
terry: 6/5/1997
mark: 5/26/1997
mark: 5/16/1997
jenny: 5/15/1997
terry: 5/12/1997
mark: 3/16/1997
terry: 3/10/1997
mark: 3/6/1997
terry: 3/5/1997
mark: 2/28/1997
terry: 2/26/1997
jamie: 2/18/1997
jenny: 1/10/1997
terry: 1/8/1997
terry: 12/30/1996
jamie: 11/15/1996
terry: 11/11/1996
terry: 10/24/1996
jamie: 10/23/1996
jamie: 10/16/1996
mark: 8/30/1996
carol: 8/23/1996
marlene: 8/2/1996
terry: 7/26/1996
mark: 7/17/1996
mark: 6/25/1996
mark: 6/24/1996
terry: 6/18/1996
terry: 5/10/1996
mark: 4/28/1996
mark: 4/25/1996
terry: 4/22/1996
mark: 2/29/1996
terry: 2/27/1996
mark: 2/23/1996
mark: 2/6/1996
terry: 1/31/1996
mark: 1/27/1996
mark: 1/21/1996
terry: 1/19/1996
mark: 1/14/1996
mark: 1/4/1996
terry: 1/4/1996
mark: 11/14/1995
terry: 11/2/1995
davew: 8/16/1994
jason: 6/28/1994
warfield: 4/15/1994
pfoster: 3/24/1994

MIM 277180
*RECORD*
*FIELD* NO
277180
*FIELD* TI
#277180 VAS DEFERENS, CONGENITAL BILATERAL APLASIA OF; CBAVD
;;CAVD
*FIELD* TX
A number sign (#) is used with this entry because at least one form of
read morethe disorder is caused by mutation in the cystic fibrosis transmembrane
conductance regulator gene (CFTR; 602421), which is located on
chromosome 7. Mutations in the same gene cause cystic fibrosis (219700).

CLINICAL FEATURES

Congenital bilateral aplasia of the vas deferens (CBAVD), which leads to
male infertility, may occur in isolation or as a manifestation of cystic
fibrosis. Kaplan et al. (1968) found that males with cystic fibrosis are
infertile because of failure of normal development of the vas deferens.
Oppenheimer and Esterly (1969) concluded that the changes in the
transport ducts of the male genital system are responsible for
infertility and are not a developmental anomaly but a degenerative
change due to obstruction similar to that which occurs in the pancreas
and salivary glands in cystic fibrosis.

Augarten et al. (1994) suggested that CBAVD patients with renal
malformations are likely not to have cystic fibrosis. They investigated
47 CBAVD patients by ultrasonography and found that 10 (21%) had renal
malformations and 37 (79%) did not. In the former group, no cystic
fibrosis mutations were found and sweat chloride concentrations were
normal. In the latter group, 18 patients (49%) carried at least 1 cystic
fibrosis mutation and sweat chloride was high in 17 of 26 tested (65%).

Dumur et al. (1996) concluded with others that, unlike forms of CBAVD
accompanied by renal maldevelopment, most cases of CBAVD without renal
agenesis are related to CF. They found that the sweat test is useful for
demonstrating the connection, especially when genetic analysis has not
characterized mutations on both alleles of the CF gene.

INHERITANCE

Schellen and van Straaten (1980) described 4 brothers, aged 31 to 42
years, with aplasia of the vasa deferentia. No parental consanguinity
could be demonstrated by a genealogic tracing 'as far back as 1750.' No
associated abnormalities were found. There was no evidence of cystic
fibrosis in this family.

In a study of families of males with azoospermia and extreme
oligozoospermia, Budde et al. (1984) found 2 brothers with congenital
aplasia of the vasa deferentia. Czeizel (1985) reported 2 unrelated male
sib-pairs with bilateral congenital aplasia of the vasa deferentia.
Kleczkowska et al. (1989) and Gilgenkrantz et al. (1990) reported
affected families.

Silber et al. (1990) used sperm aspirated from the epididymis of
patients with congenital absence of the vas deferens to fertilize human
oocytes in vitro.

Rigot et al. (1991) pointed to the risk attendant on the possibility
that these males are carriers of a mild form of cystic fibrosis. They
had examined 19 azoospermic men with aplasia of the epididymis and vas
deferens and found that 8 were heterozygous for the delF508 deletion
(602421.0001), the most common mutation causing cystic fibrosis. All but
1 had chronic sinusitis and 2 had sweat chloride levels close to 100
mmol per liter. Anguiano et al. (1992) reported similar findings. They
studied 25 unselected, unrelated azoospermic men with CBAVD, most of
them of northern European ancestry, who had presented to a male
infertility clinic of a teaching hospital. In 16 (64%), at least 1
detectable CF mutation was found. Three of these 16 men were shown to be
compound heterozygotes, one of whom had a previously undescribed
mutation. This, they suggested, represents a primarily genital phenotype
of CF.

Martin et al. (1992) reported 2 brothers with congenital absence of the
vas deferens discovered in childhood during inguinal hernia repair. The
vas was absent unilaterally in one and bilaterally in the other. Martin
et al. (1992) suggested that X-linked recessive or autosomal dominant
male-limited inheritance is more likely. All fathers of affected males
should be examined for the presence of unilateral CBAVD. Theoretically,
females carrying an autosomal dominant CBAVD gene should lack the normal
remnant of wolffian duct regression (Gartner duct), while these remnants
should be present in females carrying an X-linked recessive gene. The
Gartner duct is clinically undetectable, however.

MOLECULAR GENETICS

See 602421 (e.g., 602421.0060) for mutations of the CFTR gene
responsible for isolated bilateral absence of the vas deferens.

Goshen et al. (1992) described the case of a 2.5-year-old boy who was
found to have fibrous replacement of the vas deferens when surgery was
done for undescended testis and repair of an indirect inguinal hernia.
One year later the patient developed diarrhea with steatorrhea, and
sweat tests revealed elevated chloride. DNA studies demonstrated
compound heterozygosity for the delF508 mutation and the trp1282-to-ter
mutation (602421.0022).

To test the hypothesis of commonality of CBAVD and CF, Rave-Harel et al.
(1995) reasoned that 2 brothers with CBAVD could be expected to carry
the same 2 CFTR alleles, while their fertile brothers would be expected
to carry at least one different allele. Eleven families were studied, of
which 2 families, with unidentified CFTR mutations, did not support this
hypothesis. In these families, 2 brothers with CBAVD inherited different
CFTR alleles. Their fertile brothers inherited the same CFTR alleles as
their brothers with CBAVD. The results suggested that although in some
families CBAVD is associated with 2 CFTR mutations, in other families it
is caused by other mechanisms, such as mutations at other loci or
homozygosity or heterozygosity for partially penetrant CFTR mutations.

Mercier et al. (1995) analyzed the entire coding sequence of the CFTR
gene in a cohort of 67 men with congenital bilateral aplasia of the vas
deferens who were otherwise healthy. They identified 4 novel missense
mutations: A800G, G149R, R258G, and E193K. They showed that 42% of these
subjects were carriers of 1 CFTR allele and that 24% were compound
heterozygotes for CFTR alleles. Thus, they were unable to identify the
presence of 2 CFTR mutations in 76% of these patients. Furthermore, they
described the segregation of CFTR haplotypes in the family of 1 CBAVD
male; in this family, 2 male sibs with identical CFTR loci displayed
different phenotypes, one of them being fertile and the other sterile.
This suggested that one or more additional genes are involved in the
etiology of CBAVD.

Chillon et al. (1995) characterized the mutations in the CFTR gene in
102 patients with CBAVD. They also analyzed a DNA variant (the 5T
allele) in a noncoding region of CFTR that causes reduced levels of the
normal CFTR protein. (Studies of CFTR mRNA in tissues from normal
persons have identified various mRNA molecules that lack exon 4, 9, or
12. Whether or not CFTR mRNA contains exon 9 depends on the variable
length of a stretch of thymine residues in intron 8 of CFTR. This
sequence, known as a polyT sequence, contains 5, 7, or 9 thymines (the
5T, 7T, and 9T alleles, respectively). Since the 5T allele causes
reduced levels of normal CFTR mRNA, this variant would appear likely to
be involved in the pathogenesis of CBAVD.) In 19 of the 102 patients,
mutations in both copies of the CFTR gene were found, and none of these
had the 5T allele. A mutation was found in 1 copy of CFTR in 54
patients, and 34 of them (63%) had the 5T allele in the other CFTR gene.
No CFTR mutations were found in 29 patients, but 7 of them (24%) had the
5T allele. The frequency of this allele in the general population is
about 5%.

Chillon et al. (1995) concluded that the combination of the 5T allele in
1 copy of the CFTR gene with a cystic fibrosis mutation in the other
copy is the most common cause of CBAVD. The 5T allele mutation has a
wide range of clinical presentations, occurring in patients with CBAVD
or moderate forms of cystic fibrosis and in fertile men.

Grangeia et al. (2007) screened DNA samples from 45 patients with
congenital absence of the vas deferens by different molecular
approaches, including screening for the 31 most frequent CF mutations.
This approach identified 8 common mutations were identified in 40
patients. Denaturing gradient gel electrophoresis, denaturing high
performance liquid chromatography, and DNA sequencing identified 17
additional mutations, 3 of which were novel. Semiquantitative
fluorescent mutiplex PCR detected a 21-kb deletion (602421.0123) in 1
individual and confirmed the true homozygosity of 2 individuals.
Overall, 42 patients (93.3%) had 2 mutations and 3 patients (6.7%) had 1
mutation detected.

Sun et al. (2006) analyzed the polymorphic TG dinucleotide repeat
adjacent to the 5T variant in intron 8 and the codon 470 in exon 10 to
determine the haplotype of the 5T variant in trans. The authors
evaluated 12 males affected with congenital bilateral absence of vas
deferens and positive for the 5T variant and found that 10 of 12 had the
12TG-5T-470V haplotype.

*FIELD* RF
1. Anguiano, A.; Oates, R. D.; Amos, J. A.; Dean, M.; Gerrard, B.;
Stewart, C.; Maher, T. A.; White, M. B.; Milunsky, A.: Congenital
bilateral absence of the vas deferens: a primarily genital form of
cystic fibrosis. JAMA 267: 1794-1797, 1992.

2. Augarten, A.; Yahav, Y.; Kerem, B. S.; Halle, D.; Laufer, J.; Szeinberg,
A.; Dor, J.; Mashiach, S.; Gazit, E.; Madgar, I.: Congenital bilateral
absence of vas deferens in the absence of cystic fibrosis. Lancet 344:
1473-1474, 1994.

3. Budde, W. J. A. M.; Verjaal, M.; Hamerlynck, J. V. T. H.; Bobrow,
M.: Familial occurrence of azoospermia and extreme oligozoospermia. Clin.
Genet. 26: 555-562, 1984.

4. Chillon, M.; Casals, T.; Mercier, B.; Bassas, L.; Lissens, W.;
Silber, S.; Romey, M.-C.; Ruiz-Romero, J.; Verlingue, C.; Claustres,
M.; Nunes, V.; Ferec, C.; Estivill, X.: Mutations in the cystic fibrosis
gene in patients with congenital absence of the vas deferens. New
Eng. J. Med. 332: 1475-1480, 1995.

5. Czeizel, A.: Congenital aplasia of the vasa deferentia of autosomal
recessive inheritance in two unrelated sib-pairs. Hum. Genet. 70:
288 only, 1985.

6. Dumur, V.; Gervais, R.; Rigot, J.-M.; Delomel-Vinner, E.; Decaestecker,
B.; Lafitte, J.-J.; Roussel, P.: Congenital bilateral absence of
the vas deferens (CBAVD) and cystic fibrosis transmembrane regulator
(CFTR): correlation between genotype and phenotype. Hum. Genet. 97:
7-10, 1996.

7. Gilgenkrantz, S.; Guillemin, P.; Kimmel, B.: On the familial occurrence
of congenital bilateral absence of vas deferens. (Letter) Clin. Genet. 37:
159 only, 1990.

8. Goshen, R.; Kerem, E.; Shoshani, T.; Kerem, B.-S.; Feigin, E.;
Zamir, O.; Yahav, Y.: Cystic fibrosis manifested as undescended testis
and absence of vas deferens. Pediatrics 90: 982-983, 1992.

9. Grangeia, A.; Sa, R.; Carvalho, F.; Martin, J.; Girodon, E.; Silva,
J.; Ferraz, L.; Barros, A.; Sousa, M.: Molecular characterization
of the cystic fibrosis transmembrane conductance regulator gene in
congenital absence of the vas deferens. Genet. Med. 9: 163-172,
2007.

10. Kaplan, E.; Shwachman, H.; Perlmutter, A. D.; Rule, A.; Khaw,
K.-T.; Holsclaw, D. S.: Reproductive failure in males with cystic
fibrosis. New Eng. J. Med. 279: 65-69, 1968.

11. Kleczkowska, A.; Fryns, J. P.; Steeno, O.; van den Berghe, H.
: On the familial occurrence of congenital bilateral absence of vas
deferens. Clin. Genet. 35: 268-271, 1989.

12. Martin, R. A.; Lyons Jones, K.; Downey, E. C.: Congenital absence
of the vas deferens: recurrence in a family. Am. J. Med. Genet. 42:
714-715, 1992.

13. Mercier, B.; Verlingue, C.; Lissens, W.; Silber, S. J.; Novelli,
G.; Bonduelle, M.; Audrezet, M. P.; Ferec, C.: Is congenital bilateral
absence of vas deferens a primary form of cystic fibrosis? Analyses
of the CFTR gene in 67 patients. Am. J. Hum. Genet. 56: 272-277,
1995.

14. Oppenheimer, E. H.; Esterly, J. R.: Observations on cystic fibrosis
of the pancreas. V. Developmental changes in the male genital system. J.
Pediat. 75: 806-811, 1969.

15. Rave-Harel, N.; Madgar, I.; Goshen, R.; Nissim-Rafinia, M.; Ziadni,
A.; Rahat, A.; Chiba, O.; Kalman, Y. M.; Brautbar, C.; Levinson, D.;
Augarten, A.; Kerem, E.; Kerem, B.: CFTR haplotype analysis reveals
genetic heterogeneity in the etiology of congenital bilateral aplasia
of the vas deferens. Am. J. Hum. Genet. 56: 1359-1366, 1995.

16. Rigot, J.-M.; Lafitte, J.-J.; Dumur, V.; Gervais, R.; Manouvrier,
S.; Biserte, J.; Mazeman, E.; Roussel, P.: Cystic fibrosis and congenital
absence of the vas deferens. (Letter) New Eng. J. Med. 325: 64-65,
1991.

17. Schellen, T. M. C. M.; van Straaten, A.: Autosomal recessive
hereditary congenital aplasia of the vasa deferentia in four siblings. Fertil.
Steril. 34: 401-404, 1980.

18. Silber, S. J.; Ord, T.; Balmaceda, J.; Patrizio, P.; Asch, R.
H.: Congenital absence of the vas deferens: the fertilizing capacity
of human epididymal sperm. New Eng. J. Med. 323: 1788-1792, 1990.

19. Sun, W.; Anderson, B.; Redman, J.; Milunsky, A.; Buller, A.; McGinniss,
M. J.; Quan, F.; Anguiano, A.; Huang, S.; Hantash, F.; Strom, C.:
CFTR 5T variant has a low penetrance in females that is partially
attributable to its haplotype. Genet. Med. 8: 339-345, 2006.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GENITOURINARY:
[Internal genitalia, male];
Vas deferens aplasia;
Azoospermia

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutations in the cystic fibrosis transmembrane conductance
regulator gene (CFTR, 602421.0005)

*FIELD* CN
Ada Hamosh - reviewed: 02/13/2003

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 02/13/2003

*FIELD* CN
Ada Hamosh - updated: 8/2/2007
Ada Hamosh - updated: 7/25/2007
John F. Jackson - reorganized: 3/7/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 06/03/2009
terry: 9/26/2008
alopez: 8/2/2007
alopez: 7/31/2007
terry: 7/25/2007
carol: 9/10/2001
carol: 3/7/1998
terry: 1/6/1995
carol: 5/16/1994
mimadm: 3/12/1994
carol: 10/13/1992
carol: 9/17/1992
carol: 5/18/1992

MIM 602421
*RECORD*
*FIELD* NO
602421
*FIELD* TI
*602421 CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR
;;ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 7; ABCC7
read more*FIELD* TX

DESCRIPTION

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as
a chloride channel and controls the regulation of other transport
pathways. Mutations in the CFTR gene have been found to cause cystic
fibrosis (CF; 219700) and congenital bilateral aplasia of the vas
deferens (CBAVD; 277180).

CLONING

Riordan et al. (1989) isolated overlapping cDNA clones from epithelial
cell libraries with a genomic DNA segment containing a portion of the
putative CF gene. Transcripts approximately 6,500 nucleotides in size
were detectable in the tissues affected in patients with CF. The
predicted protein consists of 2 similar motifs, each with a domain
having properties consistent with membrane-association, and a domain
believed to be involved in ATP binding. In CF patients, a deleted
phenylalanine residue occurs at the center of the putative first
nucleotide-binding fold (NBF). The predicted protein has 1,480 amino
acids with a molecular mass of 168,138 Da. The characteristics are
remarkably similar to those of the mammalian multidrug resistant
P-glycoprotein (171050), which also maps to 7q, and to a number of other
membrane-associated proteins. To avoid confusion with the previously
named CF antigen (123885), Riordan et al. (1989) referred to the protein
as cystic fibrosis transmembrane conductance regulator (CFTR).

Cystic fibrosis represents the first genetic disorder elucidated
strictly by the process of reverse genetics (later called positional
cloning), i.e., on the basis of map location but without the
availability of chromosomal rearrangements or deletions such as those
that have greatly facilitated previous success in the cloning of human
disease genes in Duchenne muscular dystrophy (310200), retinoblastoma
(180200), and chronic granulomatous disease (306400), for example. By
use of a combination of chromosome walking and jumping, Rommens et al.
(1989) succeeded in covering the CF region on 7q. The jumping technique
was particularly useful in bypassing 'unclonable' regions, which are
estimated to constitute 5% of the human genome. (Yeast artificial
chromosome (YAC) vectors represent an alternative strategy.) The
identification of undermethylated CpG islands was 1 tip-off; another was
screening of a cDNA library constructed from cultured sweat gland cells
of a non-CF individual. The CF gene proved to be about 250,000 bp long,
a surprising finding since the absence of apparent genomic
rearrangements in CF chromosomes and the evidence of a limited number of
CF mutations predicted a small mutational target.

Green and Olson (1990) described a general strategy for cloning and
mapping large regions of human DNA with yeast artificial chromosomes
(YACs). By analyzing 30 YAC clones from the region of chromosome 7
containing the CFTR gene, a contig map spanning more than 1.5 Mbp was
assembled. Individual YACs as large as 790 kb and containing the entire
CF gene were constructed in vivo by meiotic recombination in yeast
between pairs of overlapping YACs. Anand et al. (1991) described the
physical mapping of a 1.5-Mbp region encompassing 2 genetic loci
flanking the CF locus and contained within a series of YAC clones. The
entire CFTR gene was included within 1 of these YACs, a 310-kb clone
also containing flanking sequence in both the 5-prime and 3-prime
directions from the gene.

GENE STRUCTURE

Riordan et al. (1989) identified 24 exons in the CFTR gene.

With the hope of identifying conserved regions of biologic interest by
sequence comparison, Ellsworth et al. (2000) sought to establish the
sequence of the chromosomal segments encompassing the human CFTR and
mouse Cftr genes. Bacterial clone-based physical maps of the relevant
human and mouse genomic regions were constructed, and minimally
overlapping sets of clones were selected and sequenced. Analyses of the
resulting data provided insights about the organization of the CFTR/Cftr
genes and potential sequence elements regulating their expression.

MAPPING

Riordan et al. (1989) mapped the CFTR gene to chromosome 7q. For
additional information on the mapping of the gene for cystic fibrosis,
see 219700.

The mapping of the murine equivalent of the WNT2 and MET (164860) genes
to mouse chromosome 6 (Chan et al., 1989) strongly indicated that the
mouse equivalent of the cystic fibrosis gene is also located on
chromosome 6. By Southern analysis of mouse/Chinese hamster somatic cell
hybrid DNAs, Kelley et al. (1992) mapped the Cftr gene to chromosome 6.
Using restriction fragment length variants (RFLVs) in the study of
interspecific backcrosses, Siegel et al. (1992) demonstrated that the
Cftr gene in the mouse is close to Met and Cola-2. Trezise et al. (1992)
demonstrated that the Cftr locus is on rat chromosome 4. Study of other
loci suggested that an ancestral mammalian chromosome is represented by
the present-day rat chromosome 4: 5 genes are syntenic on rat chromosome
4 and mouse chromosome 6 but are divided between human chromosomes 7 and
12. Another 5 genes that are syntenic on rat chromosome 4 and human
chromosome 7 are divided between chromosomes 5 and 6 in the mouse.

GENE FUNCTION

In addition to functioning as a chloride channel, CFTR controls the
regulation of other transport pathways. For example, patients with CF
and the homozygous CFTR-deficient mouse have enhanced sodium ion
absorption; this enhanced sodium ion absorption is corrected by addition
of a wildtype copy of CFTR. CFTR and outwardly rectifying chloride
channels (ORCCs) are distinct channels but are linked functionally via
an unknown regulatory mechanism. Schwiebert et al. (1995) presented
results from whole-cell and single-channel patch-clamp recordings,
short-circuit current recordings, and ATP-release assays of normal, CF,
and wildtype or mutant CFTR-transfected CF airway cultured epithelial
cells indicating that CFTR regulates ORCCs by triggering the transport
of the potent agonist, ATP, out of the cell. The results suggested that
CFTR functions to regulate other chloride ion secretory pathways in
addition to conducting chloride ion itself.

A quality control system that rapidly degrades abnormal membrane and
secretory protein is stringently applied to the CFTR protein;
approximately 75% of the wildtype precursor and 100% of the delF508
variant (602421.0001) are rapidly degraded before exiting from the
endoplasmic reticulum (ER). Jensen et al. (1995) demonstrated that CFTR
and presumably other intrinsic membrane proteins are substrates for
proteasomal degradation during their maturation within the endoplasmic
reticulum. Chang et al. (1999) showed that export-incompetent CFTR
proteins display multiple arginine-framed tripeptide sequences.
Inactivation of 4 of these motifs by replacement of arginine residues at
positions R29, R516, R555, and R766 with lysine residues simultaneously
caused mutant delF508 CFTR protein to escape ER quality control and
function at the cell surface. Chang et al. (1999) suggested that
interference with recognition of these signals may be helpful in the
management of CF.

Younger et al. (2006) identified an ER membrane-associated ubiquitin
ligase complex containing the E3 RMA1 (RNF5; 602677), the E2 UBC6E
(UBE2J1), and derlin-1 (DERL1; 608813) that cooperated with the
cytosolic HSC70 (HSPA8; 600816)/CHIP (STUB1; 607207) E3 complex to
triage CFTR and delFl508. Derlin-1 retained CFTR in the ER membrane and
interacted with RMA1 and UBC6E to promote proteasomal degradation of
CFTR. RMA1 could recognize folding defects in delF508 coincident with
translation, whereas CHIP appeared to act posttranslationally. A folding
defect in delF508 detected by RMA1 involved the inability of the second
membrane-spanning domain of CFTR to productively interact with
N-terminal domains. Younger et al. (2006) concluded that the RMA1 and
CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to
monitor the folding status of CFTR and delF508.

Randak et al. (1997) expressed NBF2 of CFTR as a soluble protein fused
to maltose-binding protein in E. coli and found that it catalyzed
hydrolysis of ATP to form ADP and Pi. The ADP product inhibited ATPase
activity. NBF2 also hydrolyzed GTP to GDP and Pi. In the presence of
AMP, however, the ATPase reaction was superseded by adenylate kinase
activity, resulting in formation of 2 ADP molecules from ATP and AMP.
Randak et al. (1997) identified a typical adenylate kinase-like
AMP-binding site in NBF2.

To determine the structural basis for the ATPase activity of CFTR,
Ramjeesingh et al. (1999) studied the effect of mutations in the Walker
A consensus motifs on ATP hydrolysis by the purified, intact protein.
Mutation of the lysine residue in the Walker A motif of either NBF
inhibited the ATPase activity of purified, intact CFTR protein by
greater than 50%, suggesting that the 2 NBFs function cooperatively in
catalysis. Surprisingly, the rate of channel gating was significantly
inhibited only when the mutation was in the second NBF, suggesting that
ATPase activity may not be tightly coupled to channel gating.

Randak and Welsh (2003) demonstrated that full-length CFTR and the
isolated nucleotide-binding domain-2 (NBD2) had ATPase and adenylate
kinase activities following expression in HeLa cells. The adenylate
kinase inhibitor Ap5A inhibited CFTR Cl- currents, and it inhibited
channel activity by binding an ATP site and an AMP site. Adding AMP
switched enzymatic activity of the NBD2 polypeptide from ATPase to
adenylate kinase. ATP and AMP appeared to induce dimerization between
NBD1 and NBD2, causing the channel to open. Randak and Welsh (2003)
hypothesized that at physiologic AMP concentrations, the predominant
reaction regulating channel activity is likely adenylate kinase.

Jiang and Engelhardt (1998) reviewed the cellular heterogeneity of CFTR
expression and function in the lung and the important implications for
gene therapy of cystic fibrosis.

Cystic fibrosis is characterized by persistent Pseudomonas aeruginosa
colonization of the conducting airways leading to the migration of
inflammatory cells, including polymorphonuclear leukocytes (PMNs), into
the airways of CF patients. PMNs release a potent chemokinetic and
chemoattractant, leukotriene B, during an inflammatory response,
resulting in the further migration of inflammatory cells. Cromwell et
al. (1981) demonstrated the existence of leukotrienes in the sputum of
CF patients. The oxidative metabolites of arachidonic acid and the
inflammatory cell-derived proteases have been implicated in the
destruction and shedding of the airway epithelia observed in CF. Based
on these observations, it has been proposed that antiinflammatory drugs
might be useful in CF therapy. The nonsteroidal antiinflammatory drug
(NSAID) ibuprofen inhibits 5-lipoxygenase and hence leukotriene
formation, suggesting that ibuprofen may be useful in the treatment of
CF. Its possible benefit in CF, with no apparent adverse effects, was
reported by Konstan et al. (1995). However, other effects of ibuprofen
may counteract therapeutic strategies designed to increase CFTR
expression and/or function in secretory epithelia. Devor and Schultz
(1998) evaluated the acute effects of ibuprofen and salicylic acid on
cAMP-mediated Cl- secretion in both colonic and airway epithelia and
found that at a pharmacologically relevant concentration the drugs
inhibited chloride ion secretion across these epithelia and that this
inhibition was due at least in part to the blocking of the CFTR Cl-
channels.

Wei et al. (1998) studied CFTR channel activity of mature R-domain
mutants with point mutations at sites other than the predicted
phosphorylation sites. Whole-cell chloride conduction was increased in
Xenopus oocytes injected with H620Q-CFTR mRNA, but decreased in the
E822K and E826K mutants compared to wildtype CFTR. Anion permeability
and single-channel conductances did not differ from wildtype for any of
the mutants. Cell-attached single channel studies in COS cells revealed
that both open channel probability and/or the number of functional
channels were either higher (H260Q) or lower (E822K and E826K) than in
wildtype CFTR. These results suggested that sites other than the
phosphorylation sites in the R-domain influence gating.

Chanson et al. (1999) compared gap junctional coupling in a human
pancreatic cell line harboring the delF508 mutation in CFTR and in the
same cell line in which the defect was corrected by transfection with
wildtype CFTR. Exposure to agents that elevate intracellular cAMP or
specifically activate protein kinase A evoked chloride ion currents and
markedly increased junctional conductance of CFTR-expressing cell pairs,
but not in the parental cells. Thus, the expression of functional CFTR
restored the cAMP-dependent regulation of junctional conductance as well
as the chloride ion channel in CF cells. Consequently, defective
regulation of gap junction channels may contribute to the altered
functions of tissues affected in CF.

Reddy et al. (1999) demonstrated that in freshly isolated normal sweat
ducts, epithelial sodium channel (ENaC; see 600228) activity is
dependent on, and increases with, CFTR activity. Reddy et al. (1999)
also found that the primary defect in chloride permeability in cystic
fibrosis is accompanied secondarily by a sodium conductance in this
tissue that cannot be activated. Thus, reduced salt absorption in cystic
fibrosis is due not only to poor chloride conductance but also to poor
sodium conductance.

Weixel and Bradbury (2000) used in vivo cross-linking and in vitro
pull-down assays to show that full-length CFTR binds to the endocytic
adaptor complex AP2 (see 601024). Substitution of an alanine residue for
tyrosine at position 1424 significantly reduced the ability of AP2 to
bind the C terminus of CFTR. However, mutation to a phenylalanine
residue, which is normally found in dogfish CFTR at this position, did
not perturb AP2 binding. Taken together, these data suggest that the C
terminus of CFTR contains a tyrosine-based internalization signal that
interacts with the endocytic adaptor complex AP2 to facilitate efficient
entry of CFTR into clathrin-coated vesicles.

Wang et al. (2000) identified a hydrophilic CFTR-binding protein, CAP70,
which is concentrated on the apical surfaces. CAP70 had previously been
identified by Kocher et al. (1998) as PDZK1 (603831). The protein
contains 4 PDZ domains, 3 of which are capable of binding to the CFTR C
terminus. Linking at least 2 CFTR molecules via cytoplasmic C-terminal
binding by either multivalent CAP70 or a bivalent monoclonal antibody
potentiates the CFTR chloride channel activity. Thus, the CFTR channel
can be switched to a more active conducting state via a modification of
intermolecular CFTR-CFTR contact that is enhanced by an accessory
protein.

Moyer et al. (2000) reported that the C terminus of CFTR constitutes a
PDZ-interacting domain that is required for CFTR polarization to the
apical plasma membrane and interaction with the PDZ domain-containing
protein EBP50 (604990). PDZ-interacting domains are typically composed
of the C-terminal 3 to 5 amino acids, which in CFTR are
gln-asp-thr-arg-leu. Point substitution of the leucine at position 0
with alanine abrogated apical polarization of CFTR, interaction between
CFTR and EBP50, efficient expression of CFTR in the apical membrane, and
chloride secretion. Point substitution of the threonine at position -2
with alanine or valine had no effect on the apical polarization of CFTR,
but reduced interaction between CFTR and EBP50, efficient expression of
CFTR in the apical membrane, and chloride secretion. By contrast,
individual point substitution of any of the other amino acids in the PDZ
domain had no effect on measured parameters. Moyer et al. (2000)
concluded that mutations that delete the C terminus of CFTR may cause
cystic fibrosis because CFTR is not polarized, complexed with EBP50, or
efficiently expressed in the apical membrane of epithelial cells.

CFTR regulates other transporters, including chloride-coupled
bicarbonate transport. Alkaline fluids are secreted by normal tissues,
whereas acidic fluids are secreted by mutant CFTR-expressing tissues,
indicating the importance of this activity. Bicarbonate and pH affect
mucin viscosity and bacterial binding. Choi et al. (2001) examined
chloride-coupled bicarbonate transport by CFTR mutants that retain
substantial or normal chloride channel activity. Choi et al. (2001)
demonstrated that mutants reported to be associated with cystic fibrosis
with pancreatic insufficiency do not support bicarbonate transport, and
those associated with pancreatic sufficiency show reduced bicarbonate
transport. Choi et al. (2001) concluded that their findings demonstrate
the importance of bicarbonate transport in the function of secretory
epithelia and in CF.

Rowntree et al. (2001) showed that removal of a DNase I hypersensitive
site (DHS) in intron 1 (185+10 kb) of CFTR abolished the activity of
this DHS in transient transfection assays of reporter/enhancer gene
constructs. Stable transfections of a human colon carcinoma cell line
with CFTR-containing YACs showed that transcription from the DHS
element-deleted YAC was reduced by 60% compared to the intact construct.
In transgenic mice, deletion of the intron 1 DHS had no effect on
expression in the lung, but reduced expression in the intestine by 60%.
The authors concluded that the regulatory element associated with the
intron 1 DHS is tissue-specific and is required for normal CFTR
expression levels in the intestinal epithelium in vivo.

Callen et al. (2000) developed a cAMP-mediated sweat rate test that
allows the quantitative discrimination of CFTR function, thereby
indicating CF genotype: CF, CF carrier, and non-CF. Callen et al. (2000)
remarked that this test may be helpful in the diagnosis of ambiguous
cases and in studies of new agents to increase the function of CFTR.

In CFTR, an abbreviated polypyrimidine tract between the branch point A
and the 3-prime splice site is associated with increased exon skipping
and disease. However, many exons, both in CFTR and in other genes, have
short polypyrimidine tracts in their 3-prime splice sites, yet they are
not skipped. Hefferon et al. (2002) examined the molecular basis of the
skipping of constitutive exons in mRNAs and the skipping of exon 9 in
the CFTR gene. They reported observations in human, mouse, and sheep
that placed renewed emphasis on deviations at 3-prime splice sites in
nucleotides other than the invariant GT, particularly when such changes
are found in conjunction with other altered splicing sequences, such as
a shortened polypyrimidine tract. Hefferon et al. (2002) suggested that
careful inspection of entire 5-prime splice sites may identify
constitutive exons that are vulnerable to skipping.

Using a quantitative mRNA assay at 14 time points through ovine
gestation, Broackes-Carter et al. (2002) determined that CFTR expression
was highest at the start of the second trimester followed by a gradual
decline through to term. In contrast, epithelial sodium channel (SCNN1A;
600228) expression increased from the start of the third trimester. The
authors proposed a role for CFTR in differentiation of the respiratory
epithelium and suggested that its expression levels are not merely
reflecting major changes in the sodium/chloride bulk flow close to term.

Eidelman et al. (2002) found that NBF1 of CFTR interacted selectively
with phosphatidylserine rather than phosphatidylcholine. In contrast,
NBF1 with the delta-F508 mutation lost the ability to discriminate
between these phospholipids. In mouse L cells expressing delta-F508
CFTR, replacement of phosphatidylcholine by noncharged analogs led to
increased CFTR protein expression, suggesting that aberrant interaction
between the delta-F508 NFB1 domain and phospholipid chaperones may
contribute to the processing defect of the delta-F508 CFTR mutant.

Plasma membrane expression of delta-F508 CFTR can be rescued in
epithelial cells by culturing them at 27 degrees Celsius for 24 hours.
By screening 100,000 diverse small molecules, Yang et al. (2003) found
that tetrahydrobenzothiophenes could activate cold-induced
membrane-associated delta-F508 CFTR, resulting in reversible Cl-
conductance in transfected rat thyroid epithelial cells. Single-cell
voltage clamp analysis showed characteristic CFTR currents. Activation
required low concentrations of a cAMP agonist, mimicking the normal
physiologic response.

Reddy and Quinton (2003) reported phosphorylation- and ATP-independent
activation of CFTR by cytoplasmic glutamate that exclusively elicits
chloride but not bicarbonate conductance in the human sweat duct. They
also showed that the anion selectivity of glutamate-activated CFTR is
not intrinsically fixed, but can undergo a dynamic shift to conduct
bicarbonate by a process involving ATP hydrolysis. Duct cells from
patients with the delta-F508 CFTR mutation showed no
glutamate/ATP-activated chloride or bicarbonate conductance. In
contrast, duct cells from heterozygous patients with R117H
(602421.0005)/delta-F508 mutations also lost most of the chloride
conductance, yet retained significant bicarbonate conductance. Reddy and
Quinton (2003) concluded that not only does glutamate control neuronal
ion channels, but it can also regulate anion conductance and selectivity
of CFTR in native epithelial cells. They proposed that the loss of this
uniquely regulated bicarbonate conductance is most likely responsible
for the more severe forms of cystic fibrosis pathology.

Wang et al. (2003) demonstrated that endometrial epithelial cells
possess a CFTR-mediated bicarbonate transport mechanism. Coculture of
sperm with endometrial cells treated with antisense oligonucleotide
against CFTR, or with bicarbonate secretion-defective CF epithelial
cells, resulted in lower sperm capacitation and egg-fertilizing ability.
These results were considered consistent with a critical role of CFTR in
controlling uterine bicarbonate secretion and the fertilizing capacity
of sperm, providing a link between defective CFTR and lower female
fertility in CF.

Sheep and human CFTR genes show a gradual decline in expression during
lung development, from the early midtrimester through to term. Mouchel
et al. (2003) identified a novel 5-prime exon of the sheep CFTR gene
(ov1a) that occurs in 2 splice forms (ov1aL and ov1aS), which are both
mutually exclusive with exon 1. CFTR transcripts, including ov1aL and
ov1aS, were present at low levels in many sheep tissues; however, ov1aS
showed temporal and spatial regulation during fetal lung development,
being most abundant when CFTR expression starts to decline. Alternative
5-prime exons -1a and 1a in the human CFTR gene also showed changes in
expression levels through lung development. Structural evaluation of
ov1aL and ov1aS revealed the potential to form extremely stable
secondary structures which would cause ribosomal subunit detachment.
Further, the loss of exon 1 from the CFTR transcript removed motifs that
are thought crucial for normal trafficking of the CFTR protein. Mouchel
et al. (2003) hypothesized that recruitment of these alternative
upstream exons may represent a novel mechanism of developmental
regulation of CFTR expression.

Fischer et al. (2004) found that vitamin C induced the opening of CFTR
chloride channels by increasing the average open probability in the
absence of detectable increased cAMP levels. Exposure of the apical
airway surface to physiologic concentrations of vitamin C stimulated
transepithelial chloride secretion. When instilled into the nasal
epithelium of human subjects, vitamin C activated chloride transport.
Fischer et al. (2004) concluded that cellular vitamin C, via its apical
vitamin C transporter, is a biologic regulator of CFTR-mediated chloride
secretion in epithelia.

Vergani et al. (2005) used single-channel recording methods on intact
CFTR molecules to directly follow opening and closing of the channel
gates, and related these occurrences to ATP-mediated events in the
nucleotide binding domains (NBDs). They found that energetic coupling
between 2 CFTR residues, expected to lie on opposite sides of its
predicted NBD1-NBD2 dimer interface, changes in concert with channel
gating status. The 2 monitored side chains are independent of each other
in closed channels but become coupled as the channels open. Vergani et
al. (2005) concluded that their results directly link ATP-driven tight
dimerization of CFTR's cytoplasmic nucleotide binding domains to opening
of the ion channel in the transmembrane domains. This establishes a
molecular mechanism, involving dynamic restructuring of the NBD dimer
interface, that is probably common to all members of the ABC protein
superfamily.

Using proteomics to assess global CFTR protein interactions, Wang et al.
(2006) showed that HSP90 (see 140571) cochaperones modulated
HSP90-dependent stability of CFTR protein folding in the ER. Small
interfering RNA-mediated partial silencing of the HSP90 cochaperone
ATPase regulator AHA1 (AHSA1; 608466) in human embryonic kidney and lung
cell lines rescued delivery of CFTR delta-F508 to the cell surface. Wang
et al. (2006) proposed that failure of CFTR delta-F508 to achieve an
energetically favorable fold in response to steady-state dynamics of the
chaperone folding environment is responsible for the pathophysiology of
CF.

Using proteomic approaches, Thelin et al. (2007) showed that filamin
(FLNA; 300017) associates with the extreme CFTR N terminus, and found
that the disease-causing S13F mutation disrupts this interaction. Cell
studies revealed that FLNA tethers plasma membrane CFTR to the
underlying actin network, stabilizing CFTR at the cell surface and
regulating the plasma membrane dynamics and confinement of the channel.
In the absence of filamin binding, CFTR is rapidly internalized from the
cell surface, where it accumulates prematurely in lysosomes and is
ultimately degraded. Thelin et al. (2007) concluded that the CFTR N
terminus plays a role in the regulation of the plasma membrane stability
and metabolic stability of CFTR, and stated that S13F is the first
missense mutation in CFTR found to disrupt a protein-protein
interaction.

Coimmunoprecipitation analysis and immunofluorescence microscopy by
Cheng et al. (2002) showed that CAL (GOPC; 606845) interacted with the C
terminus of CFTR in the Golgi. Functional analysis indicated that the
CAL-CFTR interaction resulted in a reduction of the CFTR chloride
current by a selective inhibition of cell surface CFTR expression; this
could be reversed by competition from NHERF (604990).

Cheng et al. (2010) showed that both syntaxin-6 (STX6; 603944) and CAL
were involved in downregulation of CFTR via lysosome-mediated
degradation. STX6 bound the N terminus of CFTR, and CAL independently
bound the C terminus of CFTR. Overexpression of STX6 reduced cell
surface expression of CFTR and caused its instability, but not in the
absence of CAL and not in the presence of a lysosome inhibitor.
Conversely, overexpression of a dominant-negative STX6 mutant or
knockdown of STX6 resulted in CFTR stability. STX6 and CAL had no effect
on the stability of delta-F508 CFTR, which is retained in the ER and
undergoes ER-associated degradation. Cheng et al. (2010) concluded that
STX6 and CAL function in the trans-Golgi network and direct trafficking
of CFTR to the lysosome.

By coimmunoprecipitation of transfected COS-7 and CHO-K1 cells, Rode et
al. (2012) found that human testis anion transporter-1 (TAT1, or
SLC26A8; 608480) interacted with the Cl- and HCO3- conductor CFTR. The 2
proteins colocalized at the equatorial segment of the human sperm head,
with partial colocalization at the annulus. Similar colocalization was
observed in mouse sperm. Voltage clamp experiments showed that TAT1
enhanced PKA (see 188830)-stimulated currents in CFTR-expressing Xenopus
oocytes and stimulated cAMP-dependent CFTR-mediated iodide efflux in
transfected CHO-K1 cells. TAT1 alone did not mediate iodide efflux in
CHO-K1 cells and did not affect whole-cell conductance in Xenopus
oocytes, suggesting that TAT1 is an electoneutral anion exchanger. Rode
et al. (2012) concluded that TAT1 and CFTR cooperate in the regulation
of Cl-/HCO3- fluxes required for sperm motility and capacitation.

BIOCHEMICAL FEATURES

Serohijos et al. (2008) presented a 3-dimensional structure of CFTR,
constructed by molecular modeling and supported biochemically, in which
phe508 mediates a tertiary interaction between the surface of the
N-terminal nucleotide-binding domain and cytoplasmic loop-4 in the
C-terminal membrane-spanning domain. This crucial cytoplasmic membrane
interface is involved in regulation of channel gating and explains the
sensitivity of CFTR assembly to disease-associated mutations in
cytoplasmic loop-4, as well as in the N-terminal nucleotide-binding
domain.

MOLECULAR GENETICS

Kerem et al. (1989) found that approximately 70% of the mutations in CF
patients correspond to a specific deletion of 3 basepairs, which results
in the loss of a phenylalanine residue at amino acid position 508 of the
putative product of the CF gene. Haplotype data based on DNA markers
closely linked to the putative disease gene locus suggested that the
remainder of the CF mutant gene pool consists of multiple, different
mutations. A small set of these latter mutant alleles (about 8%) may
confer residual pancreatic exocrine function in a subgroup of patients
who are pancreatic sufficient. The discovery that the most common CF
abnormality gives rise to the loss of a single amino acid residue in a
functional domain suggests that the phenotype of CF is not due to
complete loss of function of the gene product. The situation may be
comparable to that in sickling disorders, in which a specific subset of
mutations in the beta-globin gene gives rise to an altered protein with
unusual behavior. Complete absence of function of the beta-globin gene
gives rise to a different phenotype, namely, beta-0-thalassemia;
similarly, homozygous loss of function of the CF gene may lead to a
distinctive phenotype.

Trapnell et al. (1991) studied CFTR mRNA transcripts in respiratory
tract epithelial cells recovered by fiberoptic bronchoscopy with a
cytology brush. They found that the transcripts reflected the normal and
the delta-F508 alleles in appropriate proportions. CFTR mRNA transcripts
were expressed in nasal, tracheal, and bronchial epithelial cells in
about 1 to 2 copies per cell, more than 100-fold greater than in
pharyngeal epithelium. Zeitlin et al. (1992) identified a polyclonal
antibody that was used to detect the CFTR glycoprotein in biopsied human
nasal and bronchial tissues and in the apical membrane fraction of ileal
villus tissue. Levels of the protein were modulated pharmacologically.

Zielenski et al. (1991) found a cluster of highly polymorphic
dinucleotide repeats in intron 17b of the CFTR gene, 200 bp downstream
from the preceding exon. At least 24 alleles, with sizes ranging from 7
to 56 units of a TA repeat, were identified in a panel of 92 unrelated
carriers of CF. The common alleles had 7, 30, and 31 dinucleotide units,
with frequencies of 0.22, 0.19, and 0.12, respectively, among the non-CF
chromosomes. A less polymorphic dinucleotide cluster, a CA repeat, was
also detected in a region 167 bp downstream from the TA repeat. This
varied from 11 to 17 dinucleotide units and appeared to bear an inverse
relationship to that of the TA repeats. These repeats were considered to
be useful in genetic linkage studies, in counseling CF families with
unknown mutations, and in tracing the origins of various mutant CF
alleles. Morral et al. (1991) and Chehab et al. (1991) also described
repeats within introns of the CFTR gene. The significance of the inverse
correlation between the lengths of the 2 repeat regions was not
investigated; length compensation may be involved and may have
functional importance.

Chalkley and Harris (1991) made use of 'ectopic' or 'illegitimate'
transcription of CF mRNA in leukocytes in the detection of CF mutations.
By use of PCR, it was possible to detect such ectopic transcription as
in the case of other genes such as those for dystrophin (300377) and
factor VIII (300841). Fonknechten et al. (1992) extended these
observations, using the PCR reaction for detecting CFTR mutations in the
study of lymphocytes and lymphoblasts. Ferrie et al. (1992) applied the
amplification refractory mutation system (ARMS) to the detection of
mutations in the CFTR gene.

Cutting et al. (1990) sought mutations in the 2 NBFs of CFTR by
nucleotide sequencing of exons 9, 10, 11, and 12 (encoding the first
NBF) and exons 20, 21, and 22 (encoding most of the second NBF) from 20
Caucasian and 18 American black CF patients. They found a cluster of 4
mutations in a 30-bp region of exon 11. Three of the mutations caused
amino acid substitutions at residues that are highly conserved among the
CFTR protein, the multiple-drug-resistance proteins, and ATP-binding
membrane-associated transport proteins. The fourth mutation created a
premature termination signal.

To explore the molecular mechanisms responsible for defective chloride
transport in patients with CF, Yang et al. (1993) studied the
processing, localization, and function of wildtype, delF508
(602421.0001) and G551D (602421.0013) CFTR in retrovirus transduced L
cells. They concluded that the molecular pathology of G551D is explained
by an abnormality in channel activity, while the defect in delF508 is a
combination of mislocalization and instability of the protein in
addition to partial defects in channel function. Some of their
observations suggested the possibility of pharmacologic therapies for CF
based on activating latent CFTR.

Not only is there heterogeneity in the mutations causing cystic
fibrosis, but the pathogenetic mechanisms also vary. Deletion of
phenylalanine-508 appears to cause disease by abrogating normal
biosynthetic processing and thereby resulting in retention and
degradation of the mutant protein within the endoplasmic reticulum.
Other mutations, such as the relatively common gly551-to-asp mutation,
appear to be normally processed and, therefore, must cause disease
through some other mechanism. Because both delta-F508 and G551D occur
within a predicted nucleotide-binding domain (NBD) of CFTR, Logan et al.
(1994) tested the influence of these mutations on nucleotide binding by
the protein. They found that G551D and the corresponding mutation in the
CFTR second nucleotide binding domain, gly1349-to-asp (G1349D), led to
decreased nucleotide binding by CFTR NBDs, while the delta-F508 mutation
did not alter nucleotide binding. These results implicated defective
ATP-binding as the pathogenic mechanism of a relatively common mutation
leading to CF and suggested that structural integrity of a highly
conserved region present in over 30 prokaryotic and eukaryotic
nucleotide-binding domains may be critical for normal nucleotide
binding.

CFTR was one of the genes used by Marshal et al. (1995) to test their
method of mutation detection using bacteriophage resolvases, whose
function in vivo is to cleave branched DNA and which have the property
of recognizing mismatched bases in double-stranded DNA and cutting the
DNA at the mismatch. The new method, termed enzyme mismatch cleavage
(EMC) by Youil et al. (1995), who independently developed the method,
takes advantage of this characteristic of resolvases to detect
individuals who are heterozygous at a given site. Radiolabeled DNA is
cleaved by the resolvase at the site of mismatch in heteroduplex DNA and
digestion is monitored on a gel. Thus, both the presence and the
estimated position of an alteration is revealed. One may think of the
resolvase as a restriction enzyme that only recognizes mutations.

There is a polymorphic string of thymidines at the end of intron 8 of
the CFTR gene; 3 different alleles can be found depending on the number
of thymidines (5, 7, or 9) present at this site (Chu et al., 1991). The
number of thymidines determines the efficiency by which the intron 8
splice acceptor site is used. The efficiency decreases when a shorter
stretch of thymidine residues is found. A higher proportion of CFTR
transcripts that lack exon 9 sequences, which encode part of the
functionally important first nucleotide-binding domain, will therefore
be found when a shorter stretch of thymidine residues is present (Chu et
al., 1993). If a CFTR gene with the arg117-to-his (R117H) mutation
(602421.0005) harbors a T5 allele, the mutant gene will be responsible
for CF. An R117H mutant CFTR gene that harbors a T7 allele can either
result in CF or CBAVD (Kiesewetter et al., 1993). Teng et al. (1997)
noted that the T5 allele results in the most inefficient use of this
splice acceptor site. Most CFTR transcripts from a T5 allele will
therefore lack exon 9 sequencing. Such exon 9-deficient CFTR transcripts
are known to be translated into CFTR proteins that will not mature, and
will therefore not function as chloride channels in the apical membrane
of epithelial cells. Among CBAVD patients, the frequency of this T5
allele is 4- to 6-fold higher than in the control population (see
602421.0005). Teng et al. (1997) analyzed CFTR transcripts qualitatively
and quantitatively in nasal epithelial and vas deferens cells.
Alternative splicing of exon 9, which had been known to occur in nasal
epithelial cells, also occurred in vas deferens cells. The extent of
this alternative splicing was determined by the allele present at the Tn
locus at the end of intron 8 of the CFTR gene. However, the proportion
of transcripts lacking exon 9 sequences was increased in vas deferens
cells compared with nasal epithelial cells, independent of the Tn
genotype. Thus, Teng et al. (1997) postulated that tissue-specific
differences in the proportion of CFTR transcripts lacking exon 9
sequences may contribute to the tissue-specific disease phenotype
observed in individuals with CBAVD.

Besides the polymorphic Tn locus, more than 120 polymorphisms have been
described in the CFTR gene. Cuppens et al. (1998) hypothesized that the
combination of particular alleles at several polymorphic loci might
result in less functional or even insufficient CFTR protein. Analysis of
3 polymorphic loci with frequent alleles in the general population
showed that, in addition to the known effect of the Tn locus, the
quantity and quality of CFTR transcripts and/or proteins were affected
by 2 other polymorphic loci: M470V (602421.0023) and a dinucleotide
repeat polymorphism (TG)m. On a T7 background, the (TG)11 allele gave a
2.8-fold increase in the proportion of CFTR transcripts that lacked exon
9, and (TG)12 gave a 6-fold increase, compared with the (TG)10 allele.
T5 CFTR genes derived from patients were found to carry a high number of
TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored
a low number of TG repeats. Moreover, it was found that M470 CFTR
proteins matured more slowly, and that they had a 1.7-fold increased
intrinsic chloride channel activity compared with V470 CFTR proteins,
suggesting that the M470V locus might also play a role in the partial
penetrance of T5 as a disease mutation. Such polyvalent mutant genes
could explain why apparently normal CFTR genes cause disease. Moreover,
they might be responsible for variation in the phenotypic expression of
CFTR mutations. This study suggested that genetic and functional studies
of polymorphisms in relation to genetic diseases will become of major
interest, in relation both to monogenic disorders and complex traits.

In 9 of 16 cases of disseminated bronchiectasis (56%), Pignatti et al.
(1996) found the 5T allele in intron 8 (IVS8-5T) and/or a CFTR gene
mutation. The results confirmed, at the molecular genetic level, a
clinical connection between CF and one obstructive pulmonary disease,
disseminated bronchiectasis of unknown origin. Similarly, Girodon et al.
(1997) studied 32 patients with disseminated bronchiectasis and a
clinically isolated respiratory syndrome. Analysis of all CFTR gene
exons and their flanking regions demonstrated 13 CFTR gene mutations in
16 different alleles. Six of these mutations, which had previously been
reported as CF defects, were found in 9 alleles. Four patients were
compound heterozygotes; 6 were heterozygous for a mutation. Girodon et
al. (1997) concluded that CFTR gene mutations may play a role in
bronchiectatic lung disease, possibly in a multifactorial context.

It has been proposed that in heterozygous state mutations of the CFTR
gene provide increased resistance to infectious diseases, thereby
maintaining mutant CFTR alleles at high levels in selected populations.
Pier et al. (1998) investigated whether typhoid fever could be one such
disease. This disease is initiated when Salmonella typhi enters
gastrointestinal epithelial cells for submucosal translocation. They
found that S. typhi, but not the related murine pathogen S. typhimurium,
uses CFTR for entry into epithelial cells. Cells expressing wildtype
CFTR internalized more S. typhi than isogenic cells expressing the most
common CFTR mutation, delta-F508 (602421.0001). Monoclonal antibodies
and synthetic peptides containing a sequence corresponding to the first
predicted extracellular domain of CFTR inhibited uptake of S. typhi.
Heterozygous delta-F508 Cftr mice translocated 86% fewer S. typhi into
the gastrointestinal submucosa than did wildtype Cftr mice; no
translocation occurred in delta-F508 Cftr homozygous mice. The Cftr
genotype had no effect on the translocation of S. typhimurium.
Immunoelectron microscopy revealed that more CFTR bound S. typhi in the
submucosa of Cftr wildtype mice than in delta-F508 heterozygous mice.
Pier et al. (1998) concluded that diminished levels of CFTR in
heterozygotes decreases susceptibility to typhoid fever.

Van de Vosse et al. (2005) tested the hypothesis that CFTR heterozygotes
have a selective advantage against typhoid, which may be conferred
through reduced attachment of S. typhi to the intestinal mucosa. They
genotyped patients and controls in a typhoid endemic area in Indonesia
for 2 highly polymorphic markers in CFTR and the most common CF
mutation, F508del. Consistent with the apparently very low incidence of
CF in Indonesia, the F508del mutation was not present in any patients or
controls. However, they found significant association between a common
polymorphism in intron 8 (16 or 17 CA repeats) and selective advantage
against typhoid.

Sharer et al. (1998) studied 134 consecutive patients with chronic
pancreatitis (167800) (alcohol-related disease in 71,
hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic
disease in 60). DNA was examined for 22 mutations of the CFTR gene that
together account for 95% of all mutations in patients with cystic
fibrosis in the northwest of England where the study was performed. They
also determined the length of the noncoding sequence of thymidines in
intron 8, since the shorter the sequence, the lower the proportion of
normal CFTR mRNA. None of the patients had a mutation on both copies of
the CFTR gene. Eighteen patients (13.4%), including 12 without
alcoholism, had a CFTR mutation on 1 chromosome, as compared with a
frequency of 5.3% among 600 local unrelated partners of persons with a
family history of cystic fibrosis (P less than 0.001). A total of 10.4%
of the patients had the 5T allele in intron 8 (14 of 134), which is
twice the expected frequency (P = 0.008). Four patients were
heterozygous for both a CFTR mutation and the 5T allele. Patients with a
CFTR mutation were younger than those with no mutations (P = 0.03). None
had the combination of sinopulmonary disease, high sweat electrolyte
concentrations, and low nasal potential-difference values that is
diagnostic of cystic fibrosis.

Similarly, Cohn et al. (1998) studied 27 patients (mean age at
diagnosis, 36 years), 22 of whom were female, who had been referred for
an evaluation of idiopathic pancreatitis. DNA was tested for 17 CFTR
mutations and for the 5T allele in intron 8. The 5T allele reduces the
level of functional CFTR and is associated with an inherited form of
infertility in males, CBAVD. Cohn et al. (1998) found that 10 patients
with idiopathic chronic pancreatitis (37%) had at least 1 abnormal CFTR
allele. Eight CFTR mutations were detected. In 3 patients both alleles
were affected. These 3 patients did not have lung disease typical of
cystic fibrosis on the basis of sweat testing, spirometry, or base-line
nasal potential-difference measurements. Nonetheless, each had abnormal
nasal cyclic AMP-mediated chloride transport. The genotypes of the 3
patients were delF508/wildtype (602421.0001), 9T/5T in 2, and
delF508/R117H (602421.0005), 9T/7T in 1. These are the 2 most common
genotypes in patients with CBAVD. These genotypes do not typically cause
lung disease. In contrast, lung disease is present in patients with a
genotype of delF508/R117H, 9T/5T.

An abbreviated tract of 5T in intron 8 of the CFTR gene is found in
approximately 10% of individuals. To test whether the number of TG
repeats adjacent to 5T influences disease penetrance, Groman et al.
(2004) determined TG repeat number in 98 patients with male infertility
due to congenital absence of the vas deferens (277180), 9 patients with
nonclassic CF, and 27 unaffected individuals (fertile men). Each of the
individuals in this study had a severe CFTR mutation on one CFTR gene
and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had
5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected
individuals. Conversely, 91% (97 of 107) of affected individuals had 12
or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P
less than 0.00001). Those individuals with 5T adjacent to either 12 or
13 TG repeats were substantially more likely to exhibit an abnormal
phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0,
95% CI 11.1-103.7.7, P less than 0.00001). Thus, determination of TG
repeat number will allow for more accurate prediction of benign versus
pathogenic 5T alleles.

Lee et al. (2003) haplotyped 117 Korean controls and 75 CF patients
having bronchiectasis or chronic pancreatitis using 11 polymorphisms in
CFTR. Several haplotypes, especially those with Q1352H (602421.0133),
IVS8 T5 (602421.0086), and E217G (602421.0134), were found to have
disease associations in a case-control study. The common M470V
polymorphism (602421.0023) appeared to affect the intensity of the
disease association. The T5-V470 haplotype showed higher disease
association than T5-M470, but the Q1352H mutation in a V470 background
showed the strongest disease association. Nonsynonymous E217G and Q1352H
mutations in the M470 background caused a 60 to 80% reduction in
CFTR-dependent chloride currents and bicarbonate transport activities.
The M470V polymorphic variant in combination with the Q1352H mutation
completely abolished CFTR-dependent anion transport activities. The
results revealed that interactions between multiple genetic variants in
cis affected the final function of the gene products.

Buratti et al. (2001) showed that nuclear factor TDP43 (605078) binds
specifically to the UG repeat sequence of CFTR pre-mRNA and, in this
way, promotes skipping of CFTR exon 9. Wang et al. (2004) found that the
mouse homolog of human TDP43 also inhibits human CFTR exon 9 splicing in
a minigene system. Buratti et al. (2004) described experiments
consistent with the model in which the TG repeats in the CFTR intron 8
bind to TDP43, and this protein, in turn, inhibits splicing of exon 9.
They suggested that their results provide a mechanistic explanation for
the association data of Groman et al. (2004) and also an explanation for
the variable phenotypic penetrance of the TG repeats. Individual and
tissue-specific variability in the concentration of this inhibitory
splicing factor may even determine whether an individual will develop
multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease.

Audrezet et al. (2002) analyzed the entire coding sequence and
exon/intron junctions of the CFTR gene by denaturing high-performance
liquid chromatography (DHPLC) and direct sequencing in 39 white French
patients with idiopathic chronic pancreatitis. A total of 18 mutant
alleles were identified in 14 patients (35.9%), among whom 4 were
compound heterozygotes. None of the 4 compound heterozygotes were found
to have unrecognized CF-related pulmonary symptoms following
reevaluation. However, a sweat test done retrospectively was positive in
2 of them. The 5T allele of the polymorphic string of thymidines at the
end of intron 8 of the CFTR gene was present in 7 of the 36 patients
tested, an allele frequency (9.7%) nearly 2 times greater than the rate
of 5% in the general population (P = 0.09).

The molecular pathogenesis of cystic fibrosis has been investigated by
analysis of delF508 CFTR in different heterologous systems, revealing an
abrogation of CFTR expression by defective protein maturation. Mutant
CFTR was found arrested in an early wildtype intermediate, unable to
adopt a protease-resistant mature conformation (Cheng et al., 1990;
Gregory et al., 1991; Zhang et al., 1998) that enables exit from the
endoplasmic reticulum and processing in the Golgi compartment. Prolonged
interaction of immature delF508 CFTR with the chaperones calnexin (CANX;
114217) and Hsp70 (see 140550) in experiments by Pind et al. (1994) and
Yang et al. (1993), respectively, indicated that the aberrant protein is
recognized by the cell's quality control and that premature degradation
by the ubiquitin-proteasome pathway occurs in a pre-Golgi compartment
(Jensen et al., 1995; Sato et al., 1998). Reduction of temperature
(Denning et al., 1992) and addition of chemical chaperones such as
glycerol (Sato et al., 1996) and trimethylamine-N-oxide (Brown et al.,
1996) overcame impediments in the folding pathway of delF508 CFTR and
allowed proper targeting, thus demonstrating that the mutant protein is
still capable of assuming a mature conformation. However, at the cell
surface, the chloride channel formed therefrom showed a decreased
half-life and reduced open probability and sensitivity to stimulation
with cAMP agonists.

Kalin et al. (1999) investigated endogenous CFTR expression in skin
biopsies and respiratory and intestinal tissue specimens from delF508
homozygous patients and non-CF persons, using immunohistochemical and
immunoblot analyses with a panel of CFTR antibodies. CFTR expression was
detected at the luminal surface of reabsorptive sweat ducts and airway
submucosal glands, at the apex of ciliated cells in pseudostratified
respiratory epithelia and of isolated cells of the villi of duodenum and
jejunum, and within intracellular compartments of intestinal goblet
cells. In delF508 homozygous patients, expression of the mutant protein
proved to be tissue specific. Whereas delF508 CFTR was undetectable in
sweat glands, the expression in the respiratory and intestinal tracts
could not be distinguished from the wildtype by signal intensity or
localization. The tissue-specific variation of delF508 CFTR expression
from null to apparently normal amounts indicated that delF508 CFTR
maturation can be modulated and suggested that determinants other than
CFTR mislocalization should play a role in delF508 CF respiratory and
intestinal disease.

Welsh and Smith (1993) provided a classification of the mechanisms by
which mutations in CFTR cause cystic fibrosis. The grouping of mutations
into 5 classes was based on their functional effect: (I) defective
protein production; (II) defective protein processing; (III) defective
protein regulation; (IV) defective protein conductance; and (V) reduced
amounts of functional CFTR protein. Class I, II, and III mutations have
been associated with typical severe multiorgan disease on the basis of
clinical studies. In contrast, class IV and V mutations appeared to
confer sufficient functional CFTR to result in a mild phenotype.

Haardt et al. (1999) reviewed the various classes of CF-associated
mutations and added a tentative additional class VI. They suggested that
the mutations can be grouped into 2 major categories. The first group
includes those mutants that are unable to accumulate at the cell
surface, either because of impaired biosynthesis (class I and class V),
or because of defective folding at the endoplasmic reticulum (class II).
Mutants that belong to the second category are expressed at the cell
surface but fail to translocate chloride ions because of a defect in
activation (class IV) or channel conductance (class III). Because the
biosynthetic processing and macroscopic chloride channel function of
some of the truncated CFTR constructs appear to be normal but the
biologic stability of their mature, complex-glycosylated form is
dramatically reduced, Haardt et al. (1999) proposed a class VI, which
would include stability mutants such as those characterized by their
experiments.

To study the consequences that disease-causing mutations have on the
regulatory function of CFTR, Mickle et al. (2000) transiently expressed
CFTR-bearing mutations associated with CF or its milder phenotype,
congenital bilateral absence of the vas deferens (277180), and
determined whether mutant CFTR could regulate outwardly rectifying
chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the
first nucleotide-binding domain, delta-F508del (602421.0001), functioned
as a chloride channel but did not regulate ORCCs. However, CFTR that had
disease-associated mutations in other domains retained both functions,
regardless of the associated phenotype. Thus, a relationship between
loss of CFTR regulatory function and disease severity is evident for
NBD1, a region of CFTR that appears important for regulation of separate
channels.

Bronsveld et al. (2001) determined chloride transport properties of the
respiratory and intestinal tracts in delta-F508 twins and sibs. In
respiratory tissue, the expression of basal CFTR-mediated chloride
conductance, demonstrated by 30% of delta-F508 homozygotes, was
identified as a positive predictor of milder CF. In intestinal tissue,
4,4-prime-diisothiocyanatostilbene-2,2-prime-disulfonic acid
(DIDS)-insensitive chloride secretion, which is indicative of functional
CFTR channels, correlated with a milder phenotype, whereas
DIDS-sensitive chloride secretion was observed mainly in more severely
affected patients. Bronsveld et al. (2001) concluded that in delta-F508
patients, the ability to secrete chloride in the organs that are
primarily involved in the course of CF is predictive of the CF
phenotype.

Bobadilla et al. (2002) determined the distribution of CFTR mutations in
as many regions throughout the world as possible in an effort to
understand the evolution of the disease in each region and gain insight
for decisions regarding screening programs. Although wide mutational
heterogeneity was found throughout the world, characterization of the
most common mutations in most populations was possible. A significant
positive correlation was found between delta-F508 frequency and the CF
incidence of regional populations.

Primary sclerosing cholangitis (PSC; see 109720), a slowly progressive
cholestatic liver disease characterized by fibroobliterative
inflammation of the biliary tract, leads to cirrhosis and portal
hypertension and is a major indication for liver transplantation. Sheth
et al. (2003) stated that 75 to 80% of cases were associated with
inflammatory bowel disease (IBD; 266600) and that 2.5 to 7.5% of
patients with IBD develop PSC (Lee and Kaplan, 1995). Sheth et al.
(2003) hypothesized that dysfunction of CFTR may explain why a subset of
patients with IBD develop PSC. They prospectively evaluated CFTR
genotype and phenotype in 19 patients with PSC compared with 18 patients
with IBD and no liver disease, 17 with primary biliary cirrhosis (PBC;
109720), 81 with CF, and 51 healthy controls. They found an increased
prevalence of CFTR abnormalities in heterozygous state in PSC as
demonstrated by molecular and functional analyses, and concluded that
these abnormalities may contribute to the development of PSC in a subset
of patients with IBD. Eighty-nine percent of PSC patients carried
genotypes containing the 1540G variant (602421.0023) resulting in
decreased functional CFTR compared with 57% of disease controls (P =
0.03). Only 1 of 19 PSC patients had neither a CFTR mutation nor the
1540G variant. CFTR chloride channel function assessed by nasal
potential difference testing demonstrated a reduced median isoproterenol
response in PSC patients compared with disease controls and healthy
controls.

Pagani et al. (2003) showed that several nucleotide changes in exon 12
of the CFTR gene induced a variable extent of exon skipping, leading to
reduced levels of normal transcripts. This was the case in 2 natural
mutations--1 of which was gly576 to ala (G576A; 602421.0061), which had
previously been considered a neutral polymorphism--and several
site-directed silent substitutions. This phenomenon was due to the
interference with a regulatory element, which the authors named
composite exonic regulatory element of splicing (CERES). The effect of
single-nucleotide substitutions at CERES could not be predicted by
either serine-arginine-rich (SR) matrices or enhancer identification.
Pagani et al. (2003) suggested that appropriate functional splicing
assays should be included in genotype screenings to distinguish between
polymorphisms and pathogenic mutations.

By testing 19 synonymous changes in nucleotides 13 to 52 of the human
CFTR exon 12, Pagani et al. (2005) found that the probability of
inducing exon skipping with a single synonymous substitution was
approximately 30%, demonstrating that synonymous substitutions can
affect splicing and are not neutral in evolution as they can be
constrained by splicing requirements. Pagani et al. (2005) suggested
that evolutionary selection of genomic variation takes place at 2
sequential levels: splicing control and protein function optimization.

Aznarez et al. (2003) investigated the consequence of 2 CF
disease-causing mutations on the function of a putative exonic splicing
enhancer (ESE) in exon 13 of the CFTR gene. Both mutations caused
aberrant splicing in a predicted manner, supporting a role for the
putative ESE sequence in pre-mRNA splicing. In addition, 3 mutations,
including D648V (602421.0097), caused aberrant splicing of exon 13 by
improving the polypyrimidine tracts of 2 cryptic 3-prime splice sites.
The relative levels of 2 splicing factors, Tra2-alpha (TRA2A; 602718)
and SF2/ASF (SFRS1; 600812), altered the effect on splicing of some of
the exon 13 disease mutations. The authors suggested that the severity
of CF may be modulated by changes in the fidelity of CFTR pre-mRNA
splicing.

Audrezet et al. (2004) reported the first systematic screening of the 27
exons of the CFTR gene for large genomic rearrangements, by means of the
quantitative multiplex PCR of short fluorescent fragments (QMPSF).
Although many disease alleles of CFTR had previously been identified, up
to 30% of disease alleles still remained to be identified in some
populations, and it had been suggested that gross genomic rearrangements
could account for these unidentified alleles. Audrezet et al. (2004)
studied a well-characterized cohort of 39 patients with classic CF
carrying at least 1 unidentified allele. Using QMPSF, approximately 16%
of the previously unidentified CF mutant alleles were identified and
characterized, including 5 novel mutations (1 large deletion and 4
insertions/deletions). The breakpoints of these 5 mutations were
precisely determined. Although nonhomologous recombination may be
invoked to explain all 5 complex lesions, each mutation appeared to have
arisen through a different mechanism. One of the insertions/deletions
was highly unusual in that it involved the insertion of a short 41-bp
sequence with partial homology to a retrotranspositionally-competent
LINE-1 element. Audrezet et al. (2004) suggested that the insertion of
this ultra-short LINE-1 element (dubbed a 'hyphen element') may
constitute a novel type of mutation associated with human genetic
disease.

Dinucleotide repeats are ubiquitous features of eukaryotic genomes. The
highly variable nature of dinucleotide repeats makes them particularly
interesting candidates for modifiers of RNA splicing when they are found
near splicing signals. An example of a variable dinucleotide repeat that
affects splicing is a TG repeat located in the splice acceptor of exon 9
of the CFTR gene. Higher repeat numbers result in reduced exon 9
splicing efficiency and, in some instances, the reduction in full-length
transcript is sufficient to cause male infertility due to congenital
bilateral absence of the vas deferens (277180) or nonclassic cystic
fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied
TG tract variation and observed the same correlation between
dinucleotide repeat number and exon 9 splicing efficiency seen in vivo.
Placement of the TG dinucleotide tract in the minigene with random
sequence abolished splicing of exon 9. Replacement of the TG tract with
sequences that can self-basepair suggested that the formation of an RNA
secondary structure was associated with efficient splicing; however,
splicing efficiency was inversely correlated with the predicted
thermodynamic stability of such structures, demonstrating that
intermediate stability was optimal. Finally, substitution with TA
repeats of differing length confirmed that stability of the RNA
secondary structure, not sequence content, correlated with splicing
efficiency. Hefferon et al. (2004) concluded that dinucleotide repeats
can form secondary structures that have variable effects on RNA splicing
efficiency and clinical phenotype.

Wong et al. (2003) described pancreatic-insufficient CF in a child whose
father was from Taiwan and mother from Vietnam. The child had 2
different null mutations, glu7 to ter (602421.0131) in exon 1 and a 1-bp
insertion, 989A (602421.0132), which caused frameshift and a truncated
CFTR protein of 306 amino acids. Wong et al. (2003) commented on the
fact that East Asian CF patients did not share mutations with patients
of other ethnic backgrounds. Even within East Asians, the CFTR mutation
spectrum in Chinese patients is distinct from that of Japanese patients.

Chang et al. (2007) identified mutations in the CFTR gene in 14.1% of
total alleles and 24.4% of 78 Chinese/Taiwanese patients with idiopathic
chronic pancreatitis (ICP; 167800) compared to 4.8% of total alleles and
9.5% of 200 matched controls. The findings indicated that heterozygous
carriers of CFTR mutations have an increased risk of developing ICP. The
mutations identified were different from those usually observed in
Western countries. The T5 allele with 12 or 13 TG repeats was
significantly associated with earlier age at onset in patients with ICP,
although the frequency of this allele did not differ between patients
and controls.

Sun et al. (2006) analyzed the polymorphic TG dinucleotide repeat
adjacent to the 5T variant in intron 8 and the codon 470 in exon 10.
Patients selected for this study were positive for both the 5T variant
and the major cystic fibrosis mutation, delta-F508. Almost all
delta-F508 mutations occur in a 10TG-9T-470M haplotype. Therefore, it is
possible to determine the haplotype of the 5T variant in trans. Of the
74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were
12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which
they had clinical information, Sun et al. (2006) reported that 17.6% of
females (6 of 34) and 66.7% of males (10 of 15) showed symptoms
resembling atypical cystic fibrosis. The haplotype with the highest
penetrance in females (42%, or 5 of 12) and more than 80% (5 of 6) in
males was 12TG-5T-470V. The authors also evaluated 12 males affected
with congenital bilateral absence of vas deferens and positive for the
5T variant; 10 of 12 had the 12TG-5T-470V haplotype. Sun et al. (2006)
concluded that overall, the 5T variant has a milder clinical consequence
than previously estimated in females. The clinical presentations of the
5T variant are associated with the 5T-12TG-470M haplotype.

Alonso et al. (2006) analyzed 1,954 Spanish cystic fibrosis alleles to
define the molecular spectrum of mutations. Commercial panels showed a
limited detection power, leading to the identification of only 76% of
alleles. More sensitive assays identified 12 mutations with frequencies
above 1%, the F508del mutation being the most frequent, present on 51%
of alleles. In the Spanish population, 18 mutations were needed to
achieve a detection rate of 80%. Fifty-one mutations (42%) were observed
once. Alonso et al. (2006) identified a total of 121 disease-causing
mutations that accounted for 96% of CF alleles.

- Effect of Aminoglycoside Antibiotics

In addition to their antimicrobial activity, aminoglycoside antibiotics
can suppress premature termination codons by allowing an amino acid to
be incorporated in place of the stop codon, thus permitting translation
to continue to the normal end of the transcript. The mechanism
translation termination is highly conserved among most organisms and is
almost always signaled by an amber (UAG), ochre (UAA), or opal (UGA)
termination codon. The nucleotide sequence surrounding the termination
codon has an important role in determining the efficiency of translation
termination. Aminoglycoside antibiotics can reduce the fidelity of
translation, predominantly by inhibiting ribosomal 'proofreading,' a
mechanism to exclude poorly matched aminoacyl-tRNA from becoming
incorporated into the polypeptide chain. In this way aminoglycosides
increase the frequency of erroneous insertions at the nonsense codon and
permit translation to continue to the end of the gene, as has been shown
in eukaryotic cells (Burke and Mogg, 1985), including human fibroblasts
(Buchanan et al., 1987).

Howard et al. (1996) demonstrated that 2 CFTR-associated stop mutations
could be suppressed by treating cells with low doses of an
aminoglycoside antibiotic. Others demonstrated this effect in cultured
cells bearing CFTR nonsense mutations and in connection with stop
mutations in muscular dystrophy in mice and in vitro in Hurler syndrome
(607014), cystinosis (219800), and other disorders.

In a CF bronchial cell line carrying the CFTR W1282X (602421.0022)
mutation, Bedwell et al. (1997) demonstrated that treatment with the
aminoglycosides G418 and gentamicin restored CFTR expression, as shown
by the reappearance of cAMP-activated chloride currents, the restoration
of CFTR protein at the apical plasma membrane, and an increase in the
abundance of CFTR mRNA levels from the W1282X allele.

Wilschanski et al. (2003) performed a double-blind placebo-controlled
crossover trial of intranasal gentamicin in patients with stop mutations
in CFTR, in comparison with patients homozygous for the delta-F508
mutation. Nasal potential difference was measured at baseline and after
each treatment. Gentamicin treatment caused a significant reduction in
basal potential difference in 19 patients carrying stop mutations and a
significant response to chloride-free isoproterenol solution. This
effect of gentamicin on nasal potential difference occurred both in
patients who were homozygous for stop mutations and in those who were
heterozygous, but not in patients who were homozygous for delta-F508.
After gentamicin treatment, a significant increase in peripheral and
surface staining for CFTR was observed in the nasal epithelial cells of
patients carrying stop mutations.

ANIMAL MODEL

Tata et al. (1991) cloned the mouse homolog of the human CFTR gene.

McCombie et al. (1992) used expressed sequence tags to identify homologs
of human genes, including CFTR and the LDL receptor gene (606945), in
Caenorhabditis elegans. They suggested that C. elegans, because of the
extensive information on the physical and genetic map of the organism,
might have unique advantages for the study of the function of normal and
mutant genes. The same approach was applied even more extensively by
Waterston et al. (1992) who, by study of a cDNA library, identified
about 1,200 of the estimated 15,000 genes of C. elegans. More than 30%
of the inferred protein sequences had significant similarity to existing
sequences in databases.

Zeiher et al. (1995) noted that the F508del (602421.0001) mutation
disrupts the biosynthetic processing of CFTR so that the protein is
retained in the endoplasmic reticulum and is then degraded. As a result,
affected epithelia lack CFTR in the apical membrane and lack
cAMP-stimulated chloride ion permeability. Dorin et al. (1992) and
Snouwaert et al. (1992), as well as others, disrupted the mouse CFTR
gene to create null mutant mice that lack CFTR or express greatly
reduced amounts of wildtype protein. To understand the pathophysiology
of the disease and to evaluate new therapies, Zeiher et al. (1995) used
a targeting strategy to introduce the F508del mutation into the mouse
CFTR gene. Murine CFTR is 78% identical to human CFTR, and it contains a
phenylalanine at residue 508 flanked by 28 amino acids identical to
those in human CFTR. They could show that affected epithelia from
homozygous F508del mice lacked CFTR in the apical membrane and were
chloride ion-impermeable. Forty percent of homozygous animals survived
into adulthood and displayed several abnormalities found in human
disease and in CFTR null mice.

Van Doorninck et al. (1995) generated a mouse model of CF with the
phe508del mutation using the 'hit-and-run' mutagenesis procedure. In
this model, the intron structure was not disturbed, in contrast to
similar models (Zeiher et al., 1995; Colledge et al., 1995). French et
al. (1996) demonstrated that in this model of CF the mutant CFTR was not
processed efficiently to the fully glycosylated form in vivo. However,
the mutant protein was expressed as functional chloride channels in the
plasma membrane of cells cultured at reduced temperature. Furthermore,
they could show that the electrophysiologic characteristics of the mouse
phe508del-CFTR channels were indistinguishable from normal. In
homozygous mutant mice they did not observe a significant effect of
genetic background on the level of residual chloride channel activity.
The data showed that like its human homolog, the mouse mutant CFTR is a
temperature-sensitive processing mutant, and therefore an authentic
model for study of pathophysiology and therapy.

Dickinson et al. (2002) replicated the G480C mutation (602421.0083) in
the murine Cftr gene using the 'hit-and-run' double recombination
procedure. The G480C cystic fibrosis mouse model expressed the G480C
mutant transcript at a level comparable to that of wildtype Cftr. The
homozygous mutant mice were fertile and had normal survival, weight,
tooth color, and no evidence of cecal blockage, despite mild goblet cell
hypertrophy in the intestine. Analysis of the mutant protein revealed
that the majority of G480C CFTR was abnormally processed and no G480C
CFTR-specific immunostaining in the apical membranes of intestinal cells
was detected. The bioelectric phenotype of these mice revealed
organ-specific electrophysiological effects. In contrast to delta-F508
'hit-and-run' homozygotes, the classic defect of forskolin-induced
chloride ion transport was not replicated in the cecum, but the response
to low chloride in the nose was clearly defective in the G480C mutant
animals.

Of importance to any gene-replacement strategy for treatment of CF is
the identification of the cell type(s) within the lung milieu that need
to be corrected and an indication whether this is sufficient to restore
a normal inflammatory response and bacterial clearance. Oceandy et al.
(2002) generated G551D CF mice transgenically expressing the human CFTR
gene in 2 tissue compartments previously demonstrated to mediate a
CFTR-dependent inflammatory response: lung epithelium and alveolar
macrophages. Following chronic pulmonary infection with Pseudomonas
aeruginosa, CF mice with epithelial-expressed (but not
macrophage-specific) CFTR showed an improvement in pathogen clearance
and inflammatory markers compared with control CF animals. The authors
concluded that there may be a role for CFTR-mediated events in
epithelial cells in response of the lung to bacterial pathogens.

Di et al. (2006) found that alveolar macrophages from Cftr -/- mice
retained the ability to phagocytose and generate an oxidative burst, but
exhibited defective killing of internalized bacteria. Lysosomes from
Cftr -/- macrophages failed to acidify, although they retained normal
fusogenic capacity with nascent phagosomes. Di et al. (2006) proposed
that CFTR contributes to lysosome acidification and that in its absence
phagolysosomes acidify poorly, thus providing an environment conducive
to bacterial replication.

The delta-F508 CFTR mutation results in the production of a misfolded
CFTR protein that is retained in the endoplasmic reticulum and targeted
for degradation. Curcumin, a major component of the curry spice
turmeric, is a nontoxic calcium-adenosine triphosphatase pump inhibitor
that can be administered to humans safely. Egan et al. (2004) found that
oral administration of curcumin to homozygous delta-F508 Cftr mice in
doses comparable, on a weight-per-weight basis, to those well tolerated
by humans corrected these animals' characteristic nasal potential
difference defect. These effects were not observed in mice homozygous
for a complete knockout of the CFTR gene. Curcumin also induced the
functional appearance of delta-F508 CFTR protein in the plasma membranes
of transfected baby hamster kidney cells. Egan et al. (2004) concluded
that curcumin treatment may be able to correct defects associated with
the homozygous expression of the delta-F508 CFTR gene, as it allows for
dissociation from ER chaperone proteins and transfer to the cell
membrane.

Delayed puberty is common among individuals with cystic fibrosis and is
usually attributed to chronic disease and/or poor nutrition. However,
delayed puberty has been reported as a feature of CF even in the setting
of good nutritional and clinical status (Johannesson et al., 1997). This
finding, along with evidence that Cftr is expressed in rat brain, human
hypothalamus, and a gonadotropin-releasing hormone secreting line,
raised the possibility that some of the pubertal delay in cystic
fibrosis could stem directly from alterations in Cftr function that
affects the hypothalamic-pituitary-gonadal axis. To examine this
hypothesis, Jin et al. (2006) studied pubertal timing in a mouse model
of CF engineered to produce a truncated Cftr mRNA and referred to as
S489X. Homozygous knockout mice, which have chronic inflammation and
gastrointestinal disease, grew more slowly and had later onset of
puberty than wildtype animals. Jin et al. (2006) anticipated that the
knockout heterozygotes, which have no clinical CF phenotype, might
display an intermediate timing of puberty. They found, however, that
these mice had earlier onset of puberty, as assessed by vaginal opening
(VO), than wildtype. These findings were confirmed in a second
independent model of CF engineered to generate the delta-F508 mutation
in mice. Again the homozygotes displayed later pubertal timing, and the
heterozygotes displayed earlier VO than the wildtype animals. These data
provided further evidence that Cftr can directly modulate the
reproductive endocrine axis and raised the possibility that heterozygote
mutation carriers may have a reproductive advantage.

For further information on animal models for CF, see 219700.

To investigate the abnormalities that impair elimination when a
bacterium lands on the pristine surface of a newborn CF airway, Pezzulo
et al. (2012) interrogated the viability of individual bacteria
immobilized on solid grids and placed onto the airway surface. As a
model, they studied CF pigs, which spontaneously develop hallmark
features of CF lung disease. At birth, their lungs lack infection and
inflammation, but have a reduced ability to eradicate bacteria. Pezzulo
et al. (2012) showed that in newborn wildtype pigs, the thin layer of
airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed
from the lung, and in primary epithelial cultures. Lack of CFTR reduces
bacterial killing. Pezzulo et al. (2012) found that the ASL pH was more
acidic in CF pigs, and reducing pH inhibited the antimicrobial activity
of ASL. Reducing ASL pH diminished bacterial killing in wildtype pigs,
and, conversely, increasing ASL pH rescued killing in CF pigs. Pezzulo
et al. (2012) concluded that their results directly linked the initial
host defense defect to the loss of CFTR, an anion channel that
facilitates bicarbonate transport. Without CFTR, airway epithelial
bicarbonate secretion is defective; the ASL pH falls and inhibits
antimicrobial function, and thereby impairs the killing of bacteria that
enter the newborn lung. Pezzulo et al. (2012) also concluded that
increasing ASL pH might prevent the initial infection in patients with
CF, and that assaying bacterial killing could report on the benefit of
therapeutic interventions.

*FIELD* AV
.0001
CYSTIC FIBROSIS
BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 1, MODIFIER
OF, INCLUDED
CFTR, PHE508DEL (dbSNP rs113993960)

In individuals with cystic fibrosis (219700), Kerem et al. (1989)
identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading
to deletion of phenylalanine at codon 508 (delta-F508). The European
Working Group on CF Genetics (1990) published information on the
distribution of the delta-F508 mutation in Europe. The data, illustrated
with a useful map, indicated a striking cline across Europe from low
values of 30% in the southeast (in Turkey) to high values in the
northwest (e.g., 88% in Denmark). The group suggested that the spread of
the CF gene might have accompanied the migrations of early farmers
starting from the Middle East and slowly progressing toward the
northwest of Europe. The diffusion of the gene may have been favored by
the selective advantage conferred by the gene. Strong association with
the so-called haplotype B was demonstrated. The possibility of
'hitchhiking,' i.e., the influence of neighboring genes was discussed.
Rozen et al. (1990) found the delta-F508 mutation in 71% of CF
chromosomes from urban Quebec province French-Canadian families, 55% of
those from Saguenay-Lac-Saint-Jean region families and in 70% of those
from Louisiana Acadian families. De Braekeleer (1991) estimated that the
frequency at birth of cystic fibrosis is 1/926 in the
Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the
same region, Daigneault et al. (1991) reported a prevalence of CF at
birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al.
(1992) found that the delta-F508 mutation was present in 58% of
Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site
mutation after codon 621 being found in 23%, and the A455E mutation
(602421.0007) in 8%. The latter 2 mutations were not found in urban
Quebec families. This provided further evidence of the role of founder
effect. Among 293 patients, Kerem et al. (1990) found that those who
were homozygous for the F508 deletion had received a diagnosis of cystic
fibrosis at an earlier age and had a greater frequency of pancreatic
insufficiency. Pancreatic insufficiency was present in 99% of the
homozygous patients, 72% of those heterozygous for the deletion, and
only 36% of patients with other mutations. Wauters et al. (1991) studied
the frequency of the delta-F508 mutation among Belgian patients with CF.
The mutation was present in 80% of CF chromosomes from 36 unrelated
families. Ninety-three percent of the CF chromosomes carrying the
delta-F508 mutation also carried haplotype B in this population. Gille
et al. (1991) described a strategy for efficient heterozygote screening
for the delta-F508 mutation. They showed that PCR could detect a
heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al.
(1992) reported that the delta-F508 mutation accounts for 33.8% of
Jewish CF alleles.

The Basque population is thought to be one of the oldest in Europe,
having been established in western Europe during the late Paleolithic
Age. Euskera, the Basque language, is thought to be pre-Indo-European,
originating from the first settlers of Europe. The variable distribution
of the delF508 mutation in Europe, with higher frequencies in northern
Europe and lower frequencies in southern Europe, has been attributed to
a spread of the mutation by early farmers migrating from the Middle East
during the Neolithic period. However, a very high frequency of this
mutation was found in the Basque Provinces, where the incidence of CF is
approximately 1 in 4,500. In a study of 45 CF families from the Basque
Provinces, Casals et al. (1992) found that the frequency of the delF508
mutation was 87% in the chromosomes of individuals of pure Basque
extraction and 58% in those of mixed Basque origin. Casals et al. (1992)
proposed that the delF508 mutation was present in Europe more than
10,000 years ago, preceding the agricultural migrations which diluted
the mutation rather than introducing it. Ballabio et al. (1990)
described an allele-specific amplification method for diagnosing the
phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of
the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508
mutation in 12 affected individuals. Clinically, 6 of the affected
individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a
severe CF phenotype. Four of the 6 Zunis with CF were also
microcephalic, a finding not previously noted in CF patients. In an
analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997)
found that 75 mutations accounted for 90.2% of CF chromosomes - an
extraordinarily high heterozygosity. The frequency of the delta-F508
mutation was 53.2%. The next most frequent mutation was gly542 to ter
(602421.0009) with a frequency of 8.43%.

Using 3 intragenic microsatellites of the CFTR gene located in introns,
Russo et al. (1995) evaluated linkage disequilibrium between each marker
and various CF mutations on a total of 377 CF and 358 normal chromosomes
from Italian subjects. Results were considered consistent with the
hypothesis that all del508 chromosomes derived from a single mutational
event. The same hypothesis was valid for 3 other mutations which might
have originated more recently than del508.

Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic
individuals with cystic fibrosis in the southwestern United States. Only
46% (59 of 129) carried mutation F508del (frequency in the general
population 67.1%).

In 69 Italian patients with CF due to homozygosity for the delF508
mutation, De Rose et al. (2005) found that those who also carried the
R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see
146790.0001) had a 4-fold increased risk of acquiring chronic
Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005)
suggested that FCGR2A locus variability contributes to this infection
susceptibility in CF patients.

In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400)
and elevated sweat chloride but normal nasal potential difference, who
carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also
identified heterozygosity for a missense mutation in the SCNN1B gene
(600760.0015). The patient had a forced expiratory volume in 1 second
(FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that
variants in SCNN1B may be deleterious for sodium channel function and
lead to bronchiectasis, especially in patients who also carry a mutation
in the CFTR gene.

Okiyoneda et al. (2010) identified the components of the peripheral
protein quality control network that removes unfolded CFTR containing
the F508del mutation from the plasma membrane. Based on their results
and proteostatic mechanisms at different subcellular locations,
Okiyoneda et al. (2010) proposed a model in which the recognition of
unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in
concert with DNAJA1 (602837) and possibly by the HSP90 machinery
(140571). Prolonged interaction with the chaperone-cochaperone complex
recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of
conformationally damaged CFTR. This ubiquitination is probably
influenced by other E3 ligases and deubiquitinating enzyme activities,
culminating in accelerated endocytosis and lysosomal delivery mediated
by Ub-binding clathrin adaptors and the endosomal sorting complex
required for transport (ESCRT) machinery, respectively. In an
accompanying perspective, Hutt and Balch (2010) commented that the
'yin-yang' balance maintained by the proteostasis network is critical
for normal cellular, tissue, and organismal physiology.

Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States,
Chong et al. (2012) found 32 heterozygotes and no homozygotes for the
phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in
45.5. This frequency is lower than that for the general population for
this mutation, which is 1 in 30.

.0002
CYSTIC FIBROSIS
CFTR, ILE507DEL

In a patient with cystic fibrosis (219700), Kerem et al. (1990) detected
deletion of 3 bp in the CFTR gene, resulting in deletion of isoleucine
at either position 506 or 507 (delta-I507). Nelson et al. (1991) found
the same mutation in homozygous state in 2 sibs with severe pancreatic
insufficiency. Orozco et al. (1994) commented on the difficulties in
recognizing the ile507-to-del mutation in a compound heterozygote with
F508del.

.0003
CYSTIC FIBROSIS
CFTR, GLN493TER

In a patient with cystic fibrosis (219700), Kerem et al. (1990) detected
a C-to-T change in nucleotide 1609 in exon 10 of the CFTR gene that
caused a premature stop position 493 (Q493X).

.0004
CYSTIC FIBROSIS
CFTR, ASP110HIS

Using the method for identifying single-strand conformation
polymorphisms (SSCPs) developed by Orita et al. (1989), Dean et al.
(1990) identified 3 different mutations associated with mild cystic
fibrosis (219700). All 3 mutations replaced charged amino acids with
less polar residues and resulted in changes in the putative
transmembrane sections of the molecule. The mutated amino acids were
found to be ones conserved in both rodents and amphibians and to lie in
a region of CFTR that is believed to form a channel in the membrane. In
a family identified as BOS-7, a C-to-G transversion in exon 4 replaced
an aspartic acid residue with histidine (D110H). (The Orita method for
identifying SSCPs involves amplification of 100-400 bp segments of
radiolabeled DNA, which are subsequently denatured and electrophoresed
on high resolution, nondenaturing acrylamide gels. Under these
conditions each strand of the DNA fragment can fold back on itself in a
unique conformation. Mutations within a DNA segment will often alter the
secondary structure of the molecule and affect its electrophoretic
mobility.)

.0005
CYSTIC FIBROSIS
VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF, INCLUDED
CFTR, ARG117HIS

In 2 presumably unrelated families with mild CF (219700), Dean et al.
(1990) found a 482G-A transition in exon 4 of the CFTR gene, resulting
in an arg117-to-his (R117H) substitution.

Gervais et al. (1993) reported that the R117H mutation was present in 4
of 23 patients with congenital absence of the vas deferens (CBAVD;
277180). Three patients had compound heterozygosity for R117H and
delF508, whereas a fourth was a compound heterozygote for R117H and
2322delG. None of the 23 patients had pulmonary evidence of cystic
fibrosis. Five patients without the delF508 mutation had unilateral
renal agenesis in addition to absence of the vas deferens; these
patients may represent a different distinct subset. Bienvenu et al.
(1993) described for the first time homozygosity for the R117H mutation
in a 30-year-old French male with sterility owing to congenital
bilateral absence of the vas deferens. The subject had no respiratory or
pancreatic involvement and had a normal sweat electrolyte value. His
parents were not consanguineous, and there were no other cases of CBAVD
or CF in the family.

Kiesewetter et al. (1993) presented evidence that the chromosome
background of the R117H mutation has a profound effect on the phenotype
produced. Three length variants of CFTR have been observed with varying
degrees of exon 9 splicing depending on variation in the length of the
polypyrimidine tract in the splice acceptor site in intron 8 (Chu et
al., 1991, 1993). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts)
were noted in front of the splice acceptor site of intron 8. The 5T
variant is present in 5% of the CFTR alleles among Caucasian populations
producing almost exclusively (95%) exon 9-minus RNA. The effect of this
T-tract polymorphism in CFTR gene expression was also documented by its
relationship with the R117H mutation: R117H (5T) is found in typical CF
patients with pancreatic sufficiency; R117H (7T) is associated with
CBAVD. The R117H mutation has been reported in CF patients, males with
congenital bilateral absence of the vas deferens, and in an asymptomatic
woman. Furthermore, population screening discovered a 19-fold higher
than expected number of carriers of this CF mutation. The situation was
compared to that in Gaucher disease in which the severity of
neuronopathic disease associated with a missense mutation appears to be
altered by additional missense mutations in the same allele (Latham et
al., 1990).

White et al. (2001) reported a healthy 29-year-old female who was found
to be an R117H/delF508 heterozygote. The patient had atopic asthma and
infertility, but normal height and weight and no pulmonary symptoms of
CF. Analysis of the polythymidine tract showed that the R117H mutation
was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T
tract. The authors concluded that poly-T studies are important in any
patient found to have the R117H mutation, and recommended caution in the
genetic counseling of such families.

Thauvin-Robinet et al. (2009) reported the results of a national
collaborative study in France to establish the overall phenotype
associated with R117H and to evaluate the disease penetrance of the
R117H+F508del genotype. In 184 R117H+F508del individuals of the French
population, including 72 newborns, the disease phenotype was
predominantly mild; 1 child had classic cystic fibrosis, and 3 adults
had severe pulmonary symptoms. In 5,245 healthy adults with no family
history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7
0.27%, and R117H;T5 less than 0.01%. The theoretical number of
R117H;T7+F508del individuals in the French populations was estimated at
3650, whereas only 112 were known with CF related symptoms (3.1%). The
penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and
that of severe CF in adulthood at 0.06%. Thauvin-Robinet et al. (2009)
suggested that R117H should be withdrawn from CF mutation panels used
for screening programs.

.0006
CYSTIC FIBROSIS
CFTR, ARG347PRO

In 3 sibs with cystic fibrosis (219700) from a family identified as UT
1446, Dean et al. (1990) found a C-to-G transversion at position 1172,
resulting in substitution of proline for aspartic acid (R347P). The
mutation destroyed an HhaI restriction site and created a NcoI site.

.0007
CYSTIC FIBROSIS
CFTR, ALA455GLU

In 2 chromosomes from patients with cystic fibrosis (219700), Kerem et
al. (1990) detected a C-to-A change in nucleotide 1496 in exon 9 of the
CFTR gene that caused substitution of glutamic acid for alanine at
position 455 (A455E).

.0008
CYSTIC FIBROSIS
CFTR, IVS10, G-A, -1

In a patient with cystic fibrosis, Kerem et al. (1990) identified a
splice mutation in the CFTR gene, a G-to-A change of nucleotide -1 in
the acceptor site of intron 10. In a French patient with cystic
fibrosis, Guillermit et al. (1990) detected the same mutation: a G-to-A
change in the last nucleotide at the 3-prime end of intron 10 nucleotide
1717 minus one. The mutation destroyed a splice site.

.0009
CYSTIC FIBROSIS
CFTR, GLY542TER

In a patient with cystic fibrosis (219700), Kerem et al. (1990) found a
G-to-T change in nucleotide 1756 in exon 11 of the CFTR gene that was
responsible for a stop mutation in codon 542 (G542X). Cuppens et al.
(1990) found the same mutation in a Belgian patient. The G542X mutation
accounted for 7.3% of the CF chromosomes in Belgium, being probably the
second most frequent mutation. (In a sample of Belgian CF patients,
68.1% of all CF chromosomes carried the delta-F508 mutation.) The
clinical manifestations were mild in a homozygote but were severe in a
first cousin who was a genetic compound for G542X and gly458-to-val
(602421.0028). Lerer et al. (1992) reported that the gly542-to-ter
mutation accounts for 13% of Ashkenazi CF mutations.

Castaldo et al. (1997) described severe liver involvement associated
with pancreatic insufficiency and moderate pulmonary expression of CF in
a girl, homozygous for the G542X mutation, who died at the age of 10
years.

Loirat et al. (1997) suggested that G542X is probably the Phoenician
cystic fibrosis mutation. They showed that the frequency of G542X varies
among different towns at regions of origin, being lower in northeastern
Europeans than in southwestern Europeans. G542X mutation mapping that
they defined by multiple regression of G542X frequencies covered 28
countries (53 geographic points) and was based on data from 50
laboratories. More elevated values of G542X frequency corresponded to
ancient sites of occupation by occidental Phoenicians.

In a patient with a severe form of cystic fibrosis, Savov et al. (1995)
identified compound heterozygosity for the G542X mutation and an allele
with a double mutation (S912L and G1244V; 602421.0135).

.0010
CYSTIC FIBROSIS
CFTR, SER549ASN

In a patient with cystic fibrosis (219700), Cutting et al. (1990)
detected compound heterozygosity for a G-to-A change in nucleotide 1778
in exon 11 of the CFTR gene, responsible for substitution of asparagine
for serine at position 549 (S549N), and a premature termination
mutation, also in exon 11 (R553X; 602421.0014).

.0011
CYSTIC FIBROSIS
CFTR, SER549ILE

In a patient with cystic fibrosis (219700), Kerem et al. (1990) detected
a G-to-T change in nucleotide 1778 in exon 11 of the CFTR gene,
responsible for substitution of isoleucine for serine at amino acid 549
(S549I).

.0012
CYSTIC FIBROSIS
CFTR, SER549ARG

In a patient with cystic fibrosis (219700), Kerem et al. (1990) detected
a T-to-G change in nucleotide 1779 in exon 11 of the CFTR gene,
responsible for substitution of arginine for serine at amino acid 549
(S549R). Sangiuolo et al. (1991) found the same ser549-to-arg
substitution in an Italian patient with severe cystic fibrosis; however,
the substitution was caused by an A-to-C change in nucleotide 1777.
Thus, the 2 mutations are AGT-to-AGG and AGT-to-CGT. A T-to-C change at
nucleotide 1779 would also change serine to arginine.

Romey et al. (1999) reported a novel complex allele in the CFTR gene,
combining the S549R mutation due to a T-to-G transversion in exon 11
with the first described sequence change in the minimal CFTR promoter, a
T-to-A transversion at position -102 (602421.0122). In a separate
publication, Romey et al. (1999) compared the main clinical features of
6 CF patients carrying the complex allele with those of 16 CF patients
homozygous for the S549R mutation alone. Age at diagnosis was higher,
and current age was significantly higher (P = 0.0032), in the group with
the complex allele, compared with the S549R/S549R group. Although the
proportion of patients with lung colonization was similar in the 2
groups, the age at onset was significantly higher in the group with the
complex allele (P = 0.0022). Patients with the complex allele also had
significantly lower sweat test chloride values (P = 0.0028) and better
overall clinical scores (P = 0.004). None of the 22 patients involved in
this study had meconium ileus. All 16 patients homozygous for S549R,
however, were pancreatic insufficient, as compared with 50% of patients
carrying the complex allele (P = 0.013). Moreover, the single patient
homozygous for the complex allele presented with mild disease at 34
years of age. These observations strongly suggested that the sequence
change in the CFTR minimal promoter attenuates the severe clinical
phenotype associated with the S549R mutation.

Romey et al. (2000) postulated that the -102T-A sequence change may
attenuate the effects of the severe S549R mutation through regulation of
CFTR expression. Analysis of transiently transfected cell lines with
wildtype and -102A variant human CFTR-directed luciferase reporter genes
demonstrated that constructs containing the -102A variant, which creates
a Yin Yang 1 (YY1) core element, increases CFTR expression
significantly. Electrophoretic mobility shift assays indicated that the
-102 site is located within a region of multiple DNA-protein
interactions and that the -102A allele recruits specifically an
additional nuclear protein related to YY1.

.0013
CYSTIC FIBROSIS
CFTR, GLY551ASP

In 7 patients, including 2 sibs, with cystic fibrosis (219700), Cutting
et al. (1990) detected a G-to-A change in nucleotide 1784 in exon 11 of
the CFTR gene that was responsible for substitution of aspartic acid for
glycine at amino acid 551 (G551D). In 6 of these patients the delta-F508
mutation (602421.0001) was present on the other allele; 3 of these
patients, aged 11 to 13 years, had mild lung disease with normal
pulmonary function test results. In the seventh patient, with mild lung
disease, the mutation on the other allele was unknown.

Curtis et al. (1991) described this mutation in 2 sibs in homozygous
state and in an unrelated adult who was a compound heterozygote for
G551D and delta-I507 (602421.0002). All 3 showed clinically mild
disease. The G551D mutation creates an MboI recognition site at codon
551 in the CFTR gene. Burger et al. (1991) suggested that heterozygosity
for the G551D mutation is a causative factor in recurrent polyposis nasi
(nasal polyps). Hamosh et al. (1992) stated that the gly551-to-asp
mutation, which is within the first nucleotide-binding fold of the CFTR,
is the third most common CF mutation, with a worldwide frequency of 3.1%
among CF chromosomes. Regions with a high frequency correspond to areas
with large populations of Celtic descent. To determine whether G551D
confers a different phenotype than does delta-F508, Hamosh et al. (1992)
studied 79 compound heterozygotes for the 2 mutations in comparison with
age- and sex-matched delta-F508 homozygotes from 9 CF centers in Europe
and North America. There was less meconium ileus among the compound
heterozygotes but otherwise no statistically significant difference was
found between the 2 groups. Clinical outcome (after survival of meconium
ileus) was indistinguishable.

Delaney et al. (1996) showed that mice carrying the human G551D mutation
in the Cftr gene show cystic fibrosis pathology but have a reduced risk
of fatal intestinal blockage compared with 'null' mutants, in keeping
with the reduced incidence of meconium ileus in G551D patients. The
G551D mutant mice showed greatly reduced CFTR-related chloride
transport, displaying activity (equivalent to approximately 4% of
wildtype Cftr) intermediate between that of 'null' mice and Cftr
insertional mutants with residual activity. The authors stated that
long-term survival of these animals should provide an excellent model
for the study of cystic fibrosis.

The G551D allele is associated characteristically with populations of
Celtic descent and is seen at its highest prevalence in regions such as
Ireland and Brittany. It is seen in diminishing frequencies as one moves
to the southern and eastern portions of Europe. An initially puzzling
phenomenon was the relatively high incidence of this mutation in the
Czech Republic (3.8%). As pointed out by Bobadilla et al. (2002),
however, population movements of the past provide an explanation.

Accurso et al. (2010) reported the results of a 2-phase clinical trial
using VX-770, a CFTR potentiator, in 39 adults with cystic fibrosis and
at least 1 G551D allele. Subjects received 150 mg of VX-770 every 12
hours for 28 days in phase 2 of the study. All showed a change in the
nasal potential difference from baseline of -3.5 mV (range, -8.3 to 0.5;
P = 0.02 for the within-subject comparison; P = 0.13 vs placebo), and
the median change in the level of sweat chloride was -59.5 mmol per
liter (range, -66.0 to -19.0; P = 0.008 within-subject, P = 0.02 vs
placebo). The median change from baseline in the percent of predicted
forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P =
0.008 within-subject, P = 0.56 vs placebo). The VX-770 was well
tolerated. None of the subjects withdrew from the study. All severe
adverse events resolved without the discontinuation of VX-770.

Ramsey et al. (2011) conducted a randomized, double-blind,
placebo-controlled trial to evaluate ivacaftor (VX-770) in subjects 12
years of age or older with cystic fibrosis and at least 1 G551D-CFTR
mutation. Subjects were randomly assigned to receive 150 mg of the drug
every 12 hours (84 subjects, of whom 83 received at least 1 dose) or
placebo (83, of whom 78 received at least 1 dose) for 48 weeks. The
primary end point was the estimated mean change from baseline through
week 24 in the percent of forced expiratory volume in 1 second (FEV1).
The change from baseline through week 24 in the percent of predicted
FEV1 was greater by 10.6 percentage points in the ivacaftor group than
in the placebo group (p less than 0.001). Effects on pulmonary function
were noted by 2 weeks, and a significant treatment effect was maintained
through week 48. Subjects receiving ivacaftor were 55% less likely to
have pulmonary exacerbation than were patients receiving placebo,
through week 48 (p less than 0.001). In addition, through week 48,
subjects in the ivacaftor group scored 8.6 points higher than did
subjects in the placebo group on the respiratory symptoms domain of the
Cystic Fibrosis Questionnaire revised instrument (p less than 0.001). By
48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg
more weight than had patients receiving placebo (p less than 0.001). The
change from baseline through week 48 in the concentration of sweat
chloride with ivacaftor as compared with placebo was -48.1 mmol per
liter (p less than 0.001). The incidence of adverse events was similar
with treatment and controls, with a lower proportion of serious adverse
events with ivacaftor than with placebo (24% vs 42%).

On January 31, 2012, the FDA approved Kalydeco, formerly VX-770
(ivacaftor), for use in cystic fibrosis patients with the G551D
mutation, as reported by Ledford (2012).

.0014
CYSTIC FIBROSIS
CFTR, ARG553TER

In a patient with cystic fibrosis (219700), Cutting et al. (1990)
detected a C-to-T change in nucleotide 1789 in exon 11 of the CFTR gene
that was responsible for a stop mutation at amino acid 553 (R553X).

Bal et al. (1991) described a patient homozygous for the arg553-to-ter
mutation in exon 11. The patient was moderately severely affected.
Hamosh et al. (1991) studied a CF patient who was a compound
heterozygote for 2 nonsense mutations, R553X and W1316X (602421.0029).
The patient had undetectable CFTR mRNA in bronchial and nasal epithelial
cells associated with severe pancreatic disease but unexpectedly mild
pulmonary disease. The R553X mutation has the fourth highest frequency
worldwide, 1.5%, according to the CF Consortium (Hamosh et al., 1991).
The patient was a 22-year-old African American female, 1 of 2 patients
with mild pulmonary disease reported by Cutting et al. (1990). Cheadle
et al. (1992) described a child who despite being homozygous for the
R553X mutation had only mild pulmonary disease. They raised the
possibility that the lack of CFTR protein in airway cells may be less
damaging than the presence of an altered protein, a suggestion advanced
by Cutting et al. (1990).

Chen et al. (2005) reported a Taiwanese CF patient who was homozygous
for the R553X mutation. He had a severe clinical course, with early
onset of chronic diarrhea, failure to thrive, and frequent respiratory
infections. The parents, who were not related, were both heterozygous
for the mutation. Both of their families were native to Taiwan, having
been on the island for at least 3 generations. Chen et al. (2005) noted
that cystic fibrosis is rare among Asians and that homozygosity for
R553X had only been reported previously in Caucasian patients.

Aznarez et al. (2007) performed transcript analysis of 5 CF patients who
were compound heterozygous for the R553X and delta-F508 (602421.0001)
mutations. RT-PCR of patient lymphoblastoid cells showed variable levels
of an aberrantly spliced CFTR isoform that corresponded to the skipping
of exon 11. Use of a splice reporter construct indicated that the R553X
substitution creates a putative exonic splicing silencer (ESS) that may
result in exon skipping by preventing selection of the proximal 5-prime
splice site. Exon 11 skipping did not result from a nonsense-associated
altered splicing mechanism. Aznarez et al. (2007) concluded that
aminoglycoside treatment would not be effective for CF patients with
this mutation owing to its effect of skipping exon 11.

.0015
CYSTIC FIBROSIS
CFTR, ALA559THR

In a patient with cystic fibrosis (219700), Cutting et al. (1990)
detected a G-to-A change in nucleotide 1807 in exon 11 of the CFTR gene
that caused a substitution of threonine for alanine at amino acid 559
(A559T).

.0016
CYSTIC FIBROSIS
CFTR, ARG560THR

In a patient with cystic fibrosis (219700), Kerem et al. (1990) found a
G-to-C change in nucleotide 1811 in exon 11 of the CFTR gene responsible
for substitution of threonine for arginine at amino acid 560 (R560T).

.0017
CYSTIC FIBROSIS
CFTR, TYR563ASN

In a patient with cystic fibrosis (219700), Kerem et al. (1990) found a
T-to-A change in nucleotide 1819 in exon 12 of the CFTR gene responsible
for substitution of asparagine for tyrosine at amino acid 563 (Y563N).

.0018
CYSTIC FIBROSIS
CFTR, PRO574HIS

In a patient with cystic fibrosis (219700), Kerem et al. (1990) detected
a C-to-A change in nucleotide 1853 in exon 12 of the CFTR gene
responsible for substitution of histidine for proline at amino acid 574
(P574H).

.0019
CYSTIC FIBROSIS
CFTR, 2-BP INS, 2566AT

In a patient with cystic fibrosis (219700), White et al. (1990) detected
insertion of 2 nucleotides, AT, after nucleotide 2566 in exon 13 of the
CFTR gene, responsible for a frameshift (2566insAT).

.0020
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 3659C

In a patient with cystic fibrosis (219700), Kerem et al. (1990) detected
deletion of a C at nucleotide 3659 in exon 19 of the CFTR gene resulting
in frameshift (3659delC).

.0021
CYSTIC FIBROSIS
CFTR, SER1255TER

In an 11-year-old black boy with cystic fibrosis (219700), Cutting et
al. (1990) detected a C-to-A change in nucleotide 3896 in exon 20 of the
CFTR gene responsible for a stop mutation at amino acid 1255 (S1255X).
The boy inherited this mutation from his father. The chromosome
inherited from his mother carried another nonsense mutation,
gly542-to-ter (602421.0009). The patient had serious pancreatic disease
but only mild pulmonary involvement.

.0022
CYSTIC FIBROSIS
CFTR, TRP1282TER

In a French patient with cystic fibrosis (219700), Vidaud et al. (1990)
identified the substitution of tryptophan-1282 by a termination codon.
The other chromosome carried the delta-F508 mutation. In another French
patient with cystic fibrosis, Vidaud et al. (1990) found precisely the
same mutation on one chromosome but the mutation on the other chromosome
was unknown. A G-to-A substitution at nucleotide 3978 was responsible
for the trp1282-to-ter change. Hamosh et al. (1991) cited evidence that
the W1282X mutation, located in exon 20, is the most common CF mutation
in the Ashkenazi Jewish population where it is present on 50% of CF
chromosomes. In Israel, Shoshani et al. (1992) found the W1282X mutation
in 63 chromosomes from 97 CF families. Sixteen patients homozygous for
the W1282X mutation and 22 patients heterozygous for the delta-F508 and
W1282X mutations had similarly severe disease, reflected by pancreatic
insufficiency, high incidence of meconium ileus (37% and 27%,
respectively), early age at diagnosis, poor nutritional status, and
variable pulmonary function. Again, the W1282X mutation was the most
common form in Ashkenazi Jewish patients in Israel. In the Jewish
Ashkenazi patient population, 60% of the CF chromosomes carry the W1282X
nonsense mutation. Patients homozygous for this mutation have severe
disease with variable pulmonary complications. Studies by Shoshani et
al. (1994) demonstrated that CFTR mRNA levels in patients homozygous for
the W1282X mutation are not significantly decreased by the mutation. In
patients heterozygous for the mutation, the relative levels of mRNA with
the W1282X allele and either the delta-F508 or the normal allele were
similar in each patient. These results indicated that the severe
clinical phenotype of patients carrying the W1282X mutation is not due
to a severe deficiency of mRNA. The severity, progression, and
variability of the pulmonary disease appear to be affected by other, as
yet unknown factors.

.0023
CFTR POLYMORPHISM
CFTR, MET470VAL

Kerem et al. (1990) found 'normal' A or G variation at nucleotide 1540
resulting in methionine or valine, respectively, at position 470.

.0024
CFTR POLYMORPHISM
CFTR, ILE506VAL

This mutation was found by Kobayashi et al. (1990) in a compound
heterozygote with delta-F508 (602421.0001). Clinical and epithelial
physiologic studies yielded normal results, indicating that the I506V
mutation is benign.

.0025
CFTR POLYMORPHISM
CFTR, PHE508CYS

This mutation was found by Kobayashi et al. (1990) in a compound
heterozygote with delta-F508 (602421.0001). Clinical and epithelial
physiologic studies yielded normal results, indicating that the F508C
mutation is benign.

.0026
CYSTIC FIBROSIS
CFTR, TRP846TER

In a French patient with cystic fibrosis (219700), Vidaud et al. (1990)
found a replacement of tryptophan-846 by a stop codon on one chromosome;
the nature of the mutation on the other chromosome was unidentified.

.0027
CYSTIC FIBROSIS
CFTR, TYR913CYS

In a French patient with cystic fibrosis (219700), Vidaud et al. (1990)
identified substitution of tyrosine-913 by cysteine. The other
chromosome carried the delta-F508 mutation. An A-to-G substitution at
position 2870 was responsible for the tyr913-to-cys change.

.0028
CYSTIC FIBROSIS
CFTR, GLY458VAL

In a patient with cystic fibrosis (219700), Cuppens et al. (1990)
described compound heterozygosity for the G542X mutation (602421.0009)
and a change of glycine-458 to valine (G458V). The patient died at the
age of 12 years of respiratory insufficiency and right heart failure.

.0029
CYSTIC FIBROSIS
CFTR, TRP1316TER

In a 21-year-old black woman with cystic fibrosis (219700) with
substantial pancreatic disease but only mild pulmonary involvement,
Cutting et al. (1990) found an A-to-G substitution at nucleotide 4079 in
exon 21, leading to replacement of tryptophan at codon 1316 by a
termination signal. The mutation appeared to have been inherited from
the father; from the mother the patient had inherited the arg553-to-ter
mutation (602421.0014).

.0030
CYSTIC FIBROSIS
CFTR, 2-BP INS, 1154TC

In a 37-year-old woman with cystic fibrosis (219700) who had a high
sweat chloride level, pancreatic insufficiency since infancy, and mild
lung disease, Iannuzzi et al. (1991) identified insertion of 2
nucleotides, T and C, at position 1154 of the CFTR gene, predicting a
shift in the reading frame of the protein and the introduction of a
UAA(ochre) termination codon at residue 369. The patient carried
delta-F508 (602421.0001) on the other allele. Alper et al. (2003)
described the truncated protein as lacking ATP binding domains, the
regulatory domain, and the second transmembrane domain and as thought to
be nonfunctional.

Screening 80 CFTR patients, Alper et al. (2003) found two 1154insTC
mutations, both in Caucasians, accounting for 1.25% of the CF
chromosomes. They also reported compound heterozygosity with delF508
(602421.0001) in CF with pancreatic insufficiency and meconium ileus in
a Caucasian male.

.0031
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 1213T

In 2 sibs with cystic fibrosis (219700), Iannuzzi et al. (1991)
identified deletion of thymine at position 1213, which was predicted to
shift the reading frame of the protein and to introduce a UAA(ochre)
termination codon at residue 368. The patients had mildly impaired lung
function.

.0032
CYSTIC FIBROSIS
CFTR, ASN1303LYS

On 4 of 52 chromosomes from patients with cystic fibrosis (219700),
including 2 sibs, Osborne et al. (1991) identified a C-to-G change at
nucleotide 4041 of the CFTR gene resulting in a change from asparagine
to lysine at amino acid position 1303 (N1303K). This mutation was found
exclusively in heterozygous state and no correlation could be made
between clinical phenotype and the presence of the gene. Pooling
laboratories throughout Europe and the United States, Osborne et al.
(1992) identified 216 examples of N1303K among nearly 15,000 CF
chromosomes tested, a frequency of 1.5%. The frequency was greater in
southern than in northern Europe; it was not found in U.K. Asians,
American blacks, or Australians. Ten patients were homozygous, whereas
106 of the remainder carried 1 of 12 known CF mutations in the other
allele. Osborne et al. (1992) concluded that N1303K is a 'severe'
mutation with respect to the pancreas, but could find no correlation
between this mutation in either the homozygous or heterozygous state and
the severity of lung disease.

.0033
CYSTIC FIBROSIS
CFTR, ARG1162TER

In a study of cystic fibrosis (219700) mutations in south European
cases, Gasparini et al. (1991) found a nonsense mutation in exon 19 due
to a C-to-T substitution at nucleotide 3616. The normal codon CGA, which
codes for arginine at position 1162, was changed to a stop codon UGA
(R1162X). It was detected in 2 of 16 non-delta-F508 chromosomes. In 9
patients homozygous for this mutation, Gasparini et al. (1992) found
mild lung disease. They had expected that the interruption in the
synthesis of the CFTR protein would result in a severe clinical course.
The findings of mild to moderate involvement of the lungs (although
pancreatic insufficiency was present in all) suggested to them that this
form of truncated CFTR protein, still containing the regulatory region,
the first ATP binding domain, and both transmembrane domains, could be
partially working in lung tissues.

.0034
CYSTIC FIBROSIS
CFTR, ARG334TRP

In the course of a study of cystic fibrosis (219700) mutations in south
European cases, Gasparini et al. (1991) found a C-to-T substitution at
nucleotide 1132 in exon 7. This point mutation changed an arginine codon
to a tryptophan at position 334 of the putative first transmembrane
domain of the protein (R334W). The patient was a compound heterozygote
for mutations R334X and N1303K (602421.0032).

Antinolo et al. (1997) compared the phenotype of 12 patients with cystic
fibrosis caused by the R334W mutation with those of homozygous delF508
patients. Current age and age at diagnosis were significantly higher in
the R334W mutation group. They found a lower rate of Pseudomonas
aeruginosa colonization in patients carrying the R334W mutation,
although the difference was not statistically significant. However, they
found a statistically significant higher age of onset of Pseudomonas
aeruginosa colonization in the group of patients with the R334W
mutation. Pancreatic insufficiency was found in a lower percentage of
R334W patients (33%). The body weight expressed as a percentage of ideal
weight for height was significantly higher in patients with the R334W
mutation.

.0035
CYSTIC FIBROSIS
CFTR, 2-BP DEL, 1677TA

In both parents of a sibship in which 3 children with cystic fibrosis
(219700) had died within months of birth (2 with pneumonia and 1 with
presumed meconium ileus), Ivaschenko et al. (1991) found the same
mutation, namely, deletion of 2 nucleotides (TA) at position 1677. As a
result of the deletion, the protein reading frame was shifted,
introducing a termination codon (TAG) at amino acid position 515 in the
resulting transcript. The family was from a small Soviet ethnic group
called the Megrals in western Georgia.

.0036
CYSTIC FIBROSIS
CFTR, ARG851TER

In a compound heterozygote with cystic fibrosis (219700), White et al.
(1991) found a de novo mutation which converted codon 851 (CGA;ARG) to a
stop codon (TGA). The mother lacked any cystic fibrosis mutation and the
father was heterozygous for the common delta-F508 mutation.

.0037
CYSTIC FIBROSIS
CFTR, GLY551SER

In 2 sisters with mild cystic fibrosis (219700), the offspring of
second-cousin parents, Strong et al. (1991) found a G-to-A substitution
at basepair 1783 resulting in substitution of a serine for a glycine
residue at the highly conserved position of amino acid 551. The
proposita was a 50-year-old woman with a chronic productive cough. She
had frequent pulmonary infections. Her sweat electrolyte concentrations
were borderline normal. The patient had 2 normal pregnancies and
deliveries and raised these children while working as a truck inspector.
The patient had a sister who died of respiratory failure at the age of
48. She had delivered 4 healthy children without difficulty, had no
evidence of malabsorption, and was in good health until the age of 23
when she had an episode of hemoptysis. At that time she was reported to
have digital clubbing and bronchiectasis on chest roentgenography.
Several sweat tests were normal.

.0038
CYSTIC FIBROSIS
CFTR, GLY85GLU

In an 11-year-old boy of Iranian extraction with cystic fibrosis
(219700), Chalkley and Harris (1991) found homozygosity for a G-to-A
mutation at nucleotide 386 in exon 3 of the CFTR gene, resulting in
substitution of glutamic acid for glycine-85. The diagnosis of CF was
made when the patient presented with a nasal polyp. He had sweat sodium
values of 90 mmol per liter and mild lung disease and was pancreatic
sufficient. The G85E mutation was first defined by Zielenski et al.
(1991) in a French-Canadian patient who was a compound heterozygote.

.0039
CYSTIC FIBROSIS
CFTR, ARG1158TER

In an Italian patient with cystic fibrosis (219700) known to be a
genetic compound, Ronchetto et al. (1992) found a C-to-T transition at
nucleotide 3604 of the CFTR gene, which changed an arginine residue at
position 1158 to a stop codon (R1158X). The patient carried an unknown
mutation on the other chromosome and was pancreatic sufficient.

.0040
CYSTIC FIBROSIS
CFTR, IVS19, A-G, +4

In an Italian patient with cystic fibrosis (219700) with pancreatic
insufficiency but mild pulmonary disease, Ronchetto et al. (1992) found
an A-to-G transition located at the 5-prime end of intron 19 of the CFTR
gene, which changed the consensus sequence of the donor site from GTGAGA
to GTGGGA (3849+4A-G).

.0041
CYSTIC FIBROSIS
CFTR, 22-BP DEL

As part of a search for additional mutations causing cystic fibrosis
(219700), Dean et al. (1992) used flanking primers for exon 6A to
amplify DNA from over 150 CF patients who lacked the delta-F508 mutation
on at least 1 chromosome. In 1 individual, a 22-bp deletion, beginning
at nucleotide 852 and stopping 2 bp before the end of the exon, was
found. The deletion was predicted to alter the reading frame of the
protein, causing the introduction of an in-frame termination codon, TGA,
at amino acid 253. Dean et al. (1992) stated that were no documented
cases of large deletions and only 1 report of a de novo mutation in the
CFTR gene.

.0042
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 556A

In a patient with cystic fibrosis (219700) with pancreatic
insufficiency, Zielenski et al. (1991) identified an exon 4 mutation in
CFTR that created a new BglI site, a frameshift due to deletion of
nucleotide 556, an A.

.0043
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 557T

In a patient with cystic fibrosis (219700) with relatively mild
symptoms, Graham et al. (1992) identified deletion of a single
nucleotide, a T, in the T tract from base 557 to 561 in exon 4 of the
CFTR gene. Like the 556A deletion (602421.0042), the mutation created a
new BglI site.

.0044
CYSTIC FIBROSIS
CFTR, 84-BP DEL, NT1949

In a patient with cystic fibrosis (219700), Granell et al. (1992)
identified an 84-bp deletion in exon 13 of the CFTR gene by DNA
amplification and direct sequencing of 500 bp of the 5-prime end of exon
13. The deletion was in the maternal allele, and the patient's paternal
allele bore the delta-F508 deletion (602421.0001). The deletion spanned
from a 4-A cluster in positions 1949-1952 to another 4-A cluster in
positions 2032-2035. The mutation resulted in the loss of 28 amino acid
residues in the R domain of the CFTR protein. Since this in-frame
mutation, the largest identified to that time, began after nucleotide
1949, it was referred to as 1949del84. Out of 340 Spanish CF patients,
Nunes et al. (1992) found 3 patients who were compound heterozygotes for
the 1949del84 and delF508 mutations and 1 for 1949del84 and an unknown
mutation. The patients had a similar severity of disease to that in
delF508 homozygous patients.

.0045
CYSTIC FIBROSIS
CFTR, 1-BP INS, 2869G

In 5 patients with cystic fibrosis (219700), Nunes et al. (1992)
identified a frameshift mutation resulting from insertion of a guanine
(G) after nucleotide 2869 in exon 15. One patient was homozygous for the
mutation and the other 4 were compound heterozygous. Direct sequencing
of the person homozygous for this mutation showed that the mutation
resulted in a TGA stop codon at the site of insertion, followed by
another stop signal at the beginning of exon 16. The mutation created a
new restriction site for the MboI endonuclease. Nunes et al. (1992)
demonstrated that the mutation was present in 6 of 191 non-delF508
chromosomes in the Spanish population and in none of 86 Italian
non-delF508 chromosomes. All chromosomes carrying the mutation had the
same haplotype. A homozygous patient had a moderately severe clinical
course. (This mutation is also referred to as 2869insG.)

.0046
CYSTIC FIBROSIS
CFTR, VAL520PHE

In a patient with CF (219700), Jones et al. (1992) used the chemical
cleavage mismatch technique to demonstrate a V520F mutation which
resulted from a G-to-T transversion.

.0047
CYSTIC FIBROSIS
CFTR, CYS524TER

Using the chemical cleavage mismatch technique for the study of DNA from
a patient with CF (219700), Jones et al. (1992) discovered a nonsense
C524X mutation resulting from a C-to-A transversion.

.0048
CYSTIC FIBROSIS
CFTR, GLN1291HIS

In a patient with cystic fibrosis (219700), Jones et al. (1992)
demonstrated a Q1291H mutation caused by a G-to-C transversion at the
last nucleotide of exon 20 using the chemical cleavage mismatch
technique. Further study, involving RNA-based PCR, demonstrated that the
Q1291H is also a splice mutation. Both correctly and aberrantly spliced
mRNAs were produced by the Q1291H allele. The incorrectly spliced
product resulted from the use of a nearby cryptic splice site 29 bases
into the adjacent intron.

.0049
CYSTIC FIBROSIS
CFTR, PHE311LEU

Using DGGE in a systematic study of cystic fibrosis (219700) mutations
in a Celtic population in Brittany, Ferec et al. (1992) identified a
C-to-G mutation at nucleotide 1065 of the CFTR gene changing codon 311
from phenylalanine to leucine. The mutation was found in a compound
heterozygous child who was classified as pancreatic insufficient; the
other allele was gly551-to-asp (602421.0013).

.0050
CYSTIC FIBROSIS
CFTR, 2-BP DEL, NT1221

In a systematic study of 365 cystic fibrosis (219700) chromosomes in the
Celtic population in Brittany, Ferec et al. (1992) detected a frameshift
mutation in exon 7. The patient, who was severely pancreatic
insufficient, was a compound heterozygote for a deletion of 2
nucleotides at position 1221. The other allele had a deletion of T at
1078.

.0051
CYSTIC FIBROSIS
CFTR, SER492PHE

In a systematic study of 365 cystic fibrosis (219700) chromosomes in the
Celtic population in Brittany, Ferec et al. (1992) identified a
ser492-to-phe mutation, due to a change at nucleotide 1607 from C to T,
in a child classified as pancreatic sufficient.

.0052
CYSTIC FIBROSIS
CFTR, ARG560LYS

In a systematic study of 365 cystic fibrosis (219700) chromosomes in the
Celtic population in Brittany, Ferec et al. (1992) identified an
arg560-to-lys mutation at the 3-prime end of exon 11, resulting from a
G-to-A transition at nucleotide 1811. As well as resulting in an amino
acid change in the protein product, the substitution in the last residue
of the exon may represent a splice mutation; a similar change in exon 1
of the human beta-globin gene diminishes RNA splicing (Vidaud et al.,
1989; see hemoglobin Kairouan; HBB, ARG30THR; 141900.0144). The patient
was pancreatic insufficient.

.0053
CYSTIC FIBROSIS
CFTR, GLU827TER

In a child with pancreatic-insufficient cystic fibrosis (219700) in the
Celtic population of Brittany, Ferec et al. (1992) identified a G-to-T
change at position 2611 in exon 13 leading to change of glutamic
acid-827 to a stop codon.

.0054
CYSTIC FIBROSIS
CFTR, ARG1066HIS

In a pancreatic-insufficient cystic fibrosis (219700) patient in the
Celtic population of Brittany, Ferec et al. (1992) found an
arg1066-to-his mutation resulting from a G-to-A transition at nucleotide
3329. This CpG dinucleotide is a known hotspot for mutations. Ferec et
al. (1992) quoted unpublished results indicating that another mutation,
C3328 to T leading to arg1066-to-cys, had been discovered (602421.0058).
The child with the arg1066-to-his mutation was a compound heterozygote,
the other allele having a deletion of T at nucleotide 1078.

.0055
CYSTIC FIBROSIS
CFTR, ALA1067THR

In a pancreatic-insufficient child with cystic fibrosis (219700) in the
Celtic population in Brittany, Ferec et al. (1992) found a G-to-A
transition at position 3331 resulting in an ala1067-to-thr substitution.
The modification replaced a nonpolar residue with a polar residue. The
other chromosome carried the delta-F508 mutation (602421.0001).

.0056
CYSTIC FIBROSIS
CFTR, IVS20, G-A, +1

In a pancreatic-insufficient patient with cystic fibrosis (219700) in
the Celtic population of Brittany, Ferec et al. (1992) identified a
G-to-A mutation in the first nucleotide of the splice donor site of
intron 20.

.0057
CYSTIC FIBROSIS
CFTR, 5-BP DUP, NT3320

In a pancreatic-insufficient patient with cystic fibrosis (219700) in
the Celtic population of Brittany, Ferec et al. (1992) found duplication
of 5 nucleotides (CTATG) after nucleotide 3320, creating a frameshift.

.0058
CYSTIC FIBROSIS
CFTR, ARG1066CYS

Ferec et al. (1992) cited unpublished results of P. Fanen: a C-to-T
transition at nucleotide 3328 led to an arg1066-to-cys substitution.
This CpG dinucleotide is a hotspot for mutations; see 602421.0054.

.0059
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 1078T

See 602421.0050. Claustres et al. (1992) found this mutation in exon 7
in a CF patient with cystic fibrosis (219700) from southern France.
Romey et al. (1993) described an improved procedure that allows the
detection of single basepair deletions on nondenaturing polyacrylamide
gels and demonstrated its applicability for identifying this mutation.

.0060
VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF
CFTR, ASP1270ASN

In a study of 25 unrelated, unselected white azoospermic men with
clinically diagnosed congenital bilateral absence of the vas deferens
(CBAVD; 277180), aged 24 to 43 years, Anguiano et al. (1992) found 2 in
whom there was heterozygosity for the phe508-to-del mutation
(602421.0001) with another rare mutation on the other chromosome. In 1
patient, of English/Italian extraction, the second mutation was a G-to-A
transition resulting in substitution of asparagine for aspartic acid at
amino acid 1270 (D1270N). The patient had a normal chest x-ray and sweat
electrolytes well within the normal range. There were no signs of
pulmonary or gastrointestinal disease and no signs of overt
malabsorption. Thus, the patient had a primarily genital form of cystic
fibrosis. Both this mutation and the G576A mutation (602421.0061) occur
within the adenosine triphosphate-binding domains of the CFTR protein.
These domains are believed to play a role in the regulation of chloride
transport. It is possible that the cells of the developing wolffian duct
have regulatory pathways functionally associated to CFTR that are
different from the lung, pancreas, or sweat duct.

.0061
VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF
CFTR, GLY576ALA

In a man with isolated congenital bilateral absence of the vas deferens
(277180), Anguiano et al. (1992) found compound heterozygosity for the
phe508-to-del (602421.0001) mutation and another rare mutation: a
GGA-to-GCA transversion in codon 576 in exon 12, predicted to cause a
substitution of alanine for glycine.

.0062
CYSTIC FIBROSIS
CFTR, 3849+10KB, C-T

Abeliovich et al. (1992) found that among 94 Ashkenazi Jewish patients
with CF (219700) in Israel, 5 mutations accounted for 97% of mutant CFTR
alleles. Four of these were delF508 (602421.0001), G542X (602421.0009),
W1282X (602421.0022), and N1303K (602421.0032). The fifth, which
accounted for 4% of alleles, was an unusual mutation found by Highsmith
(1991). Referred to as 3849+10kbC-T, it was detected by cleavage of a
PCR product by HphI. Highsmith et al. (1991) detected the 3849+10kbC-T
mutation in a 19-year-old Pakistani woman with mild manifestations of CF
and normal sweat chloride values. To explain the milder course of the
disease in patients with this mutation, Highsmith et al. (1991)
hypothesized that the C-to-T base substitution created an alternative
splice site, which resulted in insertion of 84 basepairs into the CFTR
coding region. This change may cause synthesis of a protein with normal
CFTR function together with a nonfunctional protein. Alternatively, this
mutation might lead to production of a protein that is only partly
functional and causes milder disease. In Israel, Augarten et al. (1993)
investigated 15 patients with CF and this mutation, all Ashkenazi Jews.
Their clinical features were compared with those of CF patients with
mutations known to be associated with severe disease. Patients with the
3849+10kbC-T mutation were older, had been diagnosed as having CF at a
more advanced age, and were in a better nutritional state. Sweat
chloride values were normal in 5 of the 15 patients; 4 of these patients
and 6 others had normal pancreatic function. However, age-adjusted
pulmonary function did not differ between these patients and those with
mutations known to cause severe disease. None of the patients with the
3849+10kbC-T mutation had had meconium ileus and none had liver disease
or diabetes mellitus.

.0063
CYSTIC FIBROSIS
CFTR, ARG1283MET

In 3 pancreatic-insufficient patients with cystic fibrosis (219700),
Cheadle et al. (1992) identified a novel CFTR mutation which, like the
trp1282-to-ter mutation (602421.0022), abolishes an MnlII restriction
site. The new mutation was found to be a G-to-T transversion at position
3980 resulting in replacement of arginine by methionine at residue 1283
(R1283M).

.0064
CYSTIC FIBROSIS
CFTR, IVS12, G-A, +1

In 2 patients with cystic fibrosis (219700), Strong et al. (1992) used
chemical mismatch cleavage and subsequent DNA sequencing to identify a
splice mutation at the 5-prime end of intron 12 of the CFTR gene. A
G-to-A transition at position 1 of the donor-splice site resulted in
skipping of exon 12. The mutation was found in compound heterozygous
state with the delF508 mutation (602421.0001) in a 39-year-old white
male and a 9-year-old female with typical pulmonary and gastrointestinal
changes of CF. Both were pancreatic insufficient. The male had a history
of liver disease requiring splenorenal shunt for portal hypertension at
age 14 years.

.0065
CYSTIC FIBROSIS
CFTR, GLN359LYS AND THR360LYS

Shoshani et al. (1993) found that 88% of identified cystic fibrosis
(219700) chromosomes among CF patients who were Jews from Soviet Georgia
had a double mutation in adjacent codons: one alteration was a C-to-A
transversion at nucleotide position 1207, changing the glutamine codon
to lysine (Q359K); the second alteration was a C-to-A transversion at
nucleotide position 1211, changing the threonine codon to lysine
(T360K).

.0066
CYSTIC FIBROSIS
CFTR, IVS6, 12-BP DEL

In a pancreatic-insufficient CF (219700) patient, Audrezet et al. (1993)
found compound heterozygosity for a delta-F508 mutation and a novel
mutation which they designated 876--14 del 12 NT: a large deletion which
began at position -14 of exon 6b corresponded to a loss of 12
nucleotides. Because the mutation involved a 4-bp repeat (GATT), the
deletion could involve 8 nucleotides depending on the allele in which it
occurred.

.0067
CYSTIC FIBROSIS
CFTR, ARG347LEU

In a 2-year-old girl with cystic fibrosis (219700) detected during a
systematic neonatal screening who was up to that time symptom free and
pancreatic sufficient, Audrezet et al. (1993) found a G-to-T
transversion at bp 1172 changing arginine (an amino acid with a basic
side chain) to leucine (bearing a nonpolar side chain) at residue 347.
Audrezet et al. (1993) pointed out that 2 other mutations involving
nucleotide 1172 have been observed, one leading to R347P (602421.0006)
and the other to R347H (602421.0078). Both are associated with
pancreatic sufficiency.

.0068
CYSTIC FIBROSIS
CFTR, ALA349VAL

In the course of screening the normal husband of a heterozygous woman,
Audrezet et al. (1993) found a C-to-T transition at nucleotide 1178
predicting substitution of valine for alanine at residue 349. Since both
of these amino acids carry a nonpolar side chain, it was not obvious
that the variation would lead to a CF allele. However, this nucleotide
change was not observed on more than 300 normal chromosomes screened,
and alanine at position 349 is conserved in the CFTR gene of human,
Xenopus, and cow.

.0069
CYSTIC FIBROSIS
CFTR, ALA534GLU

In a screening of 48 patients with cystic fibrosis (219700) and 12
obligate carriers, Audrezet et al. (1993) observed a C-to-T transition
at nucleotide 1733 leading to substitution of glutamic acid for
alanine-534 (A534E). The change is a drastic one since it replaces an
acidic residue with one that is nonpolar. Observed in heterozygotes, the
mutation is probably of functional significance.

.0070
CYSTIC FIBROSIS
CFTR, LYS716TER

In a screening of 48 patients with cystic fibrosis (219700) and 12
obligate carriers, Audrezet et al. (1993) found an A-to-T transversion
at nucleotide 2278 resulting in a stop codon at lysine-716. The mutation
was detected in the heterozygous father of a deceased child; no clinical
data were available.

.0071
CYSTIC FIBROSIS
CFTR, IVS13, G-A, +1

In a 2-year-old child with cystic fibrosis (219700) who carried the
delta-F508 mutation (602421.0001) and manifested classic symptoms of CF,
namely, pancreatic insufficiency and pulmonary disease, Audrezet et al.
(1993) detected on the other chromosome a G-to-A transition in the first
nucleotide in the 5-prime splice site of intron 13. Audrezet et al.
(1993) referred to this mutation as 2622 +1 G-to-A.

.0072
CYSTIC FIBROSIS
CFTR, GLN1238TER

In a patient with classic pancreatic-insufficient CF (219700), Audrezet
et al. (1993) found a C-to-T transition at nucleotide 3844 creating a
stop codon (TAG) in place of glutamine (CAG). The other chromosome
carried the G542X mutation (602421.0009).

.0073
CYSTIC FIBROSIS
CFTR, IVS19, G-A, -1

In 3 children with classic cystic fibrosis (219700), all with pancreatic
insufficiency, Audrezet et al. (1993) observed a G-to-A transition at
nucleotide -1 of intron 19, involving the splice acceptor site (3850,
-1, G-to-A).

.0074
CYSTIC FIBROSIS
CFTR, 1-BP INS, 3898C

In a severely affected, pancreatic-insufficient, 20-year-old patient
with cystic fibrosis (219700), Audrezet et al. (1993) found insertion of
a C after nucleotide 3898 resulting in frameshift. The other chromosome
carried the R1162X mutation (602421.0033).

.0075
CYSTIC FIBROSIS
CFTR, TRP57TER

In 2 patients with pancreatic-insufficient cystic fibrosis (219700),
Audrezet et al. (1993) found compound heterozygosity for a G-to-A
transition at nucleotide 302 in exon 3 converting codon 57 from TGG
(trp) to TGA (stop).

.0076
CYSTIC FIBROSIS
CFTR, GLN1313TER

In a severely affected, pancreatic-insufficient patient with cystic
fibrosis (219700), Audrezet et al. (1993) found homozygosity for a
C-to-T transition at nucleotide 4069 in exon 21 converting gln1313 to a
stop codon.

.0077
CYSTIC FIBROSIS
CFTR, GLU92LYS

In a Spanish patient with mild cystic fibrosis (219700), Nunes et al.
(1993) found a G-to-A transition at nucleotide 406 resulting in a change
of codon 92 in exon 4 from glutamic acid to lysine. The same mutation
was found in homozygous state in a Turkish patient with consanguineous
parents living in Germany. Both patients were pancreatic sufficient and
had normal fat excretion. In both cases physical activity led rapidly to
excessive sweating and fatigue; the mother of the Turkish boy reported
that after 1 hour of sports the boy's skin and hair became covered with
a white salty crust which required 2 or 3 showers to remove.

.0078
CYSTIC FIBROSIS
CFTR, ARG347HIS

Audrezet et al. (1993) referred to an R347H mutation causing
pancreatic-sufficient cystic fibrosis (219700). This is 1 of 3 mutations
that involve nucleotide 1172, the others being R347P (602421.0006) and
R347L (602421.0067).

.0079
CYSTIC FIBROSIS
CFTR, GLY91ARG

In a study of 87 non-delF508 chromosomes of Breton origin, Guillermit et
al. (1993) found a G91R mutation in 3 pancreatic-sufficient cystic
fibrosis patients (219700). The 3 patients were compound heterozygous
for the G91R mutation and delF508 (602421.0001).

.0080
CYSTIC FIBROSIS
CFTR, PHE1286SER

In an analysis of 160 cystic fibrosis (219700) chromosomes, Dorval et
al. (1993) detected an F1286S mutation in exon 20 of the CFTR gene using
denaturing gel electrophoresis followed by direct sequencing of the PCR
products. A T-to-C transition at nucleotide 3989 was responsible for the
change from phenylalanine to serine.

.0081
CYSTIC FIBROSIS
CFTR, 1-BP INS, 2307A

By chemical mismatch cleavage in an African American patient with cystic
fibrosis (219700), Smit et al. (1993) found homozygosity for insertion
of an adenine after nucleotide 2307 in exon 13. The resulting shift of
the reading frame at codon 726 introduced 2 consecutive stop codons at
amino acid positions 729 and 730. To examine the mRNA level associated
with the 2307insA mutation, RNA from nasal epithelial cells of the
patient and a normal subject were reverse transcribed. Subsequent
amplification of the cDNA demonstrated that the CFTR message level
associated with 2307insA was markedly reduced compared to the normal
control, while both the patient and the normal subject showed similar
levels of expression.

.0082
CYSTIC FIBROSIS
CFTR, GLU92TER

In each of 4 German patients with cystic fibrosis (219700), Will et al.
(1994) found a G-to-T transversion that affected the first base of exon
4 and created a termination codon glu92-to-ter. Lymphocyte RNA of
patients heterozygous for the E92X mutation were found to contain the
wildtype sequence and a differentially spliced isoform lacking exon 4.
On the other hand, RNA derived from nasal epithelial cells of these
patients showed a third fragment of longer length. Sequencing revealed
the presence of E92X and an additional 183-bp fragment, inserted between
exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR
gene. It was flanked by acceptor and donor splice sites. Will et al.
(1994) concluded that the 183-bp fragment in intron 3 is a cryptic CFTR
exon that can be activated in epithelial cells by the presence of the
E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to
severe cystic fibrosis.

.0083
CYSTIC FIBROSIS
CFTR, GLY480CYS

In a pancreatic-insufficient African American CF (219700) patient, Smit
et al. (1995) found a novel CFTR missense mutation associated with a
protein trafficking defect in mammalian cells but normal chloride
channel properties in a Xenopus oocyte assay. The mutation resulted in
substitution of a cysteine for glycine at residue 480. In mammalian
cells, the encoded mutant protein was not fully glycosylated and failed
to reach the plasma membrane, suggesting that the G480C protein was
subject to defective intracellular processing. However, in Xenopus
oocytes, a system in which mutant CFTR proteins are less likely to
experience an intracellular processing/trafficking deficit, expression
of G480C CFTR was associated with a chloride conductance that exhibited
a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine
(IBMX) that was similar to that of wildtype CFTR. This appeared to be
the first identification of a CFTR mutant in which the sole basis for
disease was mislocation of the protein.

.0084
CYSTIC FIBROSIS
CFTR, LEU206TRP

The leu206-to-trp (L206W) mutation of the CFTR gene was first identified
in 3 CF (219700) patients from South France (Claustres et al., 1993).
Rozen et al. (1995) reported that it is relatively frequent in French
Canadians from Quebec. On the basis of findings in 7 French-Canadian
probands, they suggested that this mutation is likely to be present in
patients with atypical forms of CF and may be present in otherwise
healthy men and women with infertility. Their group contained
47-year-old and 48-year-old sisters and their 30-year-old brother. The
women were thought to have reduced fertility and the man had absence of
the vas deferentia. The man and 1 sister had normal pulmonary function
and high-resolution CT scan of the chest. The 47-year-old sister had had
left upper lobectomy for presumed bronchiectasis at the age of 20 years
and had had frequent pulmonary infections but had surprisingly
well-preserved lung function.

Clain et al. (2005) noted that the L206W mutation can result in variable
disease phenotypes. Individuals bearing this mutation in trans with the
severe CF-causing mutation F508del (602421.0001) may have CF or isolated
congenital bilateral absence of the vas deferens (277180). Clain et al.
(2005) studied the effect of the L206W mutation on CFTR protein
production and function and examined the genotype-phenotype correlation
of L206W/F508del compound heterozygote patients. They showed that L206W
is a processing (class II) mutation, as the CFTR biosynthetic pathway
was severely impaired, whereas single-channel measurements indicated ion
conductance similar to the wildtype protein. These data raised the
larger question of the phenotypic variability of class II mutants,
including F508del. Clain et al. (2005) concluded that since multiple
potential properties could modify the processing of the CFTR protein
during its course to the cell surface, environmental and other genetic
factors might contribute to this variability.

.0085
CYSTIC FIBROSIS
CFTR, 18-BP DEL, NT591

Varon et al. (1995) described recurrent nasal polyps as a
monosymptomatic form of cystic fibrosis (219700) in association with a
novel in-frame mutation, deletion of 18 bp in exon 4 of the CFTR gene.
Since the deletion started with nucleotide 591 of their cDNA clone, the
mutation was symbolized 591del18. It was found in male twins of Turkish
origin. The twins inherited the 591del18 mutation from their mother. On
the paternal allele, they carried the nonsense mutation glu831-to-ter
(Verlingue et al., 1994). The patients had been diagnosed as having CF
at the age of 10 years due to persistent nasal polyps and elevated sweat
electrolytes. Nasal polyps had been surgically removed on 4 occasions.
The neonatal period and early infancy were completely uneventful. They
were pancreatic sufficient and had no lung disease or other CF-related
problems.

Burger et al. (1991) suggested that heterozygosity for the G551D
mutation (602421.0013) is a causative factor in recurrent nasal polyps.
Presentation with a nasal polyp was the basis of the diagnosis of cystic
fibrosis in an 11-year-old boy of Iranian extraction in whom Chalkley
and Harris (1991) found homozygosity for a gly85-to-glu mutation
(602421.0038).

.0086
VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF
BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 1, MODIFIER
OF
CFTR, IVS8AS, 5T VARIANT

Zielenski et al. (1995) estimated that CBAVD (277180) is associated with
the 5T variant at the 3-prime end of intron 8 of the CFTR gene with a
penetrance of 0.60 in males. Chu et al. (1993) noted varied lengths of a
thymidine (T)-tract (5, 7, or 9T) in front of the splice-acceptor site
of intron 8. The length appeared to correlate with the efficiency of
exon 9 splicing, with the 5T variant that is present in 5% of the CFTR
alleles among the Caucasian population producing almost exclusively
(95%) exon 9-minus mRNA. The effect of this T-tract polymorphism in CFTR
gene expression was also documented by its relationship with the CF
mutation R117H (602421.0005): while R117H (5T) is found in typical CF
patients with pancreatic sufficiency, R117H (7T) is associated with
CBAVD (Kiesewetter et al., 1993).

Costes et al. (1995) studied the CFTR gene in 45 azoospermic individuals
with isolated CBAVD. They detected a CFTR gene defect in 86% of
chromosomes from these subjects. In addition to identifying 9 novel CFTR
gene mutations, they found that 84% of men with CBAVD who were
heterozygous for a CF mutation carried the intron 8 polypyrimidine 5T
CFTR allele on 1 chromosome.

De Meeus et al. (1998) found linkage disequilibrium between the 5T
allele and the val allele of the met470-to-val polymorphism
(602421.0023).

Groman et al. (2004) demonstrated that the number of TG repeats adjacent
to 5T influences disease penetrance. They determined TG repeat number in
98 patients with male infertility due to congenital absence of the vas
deferens, 9 patients with nonclassic CF, and 27 unaffected individuals
(fertile men). Each of the individuals in this study had a severe CFTR
mutation on one CFTR gene and 5T on the other. They found that those
individuals with 5T adjacent to either 12 or 13 TG repeats were
substantially more likely to exhibit an abnormal phenotype than those
with 5T adjacent to 11 TG repeats. Thus, determination of TG repeat
number will allows for more accurate prediction of benign versus
pathogenic 5T alleles.

The TG repeat located at the splice acceptor site of exon 9 of the CFTR
gene is an example of a variable dinucleotide repeat that affects
splicing. Higher repeat numbers result in reduced exon 9 splicing
efficiency and, in some instances, the reduction in full-length
transcript is sufficient to cause male infertility due to congenital
bilateral absence of the vas deferens or nonclassic cystic fibrosis.
Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract
variation and observed the same correlation between dinucleotide repeat
number and exon 9 splicing efficiency seen in vivo. Replacement of the
TG dinucleotide tract in the minigene with random sequence abolished
splicing of exon 9. Replacements of the TG tract with sequences that can
self-basepair suggested that the formation of an RNA secondary structure
was associated with efficient splicing. However, splicing efficiency was
inversely correlated with the predicted thermodynamic stability of such
structures, demonstrating that intermediate stability was optimal.
Finally, substitution of TA repeats of differing lengths confirmed that
stability of the RNA secondary structure, not sequence content,
correlated with splicing efficiency. Taken together, these data
indicated that dinucleotide repeats can form secondary structures that
have variable effects on RNA splicing efficiency and clinical phenotype.

In a 66-year-old woman and an unrelated 67-year-old man with idiopathic
bronchiectasis (BESC1; 211400), who were heterozygous for the 5T CFTR
variant, Fajac et al. (2008) also identified heterozygosity for a
missense mutation in the SCNN1B gene (600760.0015). The woman had a
borderline elevated sweat chloride, normal nasal potential difference
(PD), and FEV1 that was 77% of predicted. The man had normal sweat
chloride and nasal PD, and FEV1 that was 80% of predicted. Fajac et al.
(2008) concluded that variants in SCNN1B may be deleterious for sodium
channel function and lead to bronchiectasis, especially in patients who
also carry a mutation in the CFTR gene.

.0087
CYSTIC FIBROSIS
CFTR, THR338ILE

In all 8 children of Sardinian descent seen because of hypotonic
dehydration associated with hyponatremia, hypochloremia, hypokalemia,
and metabolic alkalosis, Leoni et al. (1995) found a T338I mutation
either in homozygosity or compound heterozygosity with another CF
mutation. None had pulmonary or pancreatic involvement. The T338I
mutation was not detected in patients with CF who had classic symptoms
or in healthy persons of the same descent. Their data suggested that the
T338I mutation is associated with a specific mild cystic fibrosis
(219700) phenotype. The patients were seen at ages varying between 2
months and 7 years of age. Three of the patients had failed to thrive.
The sweat chloride concentration was high in all patients but 1, who at
3 months of age had borderline values. All the patients had normal
steatocrit values for their age, and none of them required pancreatic
enzyme supplements.

.0088
CYSTIC FIBROSIS
CFTR, TRP1089TER

In 2 of 138 alleles in Jewish patients with cystic fibrosis (219700),
Shoshani et al. (1994) identified a G-to-A transition at nucleotide 3398
of exon 17b of the CFTR gene. This substitution results in a termination
codon (TAG) instead of tryptophan at residue 1089. Both mutant
chromosomes carry the same extra- and intragenic haplotype, A112.

.0089
CYSTIC FIBROSIS
CFTR, 4-BP DEL, NT4010

In a patient of Arab origin with cystic fibrosis (219700), Shoshani et
al. (1994) detected a 4-bp deletion in the CFTR gene, TATT, at position
4010 of the coding sequence using direct sequencing of exon 21. This
frameshift mutation is expected to create a termination codon (TAG) 34
amino acids downstream of the mutation. This alteration is likely to be
a disease-causing mutation since it is predicted to create a truncated
polypeptide that lacks the second ATP binding domain. The patient
inherited this deletion from her father. The CFTR chromosome carries the
D121 haplotype. Her other CFTR chromosome has the asn1303-to-lys
mutation (602421.0032).

.0090
CYSTIC FIBROSIS
CFTR, ILE556VAL

In a study of 224 non-F508del CF (219700) chromosomes, Ghanem et al.
(1994) identified a C-to-T substitution at nucleotide 223, changing
arginine to cysteine at position 31, in a French couple with cystic
fibrosis and one affected child. Since their apparently unaffected
6-year-old child was found to be homozygous for this mutation, it is
probably a polymorphism. The father and the affected child had another
substitution changing an isoleucine-556 to valine in exon 11. This
mutation can be detected by restriction analysis since it abolishes a
HhaI recognition sequence.

.0091
CYSTIC FIBROSIS
CFTR, TYR109CYS

In a 16-year-old girl with CF (219700) diagnosed at age 9 months who has
remained pancreatic-sufficient, Schaedel et al. (1994) identified an
A-to-G substitution at nucleotide 458 in exon 4 of the CFTR gene,
converting tyrosine-109 to cysteine (Y109C). Her second mutation was
3659delC (602421.0020) in exon 19. The 3659delC mutation is associated
with the pancreatic insufficiency phenotype. The authors concluded that
tyr109-to-cys is the mutation conferring pancreatic sufficiency.

.0092
CYSTIC FIBROSIS
CFTR, ARG352GLN

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified an arg352-to-glu mutation.

.0093
CYSTIC FIBROSIS
CFTR, IVS3, A-G, +4

Ghanem et al. (1994) identified an A-to-G substitution at the fourth
nucleotide of the donor splice site of intron 3. It is not known if this
mutation is drastic enough to cause aberrant splicing. It could simply
be sufficient for a cryptic splice site to be used. This mutation was
found on the maternal cystic fibrosis (219700) chromosome in an African
family originating from Cameroon. The CF-affected child, a 9-year-old
girl, had no pancreatic insufficiency and no serious lung disease, but
suffered from asthma. The sweat chloride was elevated (90 to 110 mmol
per liter).

.0094
CYSTIC FIBROSIS
CFTR, GLN524HIS

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified a gln524-to-his (Q524H) mutation.

.0095
CYSTIC FIBROSIS
CFTR, GLY542TER

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) found a point mutation creating a stop codon in
place of glycine-542. In molecular genetic analyses on 129 Hispanic
individuals with cystic fibrosis in the southwestern United States,
Grebe et al. (1994) found that 5.4% (7 of 129) individuals carried this
mutation.

.0096
CYSTIC FIBROSIS
CFTR, GLN552TER

In a cystic fibrosis (219700) patient with severe pancreatic
insufficiency, Gasparini et al. (1993) found a missense mutation
creating a stop codon in place of glutamine-552. This mutation was found
in 3 of 225 cases.

.0097
CYSTIC FIBROSIS
CFTR, ASP648VAL

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified an asp648-to-val mutation.

.0098
CYSTIC FIBROSIS
CFTR, LYS710TER

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) found a point mutation creating a stop codon in
place of lysine-710.

.0099
CYSTIC FIBROSIS
CFTR, GLN890TER

In 2 related Portuguese patients with cystic fibrosis (219700), Ghanem
et al. (1994) identified a C-to-T substitution at nucleotide 2880 in
exon 15, resulting in a stop codon at position 890. This mutation was
found in a 13-year-old girl and her 15-year-old uncle, who have a
classic form of the disease and nasal polyposis. Both patients had
F508del on the other CF chromosome, and the uncle had a positive sweat
test (140 mmol per liter). The mutation changed the restriction sites
MseI(+) and MboII(-).

.0100
CFTR POLYMORPHISM
CFTR, SER912LEU

In a study of 224 non-F508del CF chromosomes, Ghanem et al. (1994)
identified a 2867C-T transition in exon 15 of the CFTR gene, resulting
in a ser912-to-leu (S912L) substitution, in a CF carrier of French and
Spanish extraction. It was difficult to predict whether this
substitution would be deleterious.

By in vitro functional expression studies, Clain et al. (2005)
demonstrated that the S912L substitution was not disease-causing in
isolation, but significantly impaired CFTR function when inherited in
cis with another CFTR mutation (see 602421.0135). Clain et al. (2005)
identified a healthy father of a CF fetus carrying the S912L mutation. A
different CF-producing mutation was identified on the father's other
allele. Clain et al. (2005) concluded that the S912L substitution is a
neutral variant.

.0101
CYSTIC FIBROSIS
CFTR, 2-BP DEL, 936TA

In 2 Spanish patients with cystic fibrosis (219700), Chillon et al.
(1994) identified a 2-bp deletion (TA) in exon 6b of the CFTR gene at
position 936 of the coding sequence. This frameshift mutation leads to a
premature termination codon 272 nucleotides downstream and a truncated
protein. One patient was homozygous and the other compound heterozygous.

.0102
CYSTIC FIBROSIS
CFTR, HIS949TYR

In a study of 224 non-F508del CF (219700) chromosomes, Ghanem et al.
(1994) identified a C-to-T substitution at nucleotide 2977 in exon 15,
changing histidine to tyrosine at position 949, in a 60-year-old woman
with a 10-year history of chronic lung disease. The sweat chloride value
was 42 mmol per liter.

.0103
CYSTIC FIBROSIS
CFTR, LEU1065PRO

In a 10-year-old girl with cystic fibrosis (219700), Ghanem et al.
(1994) identified a T-to-C substitution at nucleotide 3326 in exon 17b,
changing leucine to proline at position 1065 (L1065P). The L1065P
mutation was found on the maternal chromosome of the patient, who bore a
F508del mutation (602421.0001) on the paternal allele. The leucine at
this position is conserved in the mouse CFTR protein. This mutation
changes the MnlI(+) restriction site. The patient had gastrointestinal
and pulmonary manifestations of cystic fibrosis, as well as high sweat
chloride values (66 mmol per liter).

.0104
CYSTIC FIBROSIS
CFTR, GLN1071PRO

In a 21-year-old woman with cystic fibrosis (219700), Ghanem et al.
(1994) identified an A-to-C substitution at nucleotide 3344 in exon 17b,
changing glutamine to proline at position 1071 (Q1071P). Since the age
of 5 years the patient had suffered from chronic gastrointestinal
disorders, pancreatic insufficiency, diarrhea, steatorrhea, and very
high sweat chloride values (160 mmol per liter). This missense mutation
occurs on an amino acid conserved in mouse CFTR. The patient carried the
F508del mutation on the other CF chromosome. The mutation changes the
restriction site HaeIII(+).

.0105
CYSTIC FIBROSIS
CFTR, HIS1085ARG

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified a his1085-to-arg mutation.

.0106
CYSTIC FIBROSIS
CFTR, TYR1092TER

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) found a point mutation creating a stop codon in
place of tyrosine-1092.

.0107
CYSTIC FIBROSIS
CFTR, TRP1204TER

In a patient with cystic fibrosis (219700), Ghanem et al. (1994)
identified a G-to-A substitution at nucleotide 3743 in exon 19,
resulting in a stop codon at position 1204. This mutation was found on
the paternal chromosome of a 4-year-old child with pancreatic
insufficiency and a sweat chloride level of 120 mmol per liter but no
pulmonary infection. The maternal chromosome bears the F508 deletion.
The mutation changes the restriction sites MaeI(+).

.0108
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 1215G

In a patient with cystic fibrosis (219700), Romey et al. (1994)
identified a 1-bp deletion (G) at nucleotide 2423 in exon 7 of the CFTR
gene. This frameshift mutation leads to a premature termination (UAA) 7
codons downstream. The deletion creates an AflIII restriction site and
was inherited from the patient's father. The patient, a 7-year-old boy
of French and Spanish origin, carries a second mutation 2423delG
(602421.0116). Despite the 2 frameshift mutations, this patient does not
present a severe form of cystic fibrosis.

.0109
CYSTIC FIBROSIS
CFTR, THR1220ILE

Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 3791
in exon 19, changing threonine to isoleucine at position 1220. It was
not known if this mutation caused CF (219700) or is a sequence
variation.

.0110
CYSTIC FIBROSIS
CFTR, ILE1234VAL

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified an ile1234-to-val mutation.

.0111
CYSTIC FIBROSIS
CFTR, GLY1249GLU

In a patient with cystic fibrosis (219700), Greil et al. (1994)
identified a G-to-A substitution at nucleotide 3878 in exon 20 of the
CFTR gene, changing a glycine (GGG) to glutamic acid (GAG) at amino acid
1249.

.0112
CYSTIC FIBROSIS
CFTR, SER1251ASN

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified a ser1251-to-asn mutation.

.0113
CYSTIC FIBROSIS
CFTR, SER1255PRO

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified a ser1255-to-pro mutation.

.0114
CYSTIC FIBROSIS
CFTR, ASN1303HIS

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1993) identified an asp1303-to-his mutation.

.0115
CYSTIC FIBROSIS
CFTR, 2-BP DEL, 1609CA

In a systematic study of 133 CF (219700) individuals in northern Italy,
Gasparini et al. (1992) identified a 2-bp deletion (CA) in exon 10 of
the CFTR gene.

.0116
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 2423G

In a patient with cystic fibrosis (219700), Romey et al. (1994)
identified a 1-bp (G) deletion at position 2423 of the coding sequence
in exon 13 of the CFTR gene. This frameshift mutation leads to a
premature termination (UGA) 6 codons downstream. The patient, a
7-year-old boy of French and Spanish origin, carried a second mutation,
1215delG (602421.0108). Despite the 2 frameshift mutations, this patient
does not present a severe form of cystic fibrosis. The mutation 2423delG
is also associated with sequence variation in intron 17a 3271+18C or T.

.0117
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 3293A

In a patient with cystic fibrosis (219700), Ghanem et al. (1994)
identified a 1-bp deletion (A) at position 3293 of the coding sequence
in exon 10 of the CFTR gene. This frameshift mutation leads to a
premature termination codon 15 nucleotides downstream and a truncated
protein. The patient, a 15-year-old F508del heterozygous girl of French
origin, has a positive sweat test (80 mmol per liter) and pancreatic
insufficiency but no chronic lung infection.

.0118
CYSTIC FIBROSIS
CFTR, 4-BP INS, NT3667

In a 20-year-old cystic fibrosis (219700) patient of north-central
Italian origin with pancreatic insufficiency and severe pulmonary
involvement, Sangiuolo et al. (1993) identified a 4-bp insertion (TCAA)
at position 3667 of the coding sequence in exon 19 of the CFTR gene.
This frameshift mutation leads to a premature termination codon (TGA) at
amino acid position 1195 and destroys a HincII restriction enzyme site.

.0119
SWEAT CHLORIDE ELEVATION WITHOUT CYSTIC FIBROSIS
CFTR, SER1455TER

Mickle et al. (1998) identified a 6.8-kb deletion and a nonsense
mutation (ser1455 to ter; S1455X) in the CFTR gene of a mother and her
youngest daughter with isolated elevated sweat chloride concentrations.
Detailed clinical evaluation of both individuals found no evidence of
pulmonary or pancreatic disease characteristic of CF. A second child in
this family had classic CF and was homozygous for the 6.8-kb deletion,
indicating that this mutation caused severe CFTR dysfunction. CFTR mRNA
transcripts bearing the S1455X mutation were stable in vivo, implying
that this allele encoded a truncated version of CFTR missing the last 26
amino acids. Loss of this region did not affect processing of
transiently expressed S1455X-CFTR compared with wildtype CFTR. When
expressed in CF airway cells, this mutant generated cAMP-activated
whole-cell chloride currents similar to wildtype CFTR. Preservation of
chloride channel function of the S1455X-CFTR mutation was consistent
with normal lung and pancreatic function in the mother and her daughter.
The study indicated that mutations in CFTR can be associated with
elevated sweat chloride concentrations in the absence of the CF
phenotype, and suggested a previously unrecognized functional role in
the sweat gland for the C-terminus of CFTR.

Salvatore et al. (2005) reported 2 asymptomatic sisters with isolated
increased sweat chloride concentrations in whom systematic scanning of
the whole coding region of the CFTR gene revealed compound
heterozygosity for S1455X and delF508 (602421.0001).

.0120
CYSTIC FIBROSIS
CFTR, IVS16, G-A, +1

Dork et al. (1998) concluded that the 3120+1G-A mutation, which is
present in African, Arab, and a few Greek families with cystic fibrosis
(219700), probably was derived from a common ancestor because the
haplotypes are very similar or identical.

.0121
CYSTIC FIBROSIS
CFTR, ARG553GLN

In a pancreatic-insufficient patient with cystic fibrosis (219700), Dork
et al. (1991) identified a G-to-A transition at nucleotide 1790 of the
CFTR gene, resulting in an arg553-to-gln substitution. See also Stern
(1997).

.0122
CYSTIC FIBROSIS
CFTR, -102T-A

See 602421.0012 and Romey et al. (1999).

.0123
CYSTIC FIBROSIS
CFTR, 21-KB DEL

Dork et al. (2000) described a large genomic deletion of the CFTR gene
that is frequently observed in Central and Eastern Europe. The mutation
deletes 21,080 bp spanning from intron 1 to intron 3 of the CFTR gene.
Transcript analyses demonstrated that the deletion results in the loss
of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature
termination signal within exon 4. A simple PCR assay for the allele was
devised and used to screen for the mutation in European and
European-derived populations. Some 197 CF (219700) patients, including 7
homozygotes, were identified. Clinical evaluation of the homozygotes and
a comparison of compound heterozygotes for delF508 (602421.0001) with
pairwise-matched delF508 homozygotes indicated that the 21-kb deletion
represents a severe mutation associated with pancreatic insufficiency
and early age at diagnosis.

.0124
PANCREATITIS, IDIOPATHIC, SUSCEPTIBILITY TO
HYPERTRYPSINEMIA, NEONATAL, SUSCEPTIBILITY TO, INCLUDED
CFTR, LEU997PHE

Gomez Lira et al. (2000) postulated that there might be particular CFTR
gene mutations involved in pancreatic ductular obstruction, as
manifested in idiopathic pancreatitis or in neonatal hypertrypsinemia.
Following up on this hypothesis, they performed a complete screening of
the CFTR gene in a group of 32 patients with idiopathic pancreatitis (14
of whom carried the 5T variant CF mutation (602421.0086) or had a
borderline sweat chloride level, and 18 of whom were without common CF
mutations or any other CF characteristic) and in 49 newborns with
hypertrypsinemia and normal sweat chloride (32 of whom had a common CF
mutation, and 17 of whom did not have a common CF mutation). Rare
mutations were found in 9 of 32 patients with idiopathic pancreatitis
and in 21 of 49 newborns with hypertrypsinemia. Of these rare mutations,
leu997 to phe (L997F) was identified in 4 (12.5%) of 32 patients with
idiopathic pancreatitis and in 4 (8%) of 39 newborns with
hypertrypsinemia. L997 is a highly conserved residue in transmembrane
domain 9.

Since most neonatal screening programs for cystic fibrosis combine the
assay of immunoreactive trypsinogen (IRT) with analysis for the most
common mutations of the CFTR gene, the identification of heterozygotes
among neonates because of increased IRT is considered a drawback. Scotet
et al. (2001) assessed the heterozygosity frequency among children with
hypertrypsinemia detected during a CF screening program in Brittany
(France) 10 years previously. A total of 160,019 babies were screened
for CF between 1992 and 1998. Of the 1,964 newborns with increased IRT
(1.2%), 60 had CF and 213 were carriers. Heterozygosity frequency was
12.8%, or 3 times greater than in the general population (3.9%). A high
proportion of mild mutations or variants was observed in carriers. The
allelic frequency of the 5T variant (5.6%) was not increased. The study
was consistent with previous ones in finding a significantly higher rate
of heterozygotes than expected among neonates with hypertrypsinemia.

Kabra et al. (2000) identified the L997F mutation in a Pakistani patient
with cystic fibrosis (219700).

Derichs et al. (2005) reported a child, born of consanguineous Turkish
parents, who was homozygous for the L997F substitution. The child showed
normal development with no evidence of pancreatic insufficiency or
cystic fibrosis. Sweat chloride tests and intestinal chloride secretion
were normal. Derichs et al. (2005) concluded that the L997F mutation
does not cause cystic fibrosis.

.0125
CYSTIC FIBROSIS
CFTR, 1-BP INS, 3622T

In an Indian child with CF (219700), Kabra et al. (2000) identified a
1-bp insertion (T) at nucleotide 3622 of the CFTR gene.

.0126
CYSTIC FIBROSIS
CFTR, 3601, T-C, -20

In 2 Indian patients with CF (219700), Kabra et al. (2000) identified a
T-to-C change at position -20 from nucleotide 3601 of the CFTR gene.

.0127
CYSTIC FIBROSIS
CFTR, 1-BP DEL, 3876A

Wang et al. (2000) found that 7 of 29 Hispanic patients with cystic
fibrosis (219700) were heterozygous for a single-basepair deletion at
nucleotide 3876 (3876delA) resulting in a frameshift and termination at
residue 1258 (L1258X). This mutation accounted for 10.3% of mutant
alleles in this group. The patients with this mutation had a severe
phenotype as determined by early age of diagnosis, high sweat chloride,
presence of allergic bronchopulmonary aspergillosis, pancreatic
insufficiency, liver disease, cor pulmonale, and early death. Wang et
al. (2000) noted that this mutation had not been reported in any other
ethnic group.

.0128
CYSTIC FIBROSIS
CFTR, 2-BP DEL, 394TT

The 394delTT mutation in CFTR causing cystic fibrosis (219700), referred
to as the 'Nordic mutation,' is found at a high frequency in the
countries bordering the Baltic Sea and associated waterways (Sweden,
Norway, Denmark, Finland, Estonia, Russia, etc.). This mutation is
associated almost exclusively with a single chromosomal haplotype, which
suggests a single origin, centered in this region (Schwartz et al.,
1994).

.0129
CYSTIC FIBROSIS
CFTR, HIS1282TER

Kulczycki et al. (2003) described their oldest patient with cystic
fibrosis (219700), a 71-year-old white male who had been diagnosed at
the age of 27 years because of recurrent nasal polyposis, elevated sweat
sodium and chloride, and a history of CF in his sister. Urologic
examination demonstrated congenital bilateral absence of the vas
deferens (277180). At the age of 60 years, genetic testing indicated
compound heterozygosity for a severe his1282-to-ter (H1282X) mutation
and a mild ala445-to-glu (602421.0130) mutation in the CFTR gene.

.0130
CYSTIC FIBROSIS
CFTR, ALA445GLU

See 602421.0129 and Kulczycki et al. (2003).

.0131
CYSTIC FIBROSIS
CFTR, GLU7TER

In a 1.5-year-old Taiwanese boy with cystic fibrosis (219700), Wong et
al. (2003) found compound heterozygosity for 2 novel mutations in the
CFTR gene, a G-to-T transversion at nucleotide 151 in exon 1 that
resulted in a glu7-to-ter (E7X) substitution in the first transmembrane
domain of the protein, and a 1-bp insertion in exon 6b (989-992insA).
The insertion caused frameshift and a truncated CFTR protein of 306
amino acids.

.0132
CYSTIC FIBROSIS
CFTR, 1-BP INS, 989A

See 602421.0131 and Wong et al. (2003).

.0133
CYSTIC FIBROSIS
CFTR, GLN1352HIS

In a patient with cystic fibrosis (219700), Lee et al. (2003) identified
a G-to-C transversion at nucleotide 4188 in exon 22 of the CFTR gene
that resulted in a gln1352-to-his (Q1352H) amino acid change.

.0134
CYSTIC FIBROSIS
CFTR, GLU217GLY

In a patient with cystic fibrosis (219700), Lee et al. (2003) identified
a 782A-G transition in exon 6a of the CFTR gene that resulted in a
glu217-to-gly (E217G) amino acid substitution.

.0135
CYSTIC FIBROSIS
CFTR, GLY1244VAL AND SER912LEU

In a patient with a severe form of cystic fibrosis (219700), Savov et
al. (1995) identified compound heterozygosity for mutations in the CFTR
gene. One allele carried a G542X substitution (602421.0009). The other
allele carried 2 mutations: S912L (see 602421.0100) and a 3863G-T
transversion in exon 20, resulting in a gly1244-to-val (G1244V)
substitution in the second nucleotide binding domain.

By in vitro functional expression studies, Clain et al. (2005)
demonstrated that the S912L substitution was not disease-causing in
isolation, but significantly impaired CFTR function when inherited in
cis with the G1244V mutation. Although the G1244V substitution alone
resulted in decreased cAMP-dependent chloride conductance (43% of
control values), the G1244V/S912L complex allele had an almost 20-fold
reduction in chloride conduction (2.4% of control values) compared with
the G1244V mutant alone.

.0136
CYSTIC FIBROSIS
CFTR, ALA561GLU

Mendes et al. (2003) stated that an ala561-to-glu (A561E) substitution
in exon 12 of the CFTR gene is the second most common mutation among
Portuguese patients with cystic fibrosis (219700), accounting for 3% of
mutant alleles. Overexpression of the A561E mutant protein in baby
hamster kidney cells showed that it was misprocessed and retained in the
endoplasmic reticulum, thus belonging to the class II type of CFTR
mutation. Low temperature treatment partially rescued a functional
A561E-CFTR channel, similar to findings with the common F508del mutation
(602421.0001).

.0137
CYSTIC FIBROSIS
CFTR, MET1101LYS (dbSNP rs36210737)

Stuhrmann et al. (1997) identified a T-to-A transversion at nucleotide
3302 of the CFTR gene, resulting in met-to-lys substitution at codon
1101 (M1101K) in a single individual from the South Tyrol.

In a carrier screening of autosomal recessive mutations involving 1,644
Schmiedeleut (S-leut) Hutterites in the United States, Chong et al.
(2012) identified this mutation in heterozygous state in 108 individuals
among 1,473 screened and in homozygous state in 6, for a carrier
frequency of 0.073 (1 in 13.5). Chong et al. (2012) noted that the South
Tyrol was the home of some of the Hutterite founders.

*FIELD* SA
Baylin et al. (1980); Chalkley and Harris (1991); Chillon et al. (1995);
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et al. (1994); The Cystic Fibrosis Genotype-Phenotype Consortium
(1993); Varon et al. (1995); Yang et al. (1993)
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*FIELD* CN
Patricia A. Hartz - updated: 07/16/2013
Ada Hamosh - updated: 2/7/2013
Ada Hamosh - updated: 9/6/2012
Ada Hamosh - updated: 6/20/2012
Ada Hamosh - updated: 3/7/2012
Patricia A. Hartz - updated: 12/16/2011
Ada Hamosh - updated: 1/3/2011
Ada Hamosh - updated: 8/31/2010
Nara Sobreira - updated: 3/11/2010
Marla J. F. O'Neill - updated: 10/29/2009
Matthew B. Gross - updated: 5/7/2009
Ada Hamosh - updated: 7/17/2008
Patricia A. Hartz - updated: 5/19/2008
Ada Hamosh - updated: 7/25/2007
Cassandra L. Kniffin - updated: 7/10/2007
Cassandra L. Kniffin - updated: 6/22/2007
Cassandra L. Kniffin - updated: 5/4/2007
Marla J. F. O'Neill - updated: 3/15/2007
Patricia A. Hartz - updated: 2/8/2007
Patricia A. Hartz - updated: 11/29/2006
Victor A. McKusick - updated: 6/27/2006
Patricia A. Hartz - updated: 6/12/2006
Cassandra L. Kniffin - updated: 5/25/2006
Cassandra L. Kniffin - updated: 2/20/2006
Ada Hamosh - updated: 2/10/2006
Paul J. Converse - updated: 2/8/2006
Cassandra L. Kniffin - updated: 12/8/2005
Marla J. F. O'Neill - updated: 11/11/2005
Victor A. McKusick - updated: 10/14/2005
George E. Tiller - updated: 9/9/2005
George E. Tiller - updated: 6/3/2005
Cassandra L. Kniffin - updated: 5/18/2005
Marla J. F. O'Neill - updated: 5/16/2005
Victor A. McKusick - updated: 4/28/2005
Victor A. McKusick - updated: 3/23/2005
George E. Tiller - updated: 2/25/2005
George E. Tiller - updated: 2/17/2005
Marla J. F. O'Neill - updated: 1/28/2005
Victor A. McKusick - updated: 1/12/2005
Patricia A. Hartz - updated: 12/2/2004
Victor A. McKusick - updated: 11/9/2004
Victor A. McKusick - updated: 5/21/2004
Victor A. McKusick - updated: 5/5/2004
Ada Hamosh - updated: 4/30/2004
Victor A. McKusick - updated: 4/27/2004
Victor A. McKusick - updated: 1/8/2004
Victor A. McKusick - updated: 11/6/2003
Ada Hamosh - updated: 9/26/2003
Victor A. McKusick - updated: 8/13/2003
Ada Hamosh - updated: 7/8/2003
Victor A. McKusick - updated: 2/4/2003
George E. Tiller - updated: 12/16/2002
Michael B. Petersen - updated: 10/8/2002
George E. Tiller - updated: 9/17/2002
Victor A. McKusick - updated: 8/16/2002
Victor A. McKusick - updated: 6/14/2002
Sonja A. Rasmussen - updated: 4/18/2002
Deborah L. Stone - updated: 4/10/2002
George E. Tiller - updated: 12/6/2001
Ada Hamosh - updated: 2/28/2001
Victor A. McKusick - updated: 2/5/2001
Michael J. Wright - updated: 1/8/2001
Ada Hamosh - updated: 11/17/2000
Stylianos E. Antonarakis - updated: 10/19/2000
Carol A. Bocchini - updated: 9/22/2000
Victor A. McKusick - updated: 7/26/2000
Victor A. McKusick - updated: 7/20/2000
Victor A. McKusick - updated: 5/18/2000
Victor A. McKusick - updated: 2/22/2000
Ada Hamosh - updated: 2/11/2000
Ada Hamosh - updated: 2/9/2000
Victor A. McKusick - updated: 10/21/1999
Wilson H. Y. Lo - updated: 9/9/1999
Victor A. McKusick - updated: 8/23/1999
Stylianos E. Antonarakis - updated: 8/3/1999
Victor A. McKusick - updated: 7/6/1999
Ada Hamosh - updated: 3/17/1999
Ada Hamosh - updated: 3/15/1999
Michael J. Wright - updated: 3/1/1999
Victor A. McKusick - updated: 11/6/1998
Victor A. McKusick - updated: 9/18/1998
Victor A. McKusick - updated: 9/17/1998
Victor A. McKusick - updated: 9/14/1998
Victor A. McKusick - updated: 5/7/1998
Victor A. McKusick - updated: 5/6/1998
Victor A. McKusick - updated: 4/30/1998
Victor A. McKusick - updated: 4/20/1998
Victor A. McKusick - updated: 3/19/1998
John F. Jackson - reorganized: 3/7/1998

*FIELD* CD
Victor A. McKusick: 3/7/1998

*FIELD* ED
mgross: 07/16/2013
alopez: 2/13/2013
alopez: 2/11/2013
terry: 2/7/2013
carol: 10/4/2012
alopez: 9/12/2012
alopez: 9/10/2012
terry: 9/6/2012
terry: 8/8/2012
alopez: 6/25/2012
alopez: 6/22/2012
terry: 6/20/2012
carol: 5/10/2012
alopez: 3/9/2012
terry: 3/7/2012
mgross: 3/6/2012
terry: 12/16/2011
terry: 10/26/2011
carol: 4/7/2011
terry: 3/18/2011
mgross: 3/17/2011
terry: 3/15/2011
alopez: 1/5/2011
terry: 1/3/2011
carol: 10/27/2010
alopez: 9/3/2010
terry: 8/31/2010
carol: 4/29/2010
carol: 3/23/2010
terry: 3/11/2010
terry: 1/20/2010
wwang: 10/29/2009
alopez: 9/30/2009
carol: 8/11/2009
terry: 6/3/2009
wwang: 5/11/2009
mgross: 5/7/2009
wwang: 4/29/2009
terry: 4/3/2009
joanna: 2/2/2009
alopez: 10/22/2008
terry: 10/20/2008
alopez: 7/17/2008
terry: 7/17/2008
mgross: 5/19/2008
terry: 12/17/2007
wwang: 9/6/2007
alopez: 8/2/2007
terry: 7/25/2007
wwang: 7/18/2007
ckniffin: 7/10/2007
wwang: 7/2/2007
ckniffin: 6/22/2007
wwang: 5/23/2007
ckniffin: 5/4/2007
wwang: 3/16/2007
terry: 3/15/2007
alopez: 2/27/2007
terry: 2/19/2007
mgross: 2/8/2007
wwang: 11/29/2006
terry: 11/16/2006
carol: 6/29/2006
terry: 6/27/2006
mgross: 6/12/2006
wwang: 6/12/2006
ckniffin: 5/25/2006
wwang: 3/14/2006
ckniffin: 2/20/2006
alopez: 2/17/2006
terry: 2/10/2006
carol: 2/8/2006
carol: 12/23/2005
ckniffin: 12/8/2005
wwang: 11/11/2005
terry: 11/11/2005
carol: 10/21/2005
terry: 10/14/2005
wwang: 10/12/2005
alopez: 10/4/2005
terry: 9/9/2005
alopez: 6/3/2005
ckniffin: 5/18/2005
wwang: 5/16/2005
tkritzer: 5/11/2005
terry: 4/28/2005
tkritzer: 3/24/2005
terry: 3/23/2005
tkritzer: 3/3/2005
terry: 2/25/2005
wwang: 2/25/2005
wwang: 2/22/2005
terry: 2/17/2005
tkritzer: 1/31/2005
terry: 1/28/2005
wwang: 1/21/2005
wwang: 1/20/2005
wwang: 1/18/2005
terry: 1/12/2005
mgross: 12/2/2004
tkritzer: 11/10/2004
terry: 11/9/2004
alopez: 5/28/2004
terry: 5/21/2004
tkritzer: 5/7/2004
terry: 5/5/2004
alopez: 5/5/2004
terry: 4/30/2004
terry: 4/27/2004
carol: 2/19/2004
cwells: 1/12/2004
terry: 1/8/2004
cwells: 11/7/2003
carol: 11/6/2003
alopez: 11/6/2003
terry: 11/6/2003
carol: 11/3/2003
alopez: 10/16/2003
tkritzer: 10/2/2003
alopez: 9/29/2003
terry: 9/26/2003
tkritzer: 8/20/2003
tkritzer: 8/19/2003
terry: 8/13/2003
mgross: 7/14/2003
terry: 7/8/2003
terry: 3/19/2003
carol: 2/28/2003
tkritzer: 2/19/2003
terry: 2/4/2003
cwells: 12/16/2002
tkritzer: 11/19/2002
cwells: 10/8/2002
cwells: 9/17/2002
tkritzer: 8/23/2002
tkritzer: 8/21/2002
terry: 8/16/2002
cwells: 6/19/2002
cwells: 6/18/2002
terry: 6/14/2002
ckniffin: 6/5/2002
carol: 4/19/2002
terry: 4/18/2002
carol: 4/10/2002
alopez: 3/14/2002
alopez: 3/13/2002
joanna: 2/14/2002
cwells: 12/18/2001
cwells: 12/6/2001
carol: 9/10/2001
alopez: 2/28/2001
terry: 2/28/2001
carol: 2/26/2001
cwells: 2/8/2001
terry: 2/5/2001
alopez: 1/8/2001
mgross: 11/17/2000
terry: 11/17/2000
mcapotos: 10/20/2000
terry: 10/19/2000
carol: 9/22/2000
mcapotos: 9/22/2000
carol: 8/3/2000
terry: 7/26/2000
mcapotos: 7/20/2000
mcapotos: 7/5/2000
carol: 6/12/2000
mcapotos: 6/7/2000
mcapotos: 5/30/2000
terry: 5/18/2000
mcapotos: 3/22/2000
mcapotos: 3/15/2000
mcapotos: 3/13/2000
terry: 2/22/2000
alopez: 2/15/2000
terry: 2/11/2000
alopez: 2/9/2000
carol: 12/13/1999
mcapotos: 12/7/1999
alopez: 11/24/1999
carol: 11/9/1999
carol: 10/21/1999
carol: 9/9/1999
jlewis: 9/8/1999
terry: 8/23/1999
carol: 8/18/1999
mgross: 8/3/1999
mgross: 7/14/1999
jlewis: 7/14/1999
terry: 7/6/1999
terry: 5/20/1999
alopez: 3/24/1999
alopez: 3/17/1999
alopez: 3/15/1999
carol: 3/1/1999
terry: 11/18/1998
carol: 11/16/1998
terry: 11/6/1998
carol: 9/28/1998
terry: 9/18/1998
terry: 9/17/1998
carol: 9/17/1998
terry: 9/14/1998
carol: 8/11/1998
carol: 8/10/1998
dkim: 7/24/1998
alopez: 5/21/1998
alopez: 5/18/1998
alopez: 5/7/1998
alopez: 5/6/1998
terry: 5/6/1998
carol: 5/2/1998
terry: 4/30/1998
alopez: 4/23/1998
terry: 4/20/1998
carol: 4/17/1998
carol: 3/28/1998
carol: 3/7/1998

RBCC Red Blood Cell Collection

Full text data of CFTR