RBCC Red Blood Cell Collection

PRSS1 (TRP1, TRY1, TRYP1) [Confidence: low (only semi-automatic identification from reviews)]
Trypsin-1; 3.4.21.4 (Beta-trypsin; Cationic trypsinogen; Serine protease 1; Trypsin I; Alpha-trypsin chain 1; Alpha-trypsin chain 2; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P07477
ID TRY1_HUMAN Reviewed; 247 AA.
AC P07477; A1A509; A6NJ71; B2R5I5; Q5NV57; Q7M4N3; Q7M4N4; Q92955;
read moreAC Q9HAN4; Q9HAN5; Q9HAN6; Q9HAN7;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 158.
DE RecName: Full=Trypsin-1;
DE EC=3.4.21.4;
DE AltName: Full=Beta-trypsin;
DE AltName: Full=Cationic trypsinogen;
DE AltName: Full=Serine protease 1;
DE AltName: Full=Trypsin I;
DE Contains:
DE RecName: Full=Alpha-trypsin chain 1;
DE Contains:
DE RecName: Full=Alpha-trypsin chain 2;
DE Flags: Precursor;
GN Name=PRSS1; Synonyms=TRP1, TRY1, TRYP1;
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].
RX PubMed=3011602; DOI=10.1016/0378-1119(86)90111-3;
RA Emi M., Nakamura Y., Ogawa M., Yamamoto T., Nishide T., Mori T.,
RA Matsubara K.;
RT "Cloning, characterization and nucleotide sequences of two cDNAs
RT encoding human pancreatic trypsinogens.";
RL Gene 41:305-310(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8650574; DOI=10.1126/science.272.5269.1755;
RA Rowen L., Koop B.F., Hood L.;
RT "The complete 685-kilobase DNA sequence of the human beta T cell
RT receptor locus.";
RL Science 272:1755-1762(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
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 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 15-67, AND VARIANT PCTT GLY-22.
RX PubMed=10930381; DOI=10.1053/gast.2000.9312;
RA Teich N., Ockenga J., Hoffmeister A., Manns M., Mossner J., Keim V.;
RT "Chronic pancreatitis associated with an activation peptide mutation
RT that facilitates trypsin activation.";
RL Gastroenterology 119:461-465(2000).
RN [9]
RP PROTEIN SEQUENCE OF 16-43 AND 123-142, FUNCTION, AND
RP POST-TRANSLATIONAL PROCESSING.
RC TISSUE=Gastric adenocarcinoma;
RX PubMed=7945238;
RA Koshikawa N., Yasumitsu H., Nagashima Y., Umeda M., Miyazaki K.;
RT "Identification of one- and two-chain forms of trypsinogen 1 produced
RT by a human gastric adenocarcinoma cell line.";
RL Biochem. J. 303:187-190(1994).
RN [10]
RP PROTEIN SEQUENCE OF 16-43.
RX PubMed=2598466; DOI=10.1016/0009-8981(89)90254-4;
RA Kimland M., Russick C., Marks W.H., Borgstroem A.;
RT "Immunoreactive anionic and cationic trypsin in human serum.";
RL Clin. Chim. Acta 184:31-46(1989).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 68-151, AND VARIANT PCTT HIS-122.
RX PubMed=8841182; DOI=10.1038/ng1096-141;
RA Whitcomb D.C., Gorry M.C., Preston R.A., Furey W., Sossenheimer M.J.,
RA Ulrich C.D., Martin S.P., Gates L.K. Jr., Amann S.T., Toskes P.P.,
RA Liddle R., McGrath K., Uomo G., Post J.C., Ehrlich G.D.;
RT "Hereditary pancreatitis is caused by a mutation in the cationic
RT trypsinogen gene.";
RL Nat. Genet. 14:141-145(1996).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 68-151, AND VARIANTS PCTT ILE-29;
RP PRO-104; CYS-116; HIS-122 AND PHE-139.
RX PubMed=11866271;
RA Teich N., Bauer N., Mossner J., Keim V.;
RT "Mutational screening of patients with nonalcoholic chronic
RT pancreatitis: identification of further trypsinogen variants.";
RL Am. J. Gastroenterol. 97:341-346(2002).
RN [13]
RP PROTEIN SEQUENCE OF 73-92, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Afjehi-Sadat L.;
RL Submitted (MAR-2007) to UniProtKB.
RN [14]
RP SULFATION AT TYR-154, AND MUTAGENESIS OF TYR-154.
RX PubMed=17087724; DOI=10.1111/j.1742-4658.2006.05501.x;
RA Sahin-Toth M., Kukor Z., Nemoda Z.;
RT "Human cationic trypsinogen is sulfated on Tyr154.";
RL FEBS J. 273:5044-5050(2006).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS), AND MASS SPECTROMETRY.
RX PubMed=8683601; DOI=10.1006/jmbi.1996.0376;
RA Gaboriaud C., Serre L., Guy-Crotte O., Forest E.,
RA Fontecilla-Camps J.-C.;
RT "Crystal structure of human trypsin 1: unexpected phosphorylation of
RT Tyr151.";
RL J. Mol. Biol. 259:995-1010(1996).
RN [16]
RP VARIANTS PCTT ILE-29 AND HIS-122.
RX PubMed=9322498;
RA Gorry M.C., Gabbaizedeh D., Furey W., Gates L.K. Jr., Preston R.A.,
RA Aston C.E., Zhang Y., Ulrich C., Ehrlich G.D., Whitcomb D.C.;
RT "Mutations in the cationic trypsinogen gene are associated with
RT recurrent acute and chronic pancreatitis.";
RL Gastroenterology 113:1063-1068(1997).
RN [17]
RP VARIANT PCTT ILE-29.
RX PubMed=9633818;
RX DOI=10.1002/(SICI)1098-1004(1998)12:1<39::AID-HUMU6>3.0.CO;2-P;
RA Teich N., Mossner J., Keim V.;
RT "Mutations of the cationic trypsinogen in hereditary pancreatitis.";
RL Hum. Mutat. 12:39-43(1998).
RN [18]
RP VARIANTS PCTT VAL-16 AND HIS-122.
RX PubMed=10381903;
RA Witt H., Luck W., Becker M.;
RT "A signal peptide cleavage site mutation in the cationic trypsinogen
RT gene is strongly associated with chronic pancreatitis.";
RL Gastroenterology 117:7-10(1999).
RN [19]
RP VARIANT PCTT ARG-23.
RX PubMed=10204851;
RA Ferec C., Raguenes O., Salomon R., Roche C., Bernard J.P., Guillot M.,
RA Quere I., Faure C., Mercier B., Audrezet M.-P., Guillausseau P.J.,
RA Dupont C., Munnich A., Bignon J.D., Le Bodic L.;
RT "Mutations in the cationic trypsinogen gene and evidence for genetic
RT heterogeneity in hereditary pancreatitis.";
RL J. Med. Genet. 36:228-232(1999).
RN [20]
RP VARIANT PCTT HIS-122.
RX PubMed=11073545; DOI=10.1136/jmg.37.11.e36;
RA Chen J.-M., Raguenes O., Ferec C., Deprez P.H., Verellen-Dumoulin C.;
RT "A CGC>CAT gene conversion-like event resulting in the R122H mutation
RT in the cationic trypsinogen gene and its implication in the genotyping
RT of pancreatitis.";
RL J. Med. Genet. 37:E36-E36(2000).
RN [21]
RP VARIANTS PCTT THR-29 AND CYS-122.
RX PubMed=11788572; DOI=10.1136/gut.50.2.271;
RA Pfutzer R., Myers E., Applebaum-Shapiro S., Finch R., Ellis I.,
RA Neoptolemos J., Kant J.A., Whitcomb D.C.;
RT "Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause
RT autosomal dominant hereditary pancreatitis.";
RL Gut 50:271-272(2002).
RN [22]
RP VARIANT PCTT LYS-79, AND CHARACTERIZATION OF VARIANT PCTT LYS-79.
RX PubMed=14695529; DOI=10.1002/humu.10285;
RA Teich N., Le Marechal C., Kukor Z., Caca K., Witzigmann H.,
RA Chen J.-M., Toth M., Moessner J., Keim V., Ferec C., Sahin-Toth M.;
RT "Interaction between trypsinogen isoforms in genetically determined
RT pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes
RT increased transactivation of anionic trypsinogen (PRSS2).";
RL Hum. Mutat. 23:22-31(2004).
RN [23]
RP VARIANTS PCTT ILE-29 AND SER-54, AND CHARACTERIZATION OF VARIANTS PCTT
RP ILE-29 AND SER-54.
RX PubMed=15776435; DOI=10.1002/humu.20148;
RA Teich N., Nemoda Z., Koehler H., Heinritz W., Moessner J., Keim V.,
RA Sahin-Toth M.;
RT "Gene conversion between functional trypsinogen genes PRSS1 and PRSS2
RT associated with chronic pancreatitis in a six-year-old girl.";
RL Hum. Mutat. 25:343-347(2005).
RN [24]
RP VARIANT [LARGE SCALE ANALYSIS] MET-137.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Has activity against the synthetic substrates Boc-Phe-
CC Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-
CC Pro-Arg-Mec. The single-chain form is more active than the two-
CC chain form against all of these substrates.
CC -!- CATALYTIC ACTIVITY: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.
CC -!- COFACTOR: Binds 1 calcium ion per subunit.
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space.
CC -!- PTM: Occurs in a single-chain form and a two-chain form, produced
CC by proteolytic cleavage after Arg-122.
CC -!- MASS SPECTROMETRY: Mass=24348; Mass_error=2; Method=Electrospray;
CC Range=24-247; Source=PubMed:8683601;
CC -!- DISEASE: Pancreatitis (PCTT) [MIM:167800]: A disease characterized
CC by the presence of calculi in pancreatic ducts. It causes severe
CC abdominal pain attacks. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- CAUTION: Tyr-154 was proposed to be phosphorylated
CC (PubMed:8683601) but it has been shown (PubMed:17087724) to be
CC sulfated instead. Phosphate and sulfate groups are similar in mass
CC and size, and this can lead to erroneous interpretation of the
CC results.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PRSS1";
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DR EMBL; M22612; AAA61231.1; -; mRNA.
DR EMBL; L36092; AAC80207.1; -; Genomic_DNA.
DR EMBL; AK312199; BAG35132.1; -; mRNA.
DR EMBL; AC231380; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236959; EAL23773.1; -; Genomic_DNA.
DR EMBL; CH471198; EAW51925.1; -; Genomic_DNA.
DR EMBL; BC128226; AAI28227.1; -; mRNA.
DR EMBL; AF314534; AAG30943.1; -; Genomic_DNA.
DR EMBL; U70137; AAC50728.1; -; Genomic_DNA.
DR EMBL; AF315309; AAG30947.1; -; Genomic_DNA.
DR EMBL; AF315310; AAG30948.1; -; Genomic_DNA.
DR EMBL; AF315311; AAG30949.1; -; Genomic_DNA.
DR PIR; A25852; A25852.
DR PIR; S50020; S50020.
DR PIR; S50021; S50021.
DR RefSeq; NP_002760.1; NM_002769.4.
DR UniGene; Hs.449281; -.
DR PDB; 1FXY; X-ray; 2.15 A; A=127-247.
DR PDB; 1TRN; X-ray; 2.20 A; A/B=24-247.
DR PDB; 2RA3; X-ray; 1.46 A; A/B=24-247.
DR PDBsum; 1FXY; -.
DR PDBsum; 1TRN; -.
DR PDBsum; 2RA3; -.
DR ProteinModelPortal; P07477; -.
DR SMR; P07477; 24-247.
DR IntAct; P07477; 3.
DR BindingDB; P07477; -.
DR ChEMBL; CHEMBL2096988; -.
DR GuidetoPHARMACOLOGY; 2397; -.
DR MEROPS; S01.127; -.
DR PhosphoSite; P07477; -.
DR DMDM; 136408; -.
DR PaxDb; P07477; -.
DR PeptideAtlas; P07477; -.
DR PRIDE; P07477; -.
DR Ensembl; ENST00000311737; ENSP00000308720; ENSG00000204983.
DR Ensembl; ENST00000561535; ENSP00000455361; ENSG00000261473.
DR GeneID; 5644; -.
DR KEGG; hsa:5644; -.
DR UCSC; uc003wak.2; human.
DR CTD; 5644; -.
DR GeneCards; GC07P142711; -.
DR HGNC; HGNC:9475; PRSS1.
DR HPA; CAB025487; -.
DR HPA; CAB025538; -.
DR MIM; 167800; phenotype.
DR MIM; 276000; gene.
DR neXtProt; NX_P07477; -.
DR Orphanet; 676; Hereditary chronic pancreatitis.
DR PharmGKB; PA33828; -.
DR eggNOG; COG5640; -.
DR HOVERGEN; HBG013304; -.
DR InParanoid; P07477; -.
DR KO; K01312; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR EvolutionaryTrace; P07477; -.
DR GeneWiki; Trypsin_1; -.
DR GenomeRNAi; 5644; -.
DR NextBio; 21926; -.
DR PMAP-CutDB; P07477; -.
DR PRO; PR:P07477; -.
DR ArrayExpress; P07477; -.
DR Bgee; P07477; -.
DR Genevestigator; P07477; -.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004252; F:serine-type endopeptidase activity; TAS:UniProtKB.
DR GO; GO:0009235; P:cobalamin metabolic process; TAS:Reactome.
DR GO; GO:0007586; P:digestion; IEA:UniProtKB-KW.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Complete proteome; Digestion;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Hydrolase; Metal-binding; Polymorphism; Protease; Reference proteome;
KW Secreted; Serine protease; Signal; Sulfation; Zymogen.
FT SIGNAL 1 15
FT PROPEP 16 23 Activation peptide.
FT /FTId=PRO_0000028197.
FT CHAIN 24 247 Trypsin-1.
FT /FTId=PRO_0000028198.
FT CHAIN 24 122 Alpha-trypsin chain 1.
FT /FTId=PRO_0000313570.
FT CHAIN 123 247 Alpha-trypsin chain 2.
FT /FTId=PRO_0000313571.
FT DOMAIN 24 244 Peptidase S1.
FT ACT_SITE 63 63 Charge relay system.
FT ACT_SITE 107 107 Charge relay system.
FT ACT_SITE 200 200 Charge relay system.
FT METAL 75 75 Calcium.
FT METAL 77 77 Calcium; via carbonyl oxygen.
FT METAL 80 80 Calcium; via carbonyl oxygen.
FT METAL 85 85 Calcium.
FT SITE 194 194 Required for specificity (By similarity).
FT MOD_RES 154 154 Sulfotyrosine.
FT DISULFID 30 160
FT DISULFID 48 64
FT DISULFID 139 206
FT DISULFID 171 185
FT DISULFID 196 220
FT VARIANT 16 16 A -> V (in PCTT; disrupts signal sequence
FT cleavage site).
FT /FTId=VAR_011693.
FT VARIANT 22 22 D -> G (in PCTT; increased rate of
FT activation).
FT /FTId=VAR_011652.
FT VARIANT 23 23 K -> R (in PCTT; increased rate of
FT activation).
FT /FTId=VAR_011653.
FT VARIANT 29 29 N -> I (in PCTT).
FT /FTId=VAR_006720.
FT VARIANT 29 29 N -> T (in PCTT).
FT /FTId=VAR_012712.
FT VARIANT 54 54 N -> S (in PCTT; associated with Ile-29;
FT the double mutant shows increased
FT autocatalytic activation which is solely
FT due to the Ile-29 mutation).
FT /FTId=VAR_037908.
FT VARIANT 79 79 E -> K (in PCTT; Lys-79 trypsin activates
FT anionic trypsinogen PRSS2 2-fold while
FT the common pancreatitis-associated
FT mutants His-122 or Ile-29 have no such
FT effect; dbSNP:rs28934902).
FT /FTId=VAR_037909.
FT VARIANT 104 104 L -> P (in PCTT).
FT /FTId=VAR_011654.
FT VARIANT 116 116 R -> C (in PCTT).
FT /FTId=VAR_011655.
FT VARIANT 122 122 R -> C (in PCTT; suppresses an
FT autocleavage site).
FT /FTId=VAR_012713.
FT VARIANT 122 122 R -> H (in PCTT; suppresses an
FT autocleavage site which is probably part
FT of a fail-safe mechanism by which
FT trypsin, which is activated within the
FT pancreas, may be inactivated; loss of
FT this cleavage site would permit
FT autodigestion resulting in pancreatitis).
FT /FTId=VAR_006721.
FT VARIANT 137 137 T -> M (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036299.
FT VARIANT 139 139 C -> F (in PCTT).
FT /FTId=VAR_011656.
FT MUTAGEN 154 154 Y->F: Lack of sulfation.
FT CONFLICT 4 4 L -> F (in Ref. 7; AAI28227).
FT STRAND 38 54
FT STRAND 57 60
FT HELIX 62 64
FT STRAND 70 74
FT STRAND 76 80
FT STRAND 86 95
FT TURN 101 103
FT STRAND 109 115
FT STRAND 120 122
FT STRAND 138 144
FT STRAND 149 151
FT STRAND 159 165
FT HELIX 168 174
FT TURN 176 178
FT STRAND 183 187
FT STRAND 192 194
FT STRAND 203 206
FT STRAND 209 216
FT STRAND 218 222
FT STRAND 227 231
FT HELIX 232 235
FT HELIX 236 245
SQ SEQUENCE 247 AA; 26558 MW; DD49A487B8062813 CRC64;
MNPLLILTFV AAALAAPFDD DDKIVGGYNC EENSVPYQVS LNSGYHFCGG SLINEQWVVS
AGHCYKSRIQ VRLGEHNIEV LEGNEQFINA AKIIRHPQYD RKTLNNDIML IKLSSRAVIN
ARVSTISLPT APPATGTKCL ISGWGNTASS GADYPDELQC LDAPVLSQAK CEASYPGKIT
SNMFCVGFLE GGKDSCQGDS GGPVVCNGQL QGVVSWGDGC AQKNKPGVYT KVYNYVKWIK
NTIAANS
//

MIM 167800
*RECORD*
*FIELD* NO
167800
*FIELD* TI
#167800 PANCREATITIS, HEREDITARY; PCTT
;;HPC;;
HP;;
PANCREATITIS, CHRONIC
PANCREATITIS, CHRONIC, SUSCEPTIBILITY TO, INCLUDED;;
read morePANCREATITIS, CALCIFIC, INCLUDED;;
PANCREATITIS, CHRONIC, PROTECTION AGAINST, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
chronic pancreatitis can be caused by mutation in the cationic
trypsinogen gene PRSS1 (276000) and the SPINK1 gene (167790).
Furthermore, idiopathic pancreatitis has been found to be associated
with mutations in the cystic fibrosis gene (CFTR; 602421). A missense
variant in the PRSS2 gene (601564.0001) confers protection against
chronic pancreatitis. Variants in the chymotrypsin C gene (601405) that
diminish activity or secretion are associated with chronic pancreatitis.

CLINICAL FEATURES

Gross et al. (1962) described a kindred with affected persons in 4
generations. Four other families had been reported from the Mayo Clinic,
including the first reported example by Comfort and Steinberg (1952). A
puzzling feature was the urinary excretion of lysine and cystine by
about half the members of affected kindreds (with or without
pancreatitis). Cystine urinary stones had not been observed.

Singer and Cohen (1966) reported onset at about age 20 in a man whose
younger sister and a cousin were similarly affected. The attacks were
characterized by severe abdominal pains, fever, and marked elevation of
serum amylase. Except for the last symptom, differentiation from
familial Mediterranean fever (249100), also called 'familial paroxysmal
peritonitis,' might be difficult. The aminoaciduria was almost certainly
an incidental finding since family members without pancreatitis showed
it and because other families with pancreatitis have not had this
feature (Davidson et al., 1968).

Robechek (1967) observed a family in which 5 individuals had hereditary
chronic relapsing pancreatitis, 3 of whom obtained symptomatic relief
after sphincterotomy or section of the hypertrophied sphincter of Oddi.
Robechek (1967) suggested that hypertrophy of the sphincter of Oddi
together with a common ampulla of the biliary and pancreatic ducts may
be the inherited factor. Mann and Rubin (1969) described a 17-month-old
boy with steatorrhea whose 26-year-old brother and mother had
steatorrhea and pancreatic calcification. Hereditary pancreatitis occurs
with hyperparathyroidism in the multiple endocrine adenomatosis syndrome
(131100). McElroy and Christiansen (1972) described a family in which 10
persons had definite pancreatitis and 16 others may have been affected.
They pointed out that thrombosis in the portal or splenic vein occurs
with significant frequency.

Sibert (1978) identified 72 patients in 7 families in England and Wales.
Penetrance was about 80%. The mean age of onset was 13.6 years. There
were 2 peaks, one at 5 years and one at 17 years. The second peak was
thought to represent genetically susceptible persons with symptoms
precipitated by alcohol, rather than genetic heterogeneity. In 5 of the
families, members with both childhood and adult onset were identified.
In most cases the attacks were of nuisance value only. Only 4 of the 72
patients had life-threatening disease. Pancreatic insufficiency (5.5%),
diabetes mellitus (12.5%), pseudocysts (5.5%) and hemorrhagic pleural
effusion were observed. Portal vein thrombosis occurred in 2 and was
suspected in 3 others. Patients seemed to improve later in life. Attacks
were precipitated by emotional upset, alcohol, or high fat intake.

Sarles et al. (1982) pointed out that chronic calcifying pancreatitis is
characterized by pancreatic stones in the ducts and acini. They had
shown that 'stone protein' (see 167770) inhibits in vitro calcium
carbonate nucleation and decreases the rate of crystal growth,
suggesting that it acts as a physiologic inhibitor of spontaneous
calcium carbonate formation in supersaturated pancreatic juice. (A
similar function has been suggested for statherin in human saliva
(Schlesinger and Hay, 1977).) Sarles et al. (1982) found absence of
stone protein in the pancreatic stones in a case of calcific
pancreatitis and interpreted this as indicating that the protein was not
secreted into the pancreatic juice.

Freud et al. (1992) described the cases of monozygotic twin girls of
Ashkenazi origin who were admitted to hospital at the age of 9 years
because of recurrent attacks of pancreatitis. Dalton-Clarke et al.
(1985) found 10 definite and 4 suspected cases of pancreatitis in an
English family. Lewis and Gazet (1993) reported pancreatitis in members
of 4 successive generations of a second English family. A male in each
of the first generations had a combination of calcific pancreatitis and
pancreatic carcinoma.

Rumenapf et al. (1994) stated that more than 50 families of hereditary
pancreatitis had been reported since the first description by Comfort
and Steinberg (1952). They reported on the case of a 26-year-old man
from a family in which 6 of 34 members had confirmed pancreatitis and an
additional 3 members had suspected pancreatitis. A great uncle had died
of pancreatic cancer after suffering from pancreatitis for years.
Numerous pancreatic calculi were removed surgically, and a side-to-side
pancreaticojejunostomy with a Roux-Y loop was performed. Rumenapf et al.
(1994) suggested that surgery may be superior to endoscopic drainage.

Sarles et al. (1996) reported 11 families with hereditary pancreatitis
characterized by the presence of calculi in pancreatic ducts. The
disorder in 1 family with 5 cases was classified as calcic lithiasis
because the calculi were composed of more than 95% calcium salts.
Protein lithiasis was present in the other 10 families, the calculi
being composed of degraded amorphous residues of lithostathine (167770),
the pancreatic secretory protein that inhibits salt crystallization.
Average age at clinical onset of symptoms was 15 years. Clinical
progression seemed to be less severe than that in alcoholic chronic
pancreatitis (alcoholic calcic lithiasis).

Lowenfels et al. (1997) assembled records on 246 patients (125 males and
121 females) thought to have hereditary pancreatitis. In 218 patients
the diagnosis appeared to be highly probable and in 28 patients it was
thought to be less certain. The mean age of onset of symptoms of
pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number
of 0.150, 8 pancreatic adenocarcinomas developed during 8,531
person-years of follow-up. The mean age at diagnosis of pancreatic
cancer was 56.9 +/- 11.2 years. Frequency of other tumors was not
increased. Eight of 20 reported deaths in the cohort were from
pancreatic cancer. Thirty members of the cohort had been tested and all
were found to have a mutated copy of the trypsinogen gene. The estimated
cumulative risk of pancreatic cancer to age 70 years in patients with
hereditary pancreatitis approached 40%. For patients with a paternal
inheritance pattern, the cumulative risk of pancreatic cancer was
approximately 75%.

MAPPING

Le Bodic et al. (1996) analyzed the genomic segregation of highly
informative microsatellite markers in a French family of 147
individuals, 47 of whom had hereditary pancreatitis. Linkage was found
between HPC and 6 chromosome 7q markers. The marker D7S661 was linked to
HPC with a lod score of 8.58 at theta = 0.077. Multipoint linkage
analysis indicated that the HPC gene is most likely located in the
region encompassed by markers D7S661 and D7S676 on 7q33-qter. Le Bodic
et al. (1996) noted that the gene encoding carboxypeptidase A1 (CPA1;
114850), which is a pancreatic exopeptidase, mapped centromeric to the
HPC locus.

Whitcomb et al. (1996) performed a genomewide linkage analysis on a
family extensively affected with hereditary pancreatitis centered in
eastern Kentucky and western Virginia. Using microsatellite markers,
they established linkage between the hereditary pancreatitis phenotype
and 7q. A maximal lod score of 4.73 at a recombination fraction of 0.0
was obtained with D7S684 located in the 7q35 region. Using 3 large HP
families located in Virginia, West Virginia, and Tennessee, Pandya et
al. (1996) confirmed the tight linkage of HP to marker D7S684. They
placed the HP locus within a 16-cM interval between markers D7S495 and
D7S688.

MOLECULAR GENETICS

Several genes previously mapped to 7q were considered candidates for HPC
because they were known to be expressed in the exocrine pancreas and to
encode enzymes that could potentially activate digestive enzymes within
the pancreas. The hypothesis that pancreatitis results from
inappropriate activation of pancreatic proenzymes was first promulgated
by Chiara (1896) and subsequently demonstrated to be an experimental
model for pancreatitis (Steer and Meldolesi, 1987). However, at least 8
trypsinogen genes are located on 7q35 between markers D7S495 and D7S498
and within the V and D-C segments of the complex T-cell receptor beta
chain gene (see 186930). Trypsinogen is an inactive proenzyme for
trypsin, which becomes active when an 8-amino acid N-terminal peptide is
removed. Of the 8 trypsinogen-like genes sequenced and identified within
the TCRB locus by Rowen et al. (1996), 3 were determined by sequence
analysis to be pseudogenes. Another group of 5 trypsinogen genes,
including the cationic and anionic pancreatic trypsinogen genes, were
found to be in a cluster located between 2 elements near the 3-prime end
of the TCRB locus.

Tzetis et al. (2007) genotyped the CFTR, SPINK1, and PRSS1 genes in 25
Greek patients with chronic pancreatitis and found that 20 (80%) of 25
had a molecular defect in 1 or both of the CFTR and SPINK1 alleles,
whereas no mutations were detected in PRSS11. The authors suggested that
mutations or variants in CFTR plus or minus mutations in SPINK1, but not
PRSS1, may confer high risk for recurrent pancreatitis.

- Mutations in the PRSS1 Gene

Whitcomb et al. (1996) noted that the 5 trypsinogen genes are highly
homologous, each residing within a tandemly duplicated 10-kb segment and
each composed of 5 exons. Mutational screening analyses for each of the
exons from the cationic and anionic trypsinogen genes in multiple
affected and unaffected family members allowed Whitcomb et al. (1996) to
identify a missense mutation in the cationic trypsinogen (PRSS1; 267000)
in all affected members and obligate carriers in 1 family (276000.0001).
The same R122H mutation (previously designated R117H by the chymotrypsin
numbering system) was identified in 5 separate kindreds, raising the
possibility that these families might be distantly related and the
mutation centuries old. Although no genealogic link could be found
through 8 generations, subsequent haplotyping revealed that all 4 of the
American families had the same high-risk haplotype over a 4-cM region
encompassing 7 STR markers, confirming the likelihood that these
kindreds share a common ancestor. A fifth family from Naples, Italy,
displayed a unique haplotype indicating that the same mutation had
occurred on at least 2 occasions. The R122H mutation created a novel
restriction enzyme recognition site for AflIII that permitted facile
screening for the mutation in the general population. The mutation was
not found in any of 140 unrelated control individuals. X-ray crystal
structure analysis, molecular modeling, and protein digest data
indicated that the arg122 residue is a trypsin-sensitive site. Whitcomb
et al. (1996) provided a diagram of a model of the trypsin self-destruct
mechanism designed to prevent pancreatic autodigestion. Active trypsin
is inhibited normally by a limited supply of trypsin inhibitor (e.g.,
SPINK1; 167790). If trypsin activity exceeds the inhibitory capacity of
PSTI, then proenzymes, including mesotrypsin (PRSS3; 613578) and enzyme
Y, are activated. The activation of these enzymes is postulated to be
part of a feedback mechanism for inactivating wildtype trypsinogen,
trypsin, and other zymogens. When the arg122 cleavage site for
mesotrypsin, enzyme Y, and trypsin is replaced by histidine, trypsin
continues to activate trypsinogen and other zymogens unabated, leading
to autodigestion of the pancreas and pancreatitis.

In affected members and obligate carriers of a large family originally
reported by Robechek (1967) with hereditary pancreatitis believed to be
due to hypertrophy of the sphincter of Oddi, Gorry et al. (1997)
identified heterozygosity for a missense mutation in the PRSS1 gene
(N21I; 276000.0002). The pancreatitis in this family appeared to be a
milder form of the disease, with a later onset of symptoms and fewer
hospitalizations than that seen in the so-called 'S-family' in which
Whitcomb et al. (1996) identified the R122H mutation. Noting that
prematurely activated trypsin must pass through the sphincter of Oddi
and may produce chronic inflammation, scarring, and stenosis, Gorry et
al. (1997) suggested that high sphincter pressures may be an independent
complication of hereditary pancreatitis rather than the cause. The
authors stated that 4 of the 5 patients reporting symptomatic
improvement after surgical sphincterotomy had progressed to chronic
pancreatitis with insulin-dependent diabetes mellitus, supporting the
hypothesis that the underlying pathophysiologic mechanism persists.
Affected members of a second, unrelated family with hereditary
pancreatitis were also found to have the N21I mutation, which was not
found in 188 control chromosomes.

Dasouki et al. (1998) reported on the results of linkage and direct
mutation analysis for the common R122H mutation (276000.0001) in the
PRSS1 gene in 8 unrelated families with hereditary pancreatitis. By
2-point linkage analysis with the 7q35 marker D7S676, done initially in
4 families, positive lod scores were found in 2, a negative lod score in
1, and a weakly positive lod score in 1. Direct mutational analysis of
exon 3 of the cationic trypsinogen gene in 6 families showed that all
symptomatic individuals tested were heterozygous for the R122H mutation.
Also, several asymptomatic but at-risk relatives were found to be
heterozygous for this mutation. Affected individuals in the remaining 2
families did not have the mutation. Radiation hybrid mapping assigned
the gene to 7q35 between 2 specific markers. The negative linkage and
absence of the trypsinogen mutation in 2 of 8 families suggested locus
heterogeneity in hereditary pancreatitis.

Ferec et al. (1999) studied 14 families with hereditary pancreatitis and
found mutations in the PRSS1 gene in 8 families. In 4 of these families,
the mutation (R122H; 276000.0001) had been described by Whitcomb et al.
(1996). Three novel mutations were described in 4 other families
(276000.0003, 276000.0004, 276000.0005).

- Mutations in the CFTR Gene

Sharer et al. (1998) and Cohn et al. (1998) demonstrated that mutations
in the cystic fibrosis gene (CFTR; 602421) can cause idiopathic
pancreatitis when present in heterozygous state in association with the
variable number of thymidines in intron 8 of the CFTR gene, specifically
the 5T allele (602421.0086).

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 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.

- Mutations in the SPINK1 Gene

Witt et al. (2000) demonstrated mutations in the SPINK1 protease
inhibitor gene (N34S, 167790.0001; L14P, 167790.0005) in children and
adolescents with chronic pancreatitis. The N34S mutation was found in 18
of 96 patients.

Chen et al. (2000) reported mutation analysis in the PSTI (SPINK1) gene
in 14 families with hereditary pancreatitis and in 30 individuals with
sporadic chronic pancreatitis. A total of 7 polymorphisms, but no
pathogenic mutations, were detected.

Audrezet et al. (2002) analyzed systematically the entire coding
sequence and exon/intron junctions of the PRSS1 (276000), SPINK1
(167790), and CFTR genes in 39 white French patients with idiopathic
chronic pancreatitis. One patient had a missense mutation (R122H;
276000.0001) in the PRSS1 gene; 4 patients had the same missense
mutation in the SPINK1 gene, 3 in heterozygosity and 1 in homozygosity
(N34S; 167790.0001); and 8 patients carried 1 of the most common
mutations of the CFTR gene. A trans-heterozygous state with sequence
variations in the SPINK1/CFTR genes was found in 3 patients. The results
demonstrated that about one-third of the patients labeled as having
idiopathic chronic pancreatitis had, in fact, a genetic defect. Audrezet
et al. (2002) noted that long-term follow-up of these patients,
including heterozygotes, homozygotes, compound heterozygotes, and
trans-heterozygotes, would improve the understanding of the complex
nature of idiopathic chronic pancreatitis.

In affected members of 2 unrelated families with autosomal dominant
chronic pancreatitis, Kiraly et al. (2007) identified a heterozygous
mutation in the SPINK1 gene (L14R; 167790.0006). The proband of the
Bulgarian family was diagnosed at age 10 years. His father had died of
acute pancreatitis, and his paternal grandmother developing pancreatitis
at age 59 years. The second family was German and had 3 affected
members. Kiraly et al. (2007) noted that the N34S mutation had not to
date been demonstrated to result in a functional defect. By expression
studies, they demonstrated that the L14P and L14R mutations markedly
reduce SPINK1 expression and result in loss of function.

- Variation in the CTRC Gene

Rosendahl et al. (2008) found that 2 alterations in the CTRC gene, R254W
(601405.0001) and K247_R254del (601405.0002), were significantly
overrepresented among German patients with idiopathic or hereditary
chronic pancreatitis. A replication study identified overrepresentation
of these variants among German patients with alcoholic chronic
pancreatitis versus control subjects with alcoholic liver disease
without pancreatitis. Functional analysis of these and other associated
CTRC variants showed impaired chymotrypsin C activity and or reduced
secretion. Rosendahl et al. (2008) concluded that loss-of-function
alterations in CTRC predispose to pancreatitis by diminishing its
protective trypsin-degrading activity.

Masson et al. (2008) sequenced the CTRC gene in 287 white French
patients with idiopathic chronic pancreatitis and 350 controls and
identified 2 common variants and 19 rare variants. The combined
frequency of the rare variants in patients with sporadic chronic
pancreatitis was significantly higher than that of controls (12% versus
1.1%; OR, 11.8; p less than 10(-6)).

HISTORY

The 'S.' family used by Whitcomb et al. (1996) in their map-based gene
discovery in hereditary pancreatitis had the name Slone, according to an
editorial accompanying the paper of Whitcomb et al. (1996) (Anonymous,
1996). This family had been reported by McElroy and Christiansen (1972).
Whitcomb (1997) indicated that the family with the R122H mutation in the
PRSS1 gene (276000.0001) was identified as the S-family, but the 'S.'
did not stand for Slone.

*FIELD* SA
Appel (1974); Carey and Fitzgerald (1968); Freeman et al. (1976);
Girard and Archambault (1980); Gross et al. (1964); Kattwinkel et
al. (1973); Makela and Aarimaa (1985); Riccardi et al. (1975); Sato
and Saitoh (1974); Sibert (1973)
*FIELD* RF
1. Anonymous: It takes a family. (Editorial) Nature Genet. 14:
117-118, 1996.

2. Appel, M. F.: Hereditary pancreatitis: review and presentation
of an additional kindred. Arch. Surg. 108: 63-65, 1974.

3. Audrezet, M.-P.; Chen, J.-M.; Le Marechal, C.; Ruszniewski, P.;
Robaszkiewicz, M.; Raguenes, O.; Quere, I.; Scotet, V.; Ferec, C.
: Determination of the relative contribution of three genes--the cystic
fibrosis transmembrane conductance regulator gene, the cationic trypsinogen
gene, and the pancreatic secretory trypsin inhibitor gene--to the
etiology of idiopathic chronic pancreatitis. Europ. J. Hum. Genet. 10:
100-106, 2002.

4. Carey, M. C.; Fitzgerald, O.: Hyperparathyroidism associated with
chronic pancreatitis in a family. Gut 9: 700-703, 1968.

5. Chang, M.-C.; Chang, Y.-T.; Wei, S.-C.; Tien, Y.-W.; Liang, P.-C.;
Jan, I.-S.; Su, Y.-N.; Wong, J.-M.: Spectrum of mutations and variants/haplotypes
of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis
and controls in Chinese by complete analysis. Clin. Genet. 71: 530-539,
2007.

6. Chen, J.-M.; Mercier, B.; Audrezet, M.-P.; Ferec, C.: Mutational
analysis of the human pancreatic secretory trypsin inhibitor (PSTI)
gene in hereditary and sporadic chronic pancreatitis. J. Med. Genet. 37:
67-69, 2000.

7. Chiara, H.: Ueber Selbstverdauung des menschlichen Pankreas. Ztschr.
Heilkunde 17: 70-96, 1896.

8. Cohn, J. A.; Friedman, K. J.; Noone, P. G.; Knowles, M. R.; Silverman,
L. M.; Jowell, P. S.: Relation between mutations of the cystic fibrosis
gene and idiopathic pancreatitis. New Eng. J. Med. 339: 653-658,
1998.

9. Comfort, M. W.; Steinberg, A. G.: Pedigree of a family with hereditary
chronic relapsing pancreatitis. Gastroenterology 21: 54-63, 1952.

10. Dalton-Clarke, H. J.; Lewis, M. H.; Levi, A. J.; Blumgart, L.
H.: Familial chronic calcific pancreatitis: a family study. Brit.
J. Surg. 72: 307-308, 1985.

11. Dasouki, M. J.; Cogan, J.; Summar, M. L.; Neblitt, W., III; Foroud,
T.; Koller, D.; Phillips, J. A., III: Heterogeneity in hereditary
pancreatitis. Am. J. Med. Genet. 77: 47-53, 1998.

12. Davidson, P.; Costanza, D.; Swieconek, J. A.; Harris, J. B.:
Hereditary pancreatitis: a kindred without gross aminoaciduria. Ann.
Intern. Med. 68: 88-96, 1968.

13. Ferec, C.; Raguenes, O.; Salomon, R.; Roche, C.; Bernard, J. P.;
Guillot, M.; Quere, I.; Faure, C.; Mercier, B.; Audrezet, M. P.; Guillausseau,
P. J.; Dupont, C.; Munnich, A.; Bignon, J. D.; Le Bodic, L.: Mutations
in the cationic trypsinogen gene and evidence for genetic heterogeneity
in hereditary pancreatitis. J. Med. Genet. 36: 228-232, 1999.

14. Freeman, H. J.; Weinstein, W. M.; Shnitka, T. K.; Crockford, P.
M.; Herbert, F. A.: Alpha-1-antitrypsin deficiency and pancreatic
fibrosis. Ann. Intern. Med. 85: 73-76, 1976.

15. Freud, E.; Barak, R.; Ziv, N.; Leiser, A.; Dinari, G.; Mor, C.;
Zer, M.: Familial chronic recurrent pancreatitis in identical twins:
case report and review of the literature. Arch. Surg. 127: 1125-1128,
1992.

16. Girard, R. M.; Archambault, A.: Hereditary chronic pancreatitis.
(Letter) New Eng. J. Med. 303: 286-287, 1980.

17. Gorry, M. C.; Gabbaizedeh, D.; Furey, W.; Gates, L. K., Jr.; Preston,
R. A.; Aston, C. E.; Zhang, Y.; Ulrich, C.; Ehrlich, G. D.; Whitcomb,
D. C.: Mutations in the cationic trypsinogen gene are associated
with recurrent acute and chronic pancreatitis. Gastroenterology 113:
1063-1068, 1997.

18. Gross, J. B.; Gambill, E. E.; Ulrich, J. A.: Hereditary pancreatitis.
Description of a fifth kindred and summary of clinical features. Am.
J. Med. 33: 358-364, 1962.

19. Gross, J. B.; Ulrich, J. A.; Jones, J. D.: Urinary excretion
of amino acids in a kindred with hereditary pancreatitis and aminoaciduria. Gastroenterology 47:
41-48, 1964.

20. Kattwinkel, J.; Lapey, A.; Di Sant'Agnese, P. A.; Edwards, W.
A.; Huffy, M. P.: Hereditary pancreatitis: three new kindreds and
a critical review of the literature. Pediatrics 51: 55-69, 1973.

21. Kiraly, O.; Boulling, A.; Witt, H.; Le Marechal, C.; Chen, J.-M.;
Rosendahl, J.; Battaggia, C.; Wartmann, T.; Sahin-Toth, M.; Feree,
C.: Signal peptide variants that impair secretion of pancreatic secretory
trypsin inhibitor (SPINK1) cause autosomal dominant hereditary pancreatitis. Hum.
Mutat. 28: 469-476, 2007.

22. Le Bodic, L.; Bignon, J.-D.; Raguenes, O.; Mercier, B.; Georgelin,
T.; Schnee, M.; Soulard, F.; Gagne, K.; Bonneville, F.; Muller, J.-Y.;
Bachner, L.; Ferec, C.: The hereditary pancreatitis gene maps to
long arm of chromosome 7. Hum. Molec. Genet. 5: 549-554, 1996.

23. Lewis, M. P. N.; Gazet, J.-C.: Hereditary calcific pancreatitis
in an English family. Brit. J. Surg. 80: 487-488, 1993.

24. Lowenfels, A. B.; Maisonneuve, P.; DiMagno, E. P.; Elitsur, Y.;
Gates, L. K., Jr.; Perrault, J.; Whitcomb, D. C.; The International
Hereditary Pancreatitis Study Group: Hereditary pancreatitis and
the risk of pancreatic cancer. J. Nat. Cancer Inst. 89: 442-446,
1997.

25. Makela, P.; Aarimaa, M.: Pancreatography in a family with hereditary
pancreatitis. Acta Radiol. 26: 63-66, 1985.

26. Mann, T. P.; Rubin, J.: Familial pancreatic exocrine dysfunction
with pancreatic calcification. Proc. Roy. Soc. Med. 62: 326, 1969.

27. Masson, E.; Chen, J.-M.; Scotet, V.; Le Marechal, C.; Ferec, C.
: Association of rare chymotrypsinogen C (CTRC) gene variations in
patients with idiopathic chronic pancreatitis. Hum. Genet. 123:
83-91, 2008.

28. McElroy, R.; Christiansen, P. A.: Hereditary pancreatitis in
a kinship associated with portal vein thrombosis. Am. J. Med. 52:
228-241, 1972.

29. Pandya, A.; Blanton, S. H.; Landa, B.; Javaheri, R.; Melvin, E.;
Nance, W. E.; Markello, T.: Linkage studies in a large kindred with
hereditary pancreatitis confirms mapping of the gene to a 16-cM region
on 7q. Genomics 38: 227-230, 1996.

30. Riccardi, V. M.; Shih, V. E.; Holmes, L. B.; Nardi, G. L.: Hereditary
pancreatitis--nonspecificity of aminoaciduria and diagnosis of occult
disease. Arch. Intern. Med. 135: 822-825, 1975.

31. Robechek, P. J.: Hereditary chronic relapsing pancreatitis: a
clue to pancreatitis in general? Am. J. Surg. 113: 819-824, 1967.

32. Rosendahl, J.; Witt, H.; Szmola, R.; Bhatia, E.; Ozsvari, B.;
Landt, O.; Schulz, H.-U.; Gress, T. M.; Ptufzer, R.; Lohr, M.; Kovacs,
P.; Bluher, M.; and 22 others: Chymotrypsin C (CTRC) variants that
diminish activity or secretion are associated with chronic pancreatitis. Nature
Genet. 40: 78-82, 2008.

33. Rowen, L.; Koop, B. F.; Hood, L.: The complete 685-kilobase DNA
sequence of the human beta T cell receptor locus. Science 272: 1755-1762,
1996.

34. Rumenapf, G.; Kamm, M.; Rupprecht, H.; Scheele, J.: Surgical
management of hereditary pancreatitis: report of a case and presentation
of a new family. (Letter) Pancreas 9: 398-399, 1994.

35. Sarles, H.; Camarena, J.; Bernard, J. P.; Sahel, J.; Laugier,
R.: Two forms of hereditary chronic pancreatitis. Pancreas 12:
138-141, 1996.

36. Sarles, H.; De Caro, A.; Multigner, L.; Martin, E.: Giant pancreatic
stones in teetotal women due to absence of the 'stone protein'? (Letter) Lancet 320:
714-715, 1982. Note: Originally Volume II.

37. Sato, T.; Saitoh, Y.: Familial chronic pancreatitis associated
with pancreatic lithiasis. Am. J. Surg. 127: 511-517, 1974.

38. Schlesinger, D. H.; Hay, D. I.: Complete covalent structure of
statherin, a tyrosine-rich acidic peptide which inhibits calcium phosphate
precipitation from human parotid saliva. J. Biol. Chem. 252: 1689-1695,
1977.

39. Sharer, N.; Schwarz, M.; Malone, G.; Howarth, A.; Painter, J.;
Super, M.; Braganza, J.: Mutations of the cystic fibrosis gene in
patients with chronic pancreatitis. New Eng. J. Med. 339: 645-652,
1998.

40. Sibert, J. R.: Hereditary pancreatitis in a Newcastle family. Arch.
Dis. Child. 48: 618-621, 1973.

41. Sibert, J. R.: Hereditary pancreatitis in England and Wales. J.
Med. Genet. 15: 189-201, 1978.

42. Singer, M.; Cohen, F. B.: Hereditary chronic relapsing pancreatitis. J.
Newark Beth Israel Hosp. 21: 121-126, 1966.

43. Steer, M. L.; Meldolesi, J.: The cell biology of experimental
pancreatitis. New Eng. J. Med. 316: 144-150, 1987.

44. Tzetis, M.; Kaliakatsos, M.; Fotoulaki, M.; Papatheodorou, A.;
Doudounakis, S.; Tsezou, A.; Makrythanasis, P.; Kanavakis, E.; Nousia-Arvanitakis,
S.: Contribution of the CFTR gene, the pancreatic secretory trypsin
inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1)
to the etiology of recurrent pancreatitis. Clin. Genet. 71: 451-457,
2007.

45. Whitcomb, D. C.: Personal Communication. Pittsburgh, Pa. 12/9/1997.

46. Whitcomb, D. C.; Gorry, M. C.; Preston, R. A.; Furey, W.; Sossenheimer,
M. J.; Ulrich, C. D.; Martin, S. P.; Gates, L. K., Jr.; Amann, S.
T.; Toskes, P. P.; Liddle, R.; McGrath, K.; Uomo, G.; Post, J. C.;
Ehrlich, G. D.: Hereditary pancreatitis is caused by a mutation in
the cationic trypsinogen gene. Nature Genet. 14: 141-145, 1996.

47. Whitcomb, D. C.; Preston, R. A.; Aston, C. E.; Sossenheimer, M.
J.; Barua, P. S.; Zhang, Y.; Wong-Chong, A.; White, G. J.; Wood, P.
G.; Gates, L. K., Jr.; Ulrich, C.; Martin, S. P.; Post, J. C.; Ehrlich,
G. D.: A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110:
1975-1980, 1996.

48. Witt, H.; Luck, W.; Hennies, H. C.; Classen, M.; Kage, A.; Lass,
U.; Landt, O.; Becker, M.: Mutations in the gene encoding the serine
protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nature
Genet. 25: 213-216, 2000.

*FIELD* CS

GI:
Pancreatitis;
Severe abdominal pain attacks;
Pancreatic insufficiency;
Steatorrhea;
Pancreatic calcification;
Pancreatic pseudocysts

Vascular:
Portal or splenic vein thrombosis

Metabolic:
Diabetes mellitus

Pulmonary:
Hemorrhagic pleural effusion

Misc:
Fever with attacks;
Emotional upset, alcohol or high fat intake produce attacks

Lab:
Urinary excretion of lysine and cystine;
Marked elevation of serum amylase with attacks

Inheritance:
Autosomal dominant

*FIELD* CN
Marla J. F. O'Neill - updated: 3/18/2008
Victor A. McKusick - updated: 2/11/2008
Marla J. F. O'Neill - updated: 1/24/2008
Cassandra L. Kniffin - updated: 7/10/2007
Cassandra L. Kniffin - updated: 5/14/2007
Marla J. F. O'Neill - updated: 3/1/2007
Michael B. Petersen - updated: 10/8/2002
Michael J. Wright - updated: 1/10/2001
Victor A. McKusick - updated: 5/26/2000
Michael J. Wright - updated: 11/3/1999
Victor A. McKusick - updated: 9/18/1998
Victor A. McKusick - updated: 4/21/1998
Victor A. McKusick - updated: 1/20/1998
Jennifer P. Macke - updated: 7/15/1997
Victor A. McKusick - updated: 6/9/1997
Moyra Smith - updated: 5/16/1996

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
mgross: 10/07/2013
carol: 12/22/2011
mgross: 9/29/2010
alopez: 4/9/2010
terry: 2/6/2009
wwang: 3/27/2008
terry: 3/18/2008
alopez: 2/11/2008
wwang: 1/29/2008
terry: 1/24/2008
wwang: 7/18/2007
ckniffin: 7/10/2007
wwang: 6/7/2007
ckniffin: 5/14/2007
carol: 3/1/2007
alopez: 5/31/2006
terry: 4/18/2005
cwells: 10/8/2002
alopez: 1/10/2001
alopez: 5/30/2000
joanna: 5/26/2000
alopez: 11/10/1999
terry: 11/3/1999
terry: 5/5/1999
carol: 9/28/1998
terry: 9/18/1998
carol: 5/9/1998
terry: 4/21/1998
mark: 1/22/1998
terry: 1/20/1998
jenny: 8/29/1997
terry: 6/23/1997
alopez: 6/9/1997
jamie: 10/18/1996
terry: 10/14/1996
mark: 10/5/1996
mark: 10/4/1996
mark: 9/30/1996
terry: 9/26/1996
terry: 9/20/1996
carol: 5/22/1996
carol: 5/16/1996
carol: 5/12/1996
mark: 3/21/1996
terry: 3/13/1996
mimadm: 1/14/1995
carol: 1/3/1995
carol: 5/28/1993
carol: 10/20/1992
supermim: 3/16/1992
supermim: 3/20/1990

MIM 276000
*RECORD*
*FIELD* NO
276000
*FIELD* TI
*276000 PROTEASE, SERINE, 1; PRSS1
;;TRYPSINOGEN 1; TRY1;;
TRYPSINOGEN, CATIONIC
TRYPSIN 1, INCLUDED
read more*FIELD* TX

DESCRIPTION

Human pancreatic juice contains 3 isoforms of trypsinogen. On the basis
of their relative electrophoretic mobility, these are commonly referred
to as cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2; 601564),
and mesotrypsinogen (PRSS3; 613578). Normally, cationic trypsinogen
represents approximately two-thirds of total trypsinogen, while anionic
trypsinogen makes up approximately one-third. Mesotrypsinogen is a minor
species, accounting for less than 5% of trypsinogens or 0.5% of
pancreatic juice proteins (Scheele et al., 1981; Rinderknecht et al.
(1984); summary by Teich et al., 2004).

Trypsin (EC 3.4.21.4) is a member of the pancreatic family of serine
proteases.

CLONING

MacDonald et al. (1982) reported nucleotide sequences of cDNAs
representing 2 pancreatic rat trypsinogens.

Emi et al. (1986) isolated cDNA clones for 2 major human trypsinogen
isozymes from a pancreatic cDNA library. The deduced amino acid
sequences had 89% homology and the same number of amino acids (247),
including a 15-amino acid signal peptide and an 8-amino acid activation
peptide.

Rowen et al. (1996) found that 2 of 3 pancreatically expressed
trypsinogen cDNAs correspond to trypsinogen genes embedded in the beta
T-cell receptor (TCRB; see 186930) cluster of genes mapping to 7q35. T4
was denoted trypsinogen-1 and T8 was denoted trypsinogen-2 (601564). The
third pancreatic cDNA, identified independently as trypsinogen-3 (Tani
et al., 1990) and -4 (Wiegand et al., 1993), is distinct from the third
apparently functional trypsinogen gene (T6) in the TCRB locus but
related to the other pancreatic trypsinogens. Rowen et al. (1996) noted
that the intercalation of the trypsinogen genes in the TCRB locus is
conserved in mouse and chicken, suggesting shared functional or
regulatory constraints, as has been postulated for genes in the major
histocompatibility complex (such as class I, II, and III genes) that
share similar long-term organizational relationships.

GENE STRUCTURE

By alignment of pancreatic trypsinogen cDNAs with the germline
sequences, Rowen et al. (1996) showed that the trypsinogen genes contain
5 exons that span approximately 3.6 kb. Further analyses revealed 2
trypsinogen pseudogenes and 1 relic trypsinogen gene at the 5-prime end
of the sequence, all in inverted transcriptional orientation. They
denoted 8 trypsinogen genes T1 through T8 from 5-prime to 3-prime.

MAPPING

Using a rat cDNA probe, Honey et al. (1984, 1984) found that a 3.8-kb
DNA fragment containing human trypsin-1 gene sequences cosegregated with
chromosome 7, and assigned the gene further to 7q22-7qter by study of
hybrids with a deletion of this segment. The trypsin gene is on mouse
chromosome 6 (Honey et al., 1984). Carboxypeptidase A (114850) and
trypsin are a syntenic pair conserved in mouse and man.

Using Southern blot analysis of human genomic DNA with a cloned cDNA as
probe, Emi et al. (1986) showed that the human trypsinogen genes
constitute a family of more than 10, some of which may be pseudogenes or
may be expressed in other stages of development.

Rowen et al. (1996) mapped the gene corresponding to the third
pancreatic trypsinogen cDNA by fluorescence in situ hybridization. They
used a cosmid clone containing 3 trypsinogen genes. Strong hybridization
to chromosome 7 and weaker hybridization to chromosome 9 were observed.
They isolated and partially sequenced 4 cosmid clones from the
chromosome 9 region. They found that the region represents a duplication
and translocation of a DNA segment from the 3-prime end of the TCRB
locus that includes at least 7 V(beta) elements and a functional
trypsinogen gene denoted T9 (PRSS3; 613578).

Rowen et al. (1996) found that there are 8 trypsinogen genes embedded in
the beta T-cell receptor locus or cluster of genes (TCRB; see 186930)
mapping to 7q35. In the 685-kb DNA segment that they sequenced they
found 5 tandemly arrayed 10-kb locus-specific repeats (homology units)
at the 3-prime end of the locus. These repeats exhibited 90 to 91%
overall nucleotide similarity, and embedded within each is a trypsinogen
gene. Since hereditary pancreatitis (167800) had been mapped rather
precisely to 7q35 and since a defect in the trypsinogen gene has been
identified in hereditary pancreatitis, the assignment of the trypsinogen
gene can be refined from 7q32-qter to 7q35.

MOLECULAR GENETICS

Whitcomb et al. (1996) stated that the high degree of DNA sequence
homology (more than 91%) present among this cluster of 5 trypsinogen
genes identified by Rowen et al. (1996) demanded that highly specific
sequence analysis strategies be developed for mutation screening in
families with hereditary pancreatitis (167800). This was necessary to
ensure that each sequencing run contained only the 2 alleles
corresponding to a single gene, thereby permitting detection of
heterozygotes in this autosomal dominant disorder, and not a dozen or
more alleles from multiple related trypsinogen-like genes, which would
make detection of heterozygotes nearly impossible. In a family with
hereditary pancreatitis, Whitcomb et al. (1996) found that affected
individuals had a single G-to-A transition mutation in the third exon of
cationic trypsinogen (276000.0001). This mutation was predicted to
result in an arg105-to-his substitution in the trypsin gene (residue
number 122 in the more common trypsinogen number system; the residue has
also been listed as 117; 276000.0001). Subsequently, the same mutation
was found in a total of 5 different hereditary pancreatitis kindreds (4
from the U.S. and 1 from Italy) containing a total of 20 affected
individuals and 6 obligate carriers. The mutation was found in none of
the obligate unaffected members (individuals who married into the
family). Subsequent haplotyping revealed that all 4 of the American
families displayed the same high risk haplotype over a 4-cM region
encompassing 7 STR markers, confirming the likelihood that these
kindreds shared a common ancestor, although no link could be found
through 8 generations. A fifth family from Italy displayed a unique
haplotype indicating that the same mutation had occurred on at least 2
occasions. The G-to-A mutation at codon 122 created a novel enzyme
recognition site for AflIII which provided a facile means to screen for
the mutation. As with the obligate unaffected members of the
pancreatitis kindreds, none of 140 controls possessed the G-to-A
mutation as assayed by the lack of AflIII digestion of the amplified
exonic DNA.

Ferec et al. (1999) studied 14 families with hereditary pancreatitis and
found mutations in the PRSS1 gene in 8 families. In 4 of these families,
the mutation (R122H; 276000.0001) had been described by Whitcomb et al.
(1996). Three mutations were described in 4 other families (276000.0002,
276000.0003, 276000.0005).

Sahin-Toth et al. (1999) studied the roles of the 2 most frequent PRSS1
mutations in hereditary pancreatitis, R122H and N29I (276000.0002). They
stated that the R122H mutation is believed to cause pancreatitis by
eliminating an essential autolytic cleavage site in trypsin, thereby
rendering the protease resistant to inactivation through autolysis.
Sahin-Toth et al. (1999) demonstrated that the R122H mutation also
significantly inhibited autocatalytic trypsinogen breakdown under
Ca(2+)-free conditions and stabilized the zymogen form of rat trypsin.
Taken together with findings demonstrating that the N29I mutation
stabilized rat trypsinogen against autoactivation and consequent
autocatalytic degradation, the observations suggested a unifying
molecular pathomechanism for hereditary pancreatitis in which zymogen
stabilization plays a central role.

Sahin-Toth and Toth (2000) demonstrated that the R122H and N29I
mutations significantly enhance autoactivation of human cationic
trypsinogen in vitro, in a manner that correlates with the severity of
clinical symptoms in hereditary pancreatitis. In addition, the R122H
mutation inhibited autocatalytic inactivation of trypsin, while the N29I
mutation had no such effect. Thus, increased trypsinogen activation in
the pancreas is presumably the common initiating step in both forms of
hereditary pancreatitis, whereas trypsin stabilization may also
contribute to hereditary pancreatitis associated with the R122H
mutation.

Chen et al. (2001) reviewed aspects of the molecular evolution and
normal physiology of trypsinogen revealed by studies of PRSS1 in
pancreatitis. First, the activation peptide of trypsinogen is under
strong selection pressure to minimize autoactivation in higher
vertebrates. Second, the R122 primary autolysis site (276000.0001) has
further evolved in mammalian trypsinogens. Third, evolutionary
divergence from threonine to asparagine at residue 29 in human cationic
trypsinogen provides additional advantage. Accordingly, Chen et al.
(2001) tentatively assigned, in human cationic trypsinogen, the strongly
selected activation peptide as the first line and the R122 autolysis
site as the second line of the built-in defensive mechanisms against
premature trypsin activation within the pancreas, and the positively
selected asparagine at residue 29 as an 'amplifier' to the R122
'fail-safe' mechanism.

Gene conversion--the substitution of genetic material from one gene to
another--in most cases takes place between a normal gene and its
pseudogene. Teich et al. (2005) reported the occurrence of
disease-associated gene conversion between 2 functional genes. They
analyzed PRSS1 in 1,106 patients with chronic pancreatitis and in 1
patient identified a novel conversion event affecting exon 2 and the
subsequent intron. The conversion replaced at least 289 nucleotides with
the paralogous sequence from the PRSS2 gene and resulted in asn29-to-ile
(N29I; 276000.0002) and asn54-to-ser (N54S) substitutions (276000.0007).
Analysis of the recombinant N29I/N54S double-mutant cationic trypsinogen
revealed increased autocatalytic activation, which was solely due to the
N29I mutation.

Teich et al. (2006) interpreted the 365_366GC-AT R122H variant
(276000.0008) as an example of a gene conversion event. In most such
cases, the donor gene is a duplicated pseudogene which has accumulated
mutations over time. However, there is evidence that gene conversion can
occur between 2 functional paralogous trypsinogen genes and cause
chronic pancreatitis. Trypsinogen genes are tandemly repeated within the
T-cell receptor beta locus (TCRB; see 186930) on 7q35. This is a hotspot
for gene conversion events to generate a broad variety of TCR-beta
genes. Therefore, conversion mutation within the interpolated
trypsinogen gene family are very likely to occur.

Teich et al. (2006) reviewed current information on trypsinogen
mutations and their role in pancreatic diseases. They pointed out that,
although the clinical presentation is highly variable, most affected
mutation carriers have relatively mild disease. Teich et al. (2006)
noted that, in addition to R122 mutations, pancreatitis-producing
mutations had also been identified in the neighboring residues ala121
and val123.

Le Marechal et al. (2006) reviewed observations suggesting that
trypsinogen may be sensitive to a gene dosage effect. They noted that
the R122H mutation (276000.0001) and other pancreatitis-causing PRSS1
missense mutations show by in vitro functional analysis an increase in
trypsin activity (see review by Sahin-Toth, 2006). On the other hand, an
N34S variation (167790.0001) in the SPINK1 gene and rare splicing and
frameshifting mutations in that gene have been detected in individuals
with chronic pancreatitis. SPINK1 encodes trypsin's physiologic
inhibitor, the physiologic function of which appears to be the
prevention of the trypsin-driven digestive enzyme activation cascade.
Loss-of-function mutations in PRSS1 (Chen et al., 2003) and a
degradation-sensitive variant (G191R; 601564.0001) in the PRSS2 gene
seem to confer protection against the disease. Le Marechal et al. (2006)
surmised that an increased copy number of the PRSS1 gene at 7q34 might
account for some of the families with hereditary pancreatitis without a
known causative mutation. They studied a well-characterized cohort of 34
French families with hereditary pancreatitis (defined as 3 or more
affected family members involving at least 2 generations) who did not
carry any causative point mutations in the PRSS1, PRSS2, SPINK1, and
CFTR genes. Analysis of 1 affected individual per family suggested that
the PRSS1 locus was triplicated, and this was confirmed in 5 of the
analyzed families. Use of walking quantitative fluorescent multiplex PCR
showed that the triplication extended approximately 605 kb and included
all members of the trypsinogen gene family on chromosome 7. The size of
the triplicated segment seemed to be the same in all carriers. Affected
individuals in these families shared an identical haplotype that
extended approximately 1,100 kb telomeric to the PRSS1 locus, suggesting
that the triplication represents an identical-by-descent mutation.

In all 6 affected members of a French family with chronic pancreatitis,
Masson et al. (2008) identified the presence of a heterozygous
PRSS1/PRSS2 hybrid gene. Quantitative fluorescent multiplex PCR and
RT-PCR revealed duplication of exons 3 to 5 of PRSS1, and further
analysis indicated that a nonallelic homologous recombination event
resulted in the generation of a hybrid gene containing exons 1 and 2
from PRSS2 and exons 3 to 5 from PRSS1. This hybrid gene was predicted
to encode a zymogen identical to a gene conversion-derived mutant
cationic trypsinogen containing the N29I (276000.0002) and N54S
(276000.0007) mutations. Masson et al. (2008) concluded that this hybrid
gene caused the disease through an inherent double gain-of-function
effect, acting simultaneously through an increased copy number effect
and the N29I mutation.

Szmola and Sahin-Toth (2010) presented evidence that the A121T variant
(276000.0011) is functionally innocuous and not a cause of pancreatitis.
The authors noted that only the index patient in the report of
Felderbauer et al. (2008) carried the A121T variant and suffered from
chronic pancreatitis. The patient's brother and first cousin, who both
carried the variant, had cholelithiasis, and his niece and her mother
were asymptomatic carriers. Functional expression studies by Szmola and
Sahin-Toth (2010) indicated that autoactivation of trypsinogens by the
A121T variant was similar to wildtype with equal enzyme kinetics. Szmola
and Sahin-Toth (2010) suggested that the variant may have been assigned
clinical relevance based on a perceived analogy with the neighboring
disease-causing R122H change (276000.0001 and 276000.0008).

HISTORY

Rowen et al. (1996) stated that the apparently functional T6 gene is
deleted in a common insertion-deletion polymorphism; if the gene is
functional, its function is apparently not essential.

*FIELD* AV
.0001
PANCREATITIS, HEREDITARY
PRSS1, ARG122HIS, 365G-A

The arg122-to-his mutation (R122H; previously designated ARG117HIS, or
R117H, by the chymotrypsin numbering system) was a consistent finding in
all cases of hereditary pancreatitis (167800) examined by Whitcomb et
al. (1996)--a total of 20 affected individuals and 6 obligate carriers
in 5 kindreds. X-ray crystal structure analysis, molecular modeling, and
protein digest data indicated that the arg117 residue is a
trypsin-sensitive site. The authors suggested that cleavage at this site
is probably part of a fail-safe mechanism by which trypsin, which is
activated within the pancreas, may be inactivated; loss of this cleavage
site would permit autodigestion resulting in pancreatitis.

Ferec et al. (1999) detected this mutation in 4 of 8 families with
hereditary pancreatitis caused by mutation in the PRSS1 gene.

In most cases the R122H mutation results from a G-to-A (CGC to CAC)
transition (365G-A), which most probably occurred as a spontaneous
deamination of 5-methylcytosine to give thymine in the CpG dinucleotides
on the opposite strand (Chen and Ferec, 2000). Chen et al. (2000)
identified a GC-to-AT (CGC to CAT) substitution (276000.0008), which
also resulted in an R122H mutation but clearly arose via a different
genetic mechanism, namely, gene conversion. This theory was strongly
supported by the presence of AT in the corresponding position of 2
homologous genes and a Chi-like sequence in the 3-prime vicinity of the
mutation. This mutation would not be detected by the generally used
screening method based on a specific restriction site.

Audrezet et al. (2002) analyzed the entire coding sequence and
exon/intron junctions of the PRSS1 gene by denaturing gradient gel
electrophoresis (DGGE) analysis and direct sequencing in 39 white French
patients with idiopathic chronic pancreatitis. The R122H missense
mutation was found in a 42-year-old male patient who had suffered the
disease from the age of 6 years, and with no family members reported to
have pancreatitis.

Simon et al. (2002) reported the trypsinogen mutation in 5 of 50
patients (10%) with idiopathic pancreatitis; all 5 had the R122H
mutation. Patients with trypsinogen mutations were significantly younger
at disease onset (mean age, 14 years) than the remaining cohort (38
years) and accounted for 35% of the patients younger than 25 years. At
least 1 of the 5 patients could be confidently stated to have a de novo
R122H mutation.

Among cases of chronic pancreatitis, mutations in arg122 and in
neighboring amino acid residues have been found with unusually high
frequency. Furthermore, the R122H mutation has been found worldwide and,
as noted, was identified as a de novo mutation in a German patient by
Simon et al. (2002). An R122C amino acid change (276000.0009) had been
found by 4 groups including their own, according to Teich et al. (2006).
Teich et al. (2006) proposed that the high frequency of mutations in or
close to arg122 causing chronic pancreatitis suggests that 'this
sequence is particularly prone to mutations.'

.0002
PANCREATITIS, HEREDITARY
PRSS1, ASN29ILE

In affected members and obligate carriers of a family originally
reported by Robechek (1967) with hereditary pancreatitis (167800)
believed to be due to hypertrophy of the sphincter of Oddi, Gorry et al.
(1997) identified heterozygosity for an A-to-T transversion in exon 2 of
the PRSS1 gene, resulting in an asn29-to-ile (N29I) substitution.
Affected members of an unrelated family with hereditary pancreatitis,
negative for the common R122H mutation in the PRSS1 gene (276000.0001),
were also found to have the N29I mutation, which was not identified in
188 unrelated control chromosomes.

In 2 unrelated families in a study of 14 hereditary pancreatitis
families, Ferec et al. (1999) reported an A-to-T transversion at codon
29 resulting in the substitution of isoleucine for asparagine.

Chen and Ferec (2000) suggested that the N29I mutation most likely arose
as a gene conversion event in which the functional anionic trypsinogen
gene (PRSS2; 601564) acted as the donor sequence. This hypothesis was
supported by the unique presence of isoleucine at residue 29 of the
anionic gene among the several highly homologous trypsinogen genes; a
single unbroken tract of nucleotides of up to 113 bp flanking the I29
residue in the anionic trypsinogen gene; and the presence of a chi-like
sequence in the 5-prime proximity and a palindromic sequence in the
3-prime vicinity of the N29I mutation. Furthermore, a multiple alignment
of the partial amino acid sequence of vertebrate trypsins around residue
29 indicated that N29 and I29 may represent advantageously selected
mutations of the 2 functional human trypsinogen genes in evolutionary
history.

This mutation has been designated ASN21ILE in a different numbering
system.

.0003
PANCREATITIS, HEREDITARY
PRSS1, LYS23ARG

In a study of 14 families with hereditary pancreatitis (167800), Ferec
et al. (1999) identified an A-to-G transition at codon 23 in the PRSS1
gene, resulting in a substitution of arginine for lysine, in 1 family.

.0004
MOVED TO 276000.0002
.0005
PANCREATITIS, HEREDITARY
PRSS1, 3-BP DEL

In a single individual with hereditary pancreatitis (167800), Ferec et
al. (1999) reported a 3-bp deletion (TCC) at position -28 (from ATG).

.0006
PANCREATITIS, HEREDITARY
PRSS1, GLU79LYS

Teich et al. (2004) identified a glu79-to-lys (E79K; 235G-A) mutation of
the PRSS1 gene in 3 European families affected by pancreatitis (167800).
The index patient was a 57-year-old German woman who 6 years previously
had developed recurrent diarrhea that was assumed to be of psychosomatic
origin. Two years previously, she complained of permanently increased
stool frequency, fatty stools, and the recurrent appearance of
undigested nutrients in the stool. Ultrasound revealed calcifications in
the pancreas and a dilated pancreatic duct. Pancreatic enzyme
replacement therapy allowed her to regain weight and relieve her
symptoms. Because of increasing obstruction of the bile duct, a
duodenum-preserving pancreatic head resection was performed. A
68-year-old brother was similarly affected and both were heterozygous
for the E79K mutation.

Teich et al. (2004) described peculiar characteristics of the E79K
mutation. In vitro analysis of recombinant wildtype in mutant enzymes
revealed that the catalytic activity of E79K trypsin was normal, and its
inhibition by pancreatic secretory trypsin inhibitor (PSTI; 167790) was
unaffected. Although the E79K mutation produced a potential new tryptic
cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was
also unchanged. In contrast to previously characterized disease-causing
mutations, E79K markedly inhibited autoactivation of cationic
trypsinogen. Remarkably, however, E79K trypsin activated anionic
trypsinogen PRSS2 (601564) 2-fold while the common
pancreatitis-associated mutants R122H (276000.0001) or N29I
(276000.0002), had no such effect. The observations not only suggested a
novel mechanism of action for pancreatitis-associated trypsinogen
mutations, but also highlighted the importance of interactions between
the 2 major trypsinogen isoforms in the development of genetically
determined chronic pancreatitis.

.0007
PANCREATITIS, HEREDITARY
PRSS1, ASN54SER

In a patient with chronic pancreatitis (167800), Teich et al. (2005)
identified a conversion event whereby at least 289 nucleotides in exon 2
and the subsequent intron of the PRSS1 gene were replaced with the
paralogous sequence from the PRSS2 gene (601564), resulting in an 86A-T
transversion and a 161A-G transition, which caused asn29-to-ile (N29I;
276000.0002) and asn54-to-ser (N54S) substitutions, respectively. The
double-mutant cationic trypsinogen showed increased autocatalytic
activation, which was solely due to the N29I mutation.

.0008
PANCREATITIS, HEREDITARY
PRSS1, ARG122HIS, 365GC-AT

In addition to the originally reported and frequently found R122H
mutation due to a single-nucleotide substitution (276000.0001), Chen et
al. (2000) identified a GC-to-AT (CGC to CAT; 365-366GC-AT) substitution
which also causes an R122H mutation and results in chronic pancreatitis
(167800). Teich et al. (2006) interpreted this variant as an example of
a gene conversion event, i.e., the substitution of genetic material from
another gene.

.0009
PANCREATITIS, HEREDITARY
PRSS1, ARG122CYS

Four independent groups (see review by Teich et al., 2006) found this
mutation in arg122, R122C, resulting from a 364C-T transition in exon 3
of the PRSS1 gene in patients with hereditary pancreatitis (167800).

.0010
PANCREATITIS, HEREDITARY
PRSS1, TRIPLICATION

In a study of a cohort of 34 families with hereditary pancreatitis
(167800) but no known missense mutations in PRSS1, PRSS2, SPINK1, or
CFTR, Le Marechal et al. (2006) identified triplication of the PRSS1
gene. Some unaffected members of the family were heterozygous for the
same triplication, indicating a high but incomplete penetrance of the
hereditary pancreatitis caused by the triplication.

Chauvin et al. (2009) characterized the triplication copy number
mutation in the PRSS1 gene and found it to be part of a complex
rearrangement that also contains a triplicated 137-kb segment and 21-bp
sequence tract. The triplication allele constitutes a gain of 2 tandemly
arranged composite duplication blocks, each comprising a copy of the
605-kb segment, a copy of the inverted 137-kb segment, and a copy of the
inverted 21-bp sequence tract. All triplications and duplications
identified were found to arise from a common founder chromosome. The
authors proposed a 2-step process for the generation of the triplication
copy number mutation. Chauvin et al. (2009) hypothesized that many human
germline copy number variants may arise through replication-based
mechanisms during the premeiotic mitotic divisions of germ cells. The
low copy repeats generated could then serve to promote nonallelic
homologous recombination (NAHR) during meiosis, giving rise to amplified
DNA sequences, which could themselves predispose to further
recombination events during both mitosis and meiosis.

.0011
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
PRSS1, ALA121THR

This variant, formerly titled HEREDITARY PANCREATITIS, has been
reclassified based on the findings of Szmola and Sahin-Toth (2010).

In affected members of a family with hereditary pancreatitis (167800),
Felderbauer et al. (2008) identified a heterozygous G-to-A transition in
exon 3 of the PRSS1 gene, resulting in an ala121-to-thr (A121T)
substitution. The proband had relatively late disease onset in his
thirties, and family history indicated reduced penetrance. In vitro
functional expression studies showed that the mutant protein resulted in
increased digestion by trypsin (more than 80% compared to wildtype
PRSS1) that was calcium-dependent. The findings were consistent with a
increased autodegradation and a loss of function mechanism, which was
opposite to that observed with the common R122H mutation (276000.0001).

Szmola and Sahin-Toth (2010) presented evidence that the A121T variant
is functionally innocuous and not a cause of pancreatitis. The authors
noted that only the index patient in the report of Felderbauer et al.
(2008) carried the A121T variant and suffered from chronic pancreatitis.
The patient's brother and first cousin, who both carried the variant,
had cholelithiasis, and his niece and her mother were asymptomatic
carriers. Functional expression studies by Szmola and Sahin-Toth (2010)
indicated that autoactivation of trypsinogens by the A121T variant was
similar to wildtype with equal enzyme kinetics. Szmola and Sahin-Toth
(2010) suggested that the variant may have been assigned clinical
relevance based on a perceived analogy with the neighboring
disease-causing R122H mutations (276000.0001 and 276000.0008).

.0012
PANCREATITIS, HEREDITARY
PRSS1, ARG116CYS

Teich et al. (2006) reported that the 346C-T transition in exon 3 of the
PRSS1 gene, resulting in an arg116-to-cys (R116C) substitution, had been
identified by 4 independent groups in Turkish, German, and Thai families
with hereditary pancreatitis (167800) and in 2 unrelated French patients
with pancreatitis.

In an 11-year-old German girl with hereditary pancreatitis, originally
reported by Teich et al. (2002), Kereszturi et al. (2009) showed that
trypsinogen misfolding is the likely disease mechanism. The R116C
substitution occurs in a surface loop that is highly sensitive to
autolytic cleavage. In vitro functional expression studies showed that
the R116C mutation resulted in misfolding of the protein, but residual
amounts of properly folded protein showed normal activation, catalytic
properties, and degradation. Expression of the mutant protein in HEK
293T cells showed decreased secretion compared to wildtype, suggesting
that the unpaired cysteine residue at codon 116 interferes with proper
protein folding, resulting in the mutant protein being retained inside
the cell. Biochemical evidence indicated activation of the unfolded
protein response, although there was no evidence of increased caspase-3
(CASP3; 600636) activity. The R116C mutation was also found in the
girl's 57-year-old affected maternal grandfather and her 38-year-old
unaffected mother, indicating incomplete penetrance.

*FIELD* RF
1. Audrezet, M.-P.; Chen, J.-M.; Le Marechal, C.; Ruszniewski, P.;
Robaszkiewicz, M.; Raguenes, O.; Quere, I.; Scotet, V.; Ferec, C.
: Determination of the relative contribution of three genes--the cystic
fibrosis transmembrane conductance regulator gene, the cationic trypsinogen
gene, and the pancreatic secretory trypsin inhibitor gene--to the
etiology of idiopathic chronic pancreatitis. Europ. J. Hum. Genet. 10:
100-106, 2002.

2. Chauvin, A.; Chen, J.-M.; Quemener, S.; Masson, E.; Kehrer-Sawatzki,
H.; Ohmle, B.; Cooper, D. N.; Le Marechal, C.; Ferec, C.: Elucidation
of the complex structure and origin of the human trypsinogen locus
triplication. Hum. Molec. Genet. 18: 3605-3614, 2009.

3. Chen, J.-M.; Ferec, C.: Molecular basis of hereditary pancreatitis. Europ.
J. Hum. Genet. 8: 473-479, 2000.

4. Chen, J.-M.; Ferec, C.: Origin and implication of the hereditary
pancreatitis-associated N21I mutation in the cationic trypsinogen
gene. Hum. Genet. 106: 125-126, 2000.

5. Chen, J.-M.; Montier, T.; Ferec, C.: Molecular pathology and evolutionary
and physiological implications of pancreatitis-associated cationic
trypsinogen mutations. Hum. Genet. 109: 245-252, 2001.

6. Chen, J.-M.; Raguenes, O.; Ferec, C.; Deprez, P. H.; Verellen-Dumoulin,
C.: A CGC-to-CAT gene conversion-like event resulting in the R122H
mutation in the cationic trypsinogen gene and its implication in the
genotyping of pancreatitis. (Letter) J. Med. Genet. 37: e36 only,
2000.

7. Chen, J. M.; Le Marechal, C.; Lucas, D.; Raguenes, O.; Ferec, C.
: 'Loss of function' mutations in the cationic trypsinogen gene (PRSS1)
may act as a protective factor against pancreatitis. Molec. Genet.
Metab. 79: 67-70, 2003.

8. Emi, M.; Nakamura, Y.; Ogawa, M.; Yamamoto, T.; Nishide, T.; Mori,
T.; Matsubara, K.: Cloning, characterization and nucleotide sequences
of two cDNAs encoding human pancreatic trypsinogens. Gene 41: 305-310,
1986.

9. Felderbauer, P.; Schnekenburger, J.; Lebert, R.; Bulut, K.; Parry,
M.; Meister, T.; Schick, V.; Schmitz, F.; Domschke, W.; Schmidt, W.
E.: A novel A121T mutation in human cationic trypsinogen associated
with hereditary pancreatitis: functional data indicating a loss-of-function
mutation influencing the R122 trypsin cleavage site. J. Med. Genet. 45:
507-512, 2008.

10. Ferec, C.; Raguenes, O.; Salomon, R.; Roche, C.; Bernard, J. P.;
Guillot, M.; Quere, I.; Faure, C.; Mercier, B.; Audrezet, M. P.; Guillausseau,
P. J.; Dupont, C.; Munnich, A.; Bignon, J. D.; Le Bodic, L.: Mutations
in the cationic trypsinogen gene and evidence for genetic heterogeneity
in hereditary pancreatitis. J. Med. Genet. 36: 228-232, 1999.

11. Gorry, M. C.; Gabbaizedeh, D.; Furey, W.; Gates, L. K., Jr.; Preston,
R. A.; Aston, C. E.; Zhang, Y.; Ulrich, C.; Ehrlich, G. D.; Whitcomb,
D. C.: Mutations in the cationic trypsinogen gene are associated
with recurrent acute and chronic pancreatitis. Gastroenterology 113:
1063-1068, 1997.

12. Honey, N. K.; Sakaguchi, A. Y.; Lalley, P. A.; Quinto, C.; MacDonald,
R. J.; Rutter, W. J.; Bell, G. I.; Naylor, S. L.: Chromosomal assignments
of the genes for trypsin, chymotrypsin B, and elastase in mouse. Somat.
Cell Molec. Genet. 10: 377-383, 1984.

13. Honey, N. K.; Sakaguchi, A. Y.; Quinto, C.; MacDonald, R. J.;
Rutter, W. J.; Bell, G. I.; Naylor, S. L.: Chromosomal assignments
of the human genes for the serine proteases trypsin, chymotrypsin
B, and elastase. Somat. Cell Molec. Genet. 10: 369-376, 1984.

14. Honey, N. K.; Sakaguchi, A. Y.; Quinto, C.; MacDonald, R. J.;
Rutter, W. J.; Naylor, S. L.: Assignment of the human genes for elastase
to chromosome 12, and for trypsin and carboxypeptidase A to chromosome
7. (Abstract) Cytogenet. Cell Genet. 37: 492 only, 1984.

15. Kereszturi, E.; Szmola, R.; Kukor, Z.; Simon, P.; Weiss, F. U.;
Lerch, M. M.; Sahin-Toth, M.: Hereditary pancreatitis caused by mutation-induced
misfolding of human cationic trypsinogen: a novel disease mechanism. Hum.
Mutat. 30: 575-582, 2009.

16. Le Marechal, C.; Masson, E.; Chen, J.-M.; Morel, F.; Ruszniewski,
P.; Levy, P.; Ferec, C.: Hereditary pancreatitis caused by triplication
of the trypsinogen locus. Nature Genet. 38: 1372-1374, 2006.

17. MacDonald, R. J.; Stary, S. J.; Swift, G. H.: Two similar but
nonallelic rat pancreatic trypsinogens: nucleotide sequences of the
cloned cDNAs. J. Biol. Chem. 257: 9724-9732, 1982.

18. Masson, E.; Le Marechal, C.; Delcenserie, R.; Chen, J.-M.; Ferec,
C.: Hereditary pancreatitis caused by a double gain-of-function trypsinogen
mutation. Hum. Mutat. 123: 521-529, 2008.

19. Rinderknecht, H.; Renner, I. G.; Abramson, S. B.; Carmack, C.
: Mesotrypsin: a new inhibitor-resistant protease from a zymogen in
human pancreatic tissue and fluid. Gastroenterology 86: 681-692,
1984.

20. Robechek, P. J.: Hereditary chronic relapsing pancreatitis: a
clue to pancreatitis in general? Am. J. Surg. 113: 819-824, 1967.

21. Rowen, L.; Koop, B. F.; Hood, L.: The complete 685-kilobase DNA
sequence of the human beta T cell receptor locus. Science 272: 1755-1762,
1996.

22. Sahin-Toth, M.: Biochemical models of hereditary pancreatitis. Endocr.
Metab. Clin. North Am. 35: 303-312, 2006.

23. Sahin-Toth, M.; Graf, L.; Toth, M.: Trypsinogen stabilization
by mutation arg117-to-his: a unifying pathomechanism for hereditary
pancreatitis? Biochem. Biophys. Res. Commun. 264: 505-508, 1999.

24. Sahin-Toth, M.; Toth, M.: Gain-of-function mutations associated
with hereditary pancreatitis enhance autoactivation of human cationic
trypsinogen. Biochem. Biophys. Res. Commun. 278: 286-289, 2000.

25. Scheele, G.; Bartelt, D.; Bieger, W.: Characterization of human
exocrine pancreatic proteins by two-dimensional isoelectric focusing/sodium
dodecyl sulfate gel electrophoresis. Gastroenterology 80: 461-473,
1981.

26. Simon, P.; Weiss, F. U.; Zimmer, K. P.; Rand, S.; Brinkmann, B.;
Domschke, W.; Lerch, M. M.: Spontaneous and sporadic trypsinogen
mutations in idiopathic pancreatitis. (Letter) JAMA 288: 2122 only,
2002.

27. Szmola, R.; Sahin-Toth, M.: Uncertainties in the classification
of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated
mutations. J. Med. Genet. 47: 348-350, 2010.

28. Tani, T.; Kawashima, I.; Mita, K.; Takiguchi, Y.: Nucleotide
sequence of the human pancreatic trypsinogen III cDNA. Nucleic Acids
Res. 18: 1631 only, 1990.

29. Teich, N.; Bauer, N.; Mossner, J.; Keim, V.: Mutational screening
of patients with nonalcoholic chronic pancreatitis: identification
of further trypsinogen variants. Am. J. Gastroenterol. 97: 341-346,
2002.

30. Teich, N.; Le Marechal, C.; Kukor, Z.; Caca, K.; Witzigmann, H.;
Chen, J.-M.; Toth, M.; Mossner, J.; Keim, V.; Ferec, C.; Sahin-Toth,
M.: Interaction between trypsinogen isoforms in genetically determined
pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased
transactivation of anionic trypsinogen (PRSS2). Hum. Mutat. 23:
22-31, 2004.

31. Teich, N.; Nemoda, Z.; Kohler, H.; Heinritz, W.; Mossner, J.;
Keim, V.; Sahin-Toth, M.: Gene conversion between functional trypsinogen
genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old
girl. Hum. Mutat. 25: 343-347, 2005.

32. Teich, N.; Rosendahl, J.; Toth, M.; Mossner, J.; Sahin-Toth, M.
: Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Hum.
Mutat. 27: 721-730, 2006.

33. Whitcomb, D. C.; Gorry, M. C.; Preston, R. A.; Furey, W.; Sossenheimer,
M. J.; Ulrich, C. D.; Martin, S. P.; Gates, L. K., Jr.; Amann, S.
T.; Toskes, P. P.; Liddle, R.; McGrath, K.; Uomo, G.; Post, J. C.;
Ehrlich, G. D.: Hereditary pancreatitis is caused by a mutation in
the cationic trypsinogen gene. Nature Genet. 14: 141-145, 1996.

34. Wiegand, U.; Corbach, S.; Minn, A.; Kang, J.; Muller-Hill, B.
: Cloning of the cDNA encoding human brain trypsinogen and characterization
of its product. Gene 136: 167-175, 1993.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/19/2011
George E. Tiller - updated: 7/8/2010
Cassandra L. Kniffin - updated: 6/3/2010
Cassandra L. Kniffin - updated: 2/9/2009
Cassandra L. Kniffin - updated: 9/18/2008
Marla J. F. O'Neill - updated: 3/1/2007
Victor A. McKusick - updated: 1/5/2007
Victor A. McKusick - updated: 8/24/2006
Victor A. McKusick - updated: 4/28/2005
Victor A. McKusick - updated: 2/3/2004
Victor A. McKusick - updated: 12/27/2002
Michael B. Petersen - updated: 10/8/2002
Victor A. McKusick - updated: 10/12/2001
Victor A. McKusick - updated: 3/27/2001
Victor A. McKusick - updated: 3/15/2001
Victor A. McKusick - updated: 12/19/2000
Victor A. McKusick - updated: 2/17/2000
Victor A. McKusick - updated: 12/20/1999
Michael J. Wright - updated: 11/3/1999
Victor A. McKusick - updated: 1/20/1998

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

*FIELD* ED
mgross: 10/04/2013
carol: 6/16/2011
wwang: 2/4/2011
ckniffin: 1/19/2011
mgross: 9/29/2010
wwang: 7/22/2010
terry: 7/8/2010
wwang: 6/7/2010
ckniffin: 6/3/2010
terry: 6/3/2009
wwang: 4/6/2009
ckniffin: 2/9/2009
terry: 2/2/2009
wwang: 10/2/2008
ckniffin: 9/18/2008
terry: 8/26/2008
carol: 3/1/2007
carol: 1/9/2007
terry: 1/5/2007
alopez: 9/5/2006
terry: 8/24/2006
alopez: 5/31/2006
tkritzer: 5/10/2005
terry: 4/28/2005
terry: 2/2/2005
joanna: 3/17/2004
cwells: 2/6/2004
terry: 2/3/2004
cwells: 12/31/2002
terry: 12/27/2002
cwells: 10/8/2002
carol: 1/28/2002
carol: 10/29/2001
mcapotos: 10/12/2001
carol: 4/2/2001
mcapotos: 3/27/2001
terry: 3/27/2001
terry: 3/15/2001
mcapotos: 1/4/2001
mcapotos: 1/3/2001
terry: 12/19/2000
alopez: 2/29/2000
terry: 2/17/2000
mgross: 1/11/2000
terry: 12/20/1999
alopez: 11/10/1999
terry: 11/3/1999
dkim: 9/9/1998
mark: 1/22/1998
terry: 1/20/1998
terry: 9/15/1997
terry: 12/12/1996
terry: 12/4/1996
jamie: 10/23/1996
jamie: 10/18/1996
jamie: 10/16/1996
mark: 9/30/1996
terry: 9/26/1996
mark: 8/18/1996
terry: 8/16/1996
mark: 7/9/1995
davew: 7/6/1994
carol: 4/18/1994
mimadm: 3/12/1994
supermim: 3/17/1992