RBCC Red Blood Cell Collection

SLC4A1 (AE1, DI, EPB3) [Confidence: high (a blood group or CD marker)]
Band 3 anion transport protein (Anion exchange protein 1; AE 1; Anion exchanger 1; Solute carrier family 4 member 1; CD233)

hRBCD IPI00022361
IPI00022361 Band 3 anion transport protein Band 3 anion transport protein membrane 6 36 98 73 93 71 95 62 391 4 151 88 14 23 22 6 22 38 28 28 integral membrane protein n/a found at its expected molecular weight found at molecular weight

BGMUT diego
178 diego SLC4A1 SLC4A1 118A Diego Montefiore 118G>A E40K rare 8471774 Rybicki et al. Blumenfeld OO, curator 2008-10-02 17:31:44.180 NA

UniProt P02730
ID B3AT_HUMAN Reviewed; 911 AA.
AC P02730; G4V2I6; P78487; Q1ZZ45; Q4KKW9; Q4VB84; Q9UCY7; Q9UDJ1;
read moreDT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1990, sequence version 3.
DT 22-JAN-2014, entry version 190.
DE RecName: Full=Band 3 anion transport protein;
DE AltName: Full=Anion exchange protein 1;
DE Short=AE 1;
DE Short=Anion exchanger 1;
DE AltName: Full=Solute carrier family 4 member 1;
DE AltName: CD_antigen=CD233;
GN Name=SLC4A1; Synonyms=AE1, DI, EPB3;
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].
RC TISSUE=Blood;
RX PubMed=3223947;
RA Tanner M.J.A., Martin P.G., High S.;
RT "The complete amino acid sequence of the human erythrocyte membrane
RT anion-transport protein deduced from the cDNA sequence.";
RL Biochem. J. 256:703-712(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2594752; DOI=10.1073/pnas.86.23.9089;
RA Lux S.E., John K.M., Kopito R.R., Lodish H.F.;
RT "Cloning and characterization of band 3, the human erythrocyte anion-
RT exchange protein (AE1).";
RL Proc. Natl. Acad. Sci. U.S.A. 86:9089-9093(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ALA-38.
RX PubMed=16252102; DOI=10.1007/s00467-005-2061-z;
RA Choo K.E., Nicoli T.K., Bruce L.J., Tanner M.J., Ruiz-Linares A.,
RA Wrong O.M.;
RT "Recessive distal renal tubular acidosis in Sarawak caused by AE1
RT mutations.";
RL Pediatr. Nephrol. 21:212-217(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Blood;
RA Hsu K., Huang S.-Y., Chi N., Lin M.;
RT "Novel anion exchanger-1 expression in Southeast Asian populations.";
RL Submitted (SEP-2009) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ALA-38; GLU-56;
RP LYS-508 AND ILE-862.
RG SeattleSNPs variation discovery resource;
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-27.
RC TISSUE=Cerebellum;
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 PROTEIN SEQUENCE OF 1-199; 220-292 AND 347-370.
RX PubMed=2790053; DOI=10.1016/0167-4838(89)90116-7;
RA Yannoukakos D., Vasseur C., Blouquit Y., Bursaux E., Wajcman H.;
RT "Primary structure of the cytoplasmic domain of human erythrocyte
RT protein band 3. Comparison with its sequence in the mouse.";
RL Biochim. Biophys. Acta 998:43-49(1989).
RN [9]
RP PROTEIN SEQUENCE OF 1-201.
RX PubMed=6345535;
RA Kaul R.K., Murthy S.N.P., Reddy A.G., Steck T.L., Kohler H.;
RT "Amino acid sequence of the N alpha-terminal 201 residues of human
RT erythrocyte membrane band 3.";
RL J. Biol. Chem. 258:7981-7990(1983).
RN [10]
RP PROTEIN SEQUENCE OF 1-3.
RX PubMed=701248;
RA Drickamer L.K.;
RT "Orientation of the band 3 polypeptide from human erythrocyte
RT membranes. Identification of NH2-terminal sequence and site of
RT carbohydrate attachment.";
RL J. Biol. Chem. 253:7242-7248(1978).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 66-180.
RX PubMed=7506871;
RA Kollert-Jons A., Wagner S., Hubner S., Appelhans H., Drenckhahn D.;
RT "Anion exchanger 1 in human kidney and oncocytoma differs from
RT erythroid AE1 in its NH2 terminus.";
RL Am. J. Physiol. 265:F813-F821(1993).
RN [12]
RP PROTEIN SEQUENCE OF 361-372; 390-399; 604-613; 632-639; 647-656;
RP 699-729; 731-743; 761-781 AND 818-826, AND SYNTHESIS OF 646-656 AND
RP 817-827.
RX PubMed=1527044;
RA Kang D., Okubo K., Hamasaki N., Kuroda N., Shiraki H.;
RT "A structural study of the membrane domain of band 3 by tryptic
RT digestion. Conformational change of band 3 in situ induced by alkali
RT treatment.";
RL J. Biol. Chem. 267:19211-19217(1992).
RN [13]
RP PROTEIN SEQUENCE OF 559-630.
RX PubMed=6615451;
RA Brock C.J., Tanner M.J.A., Kempf C.;
RT "The human erythrocyte anion-transport protein. Partial amino acid
RT sequence, conformation and a possible molecular mechanism for anion
RT exchange.";
RL Biochem. J. 213:577-586(1983).
RN [14]
RP PROTEIN SEQUENCE OF 665-688, AND ROLE OF GLU-681.
RX PubMed=1352774;
RA Jennings M.L., Smith J.S.;
RT "Anion-proton cotransport through the human red blood cell band 3
RT protein. Role of glutamate 681.";
RL J. Biol. Chem. 267:13964-13971(1992).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 757-778, AND VARIANT SPH4 ASP-771.
RX PubMed=8547122; DOI=10.1111/j.1365-2141.1995.tb05393.x;
RA Maillet P., Vallier A., Reinhart W.H., Wyss E.J., Ott P., Texier P.,
RA Baklouti F., Tanner M.J.A., Delaunay J., Alloisio N.;
RT "Band 3 Chur: a variant associated with band 3-deficient hereditary
RT spherocytosis and substitution in a highly conserved position of
RT transmembrane segment 11.";
RL Br. J. Haematol. 91:804-810(1995).
RN [16]
RP PROTEIN SEQUENCE OF 834-911.
RX PubMed=3372523;
RA Kawano Y., Okubo K., Tokunaga F., Miyata T., Iwanaga S., Hamasaki N.;
RT "Localization of the pyridoxal phosphate binding site at the COOH-
RT terminal region of erythrocyte band 3 protein.";
RL J. Biol. Chem. 263:8232-8238(1988).
RN [17]
RP PHOSPHORYLATION AT TYR-8; TYR-21 AND TYR-46.
RX PubMed=1998697; DOI=10.1016/0005-2736(91)90291-F;
RA Yannoukakos D., Vasseur C., Piau J.-P., Wajcman H., Bursaux E.;
RT "Phosphorylation sites in human erythrocyte band 3 protein.";
RL Biochim. Biophys. Acta 1061:253-266(1991).
RN [18]
RP PALMITOYLATION AT CYS-843.
RX PubMed=1885574;
RA Okubo K., Hamasaki N., Hara K., Kageura M.;
RT "Palmitoylation of cysteine 69 from the COOH-terminal of band 3
RT protein in the human erythrocyte membrane. Acylation occurs in the
RT middle of the consensus sequence of F--I-IICLAVL found in band 3
RT protein and G2 protein of Rift Valley fever virus.";
RL J. Biol. Chem. 266:16420-16424(1991).
RN [19]
RP INTERACTION WITH ANK1.
RX PubMed=7665627; DOI=10.1074/jbc.270.37.22050;
RA Michaely P., Bennett V.;
RT "The ANK repeats of erythrocyte ankyrin form two distinct but
RT cooperative binding sites for the erythrocyte anion exchanger.";
RL J. Biol. Chem. 270:22050-22057(1995).
RN [20]
RP GLYCOSYLATION AT ASN-642.
RX PubMed=10861210; DOI=10.1042/0264-6021:3490051;
RA Li J., Quilty J., Popov M., Reithmeier R.A.;
RT "Processing of N-linked oligosaccharide depends on its location in the
RT anion exchanger, AE1, membrane glycoprotein.";
RL Biochem. J. 349:51-57(2000).
RN [21]
RP PHOSPHORYLATION AT TYR-8; TYR-21; TYR-359 AND TYR-904.
RX PubMed=10942405;
RA Brunati A.M., Bordin L., Clari G., James P., Quadroni M., Baritono E.,
RA Pinna L.A., Donella-Deana A.;
RT "Sequential phosphorylation of protein band 3 by Syk and Lyn tyrosine
RT kinases in intact human erythrocytes: identification of primary and
RT secondary phosphorylation sites.";
RL Blood 96:1550-1557(2000).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP STRUCTURE BY ELECTRON CRYOMICROSCOPY.
RX PubMed=8508760;
RA Wang D.N., Kuehlbrandt W., Sarabia V.E., Reithmeier R.A.F.;
RT "Two-dimensional structure of the membrane domain of human band 3, the
RT anion transport protein of the erythrocyte membrane.";
RL EMBO J. 12:2233-2239(1993).
RN [24]
RP STRUCTURE BY ELECTRON CRYOMICROSCOPY.
RX PubMed=8045253;
RA Wang D.N., Sarabia V.E., Reithmeier R.A.F., Kuehlbrandt W.;
RT "Three-dimensional map of the dimeric membrane domain of the human
RT erythrocyte anion exchanger, Band 3.";
RL EMBO J. 13:3230-3235(1994).
RN [25]
RP STRUCTURE BY NMR OF 405-424 AND 436-456.
RX PubMed=8168533; DOI=10.1111/j.1432-1033.1994.tb18757.x;
RA Gargaro A.R., Bloomberg G.B., Dempsey C.E., Murray M., Tanner M.J.A.;
RT "The solution structures of the first and second transmembrane-
RT spanning segments of band 3.";
RL Eur. J. Biochem. 221:445-454(1994).
RN [26]
RP STRUCTURE BY NMR OF 1-16.
RX PubMed=8527430; DOI=10.1021/bi00051a005;
RA Schneider M.L., Post C.B.;
RT "Solution structure of a band 3 peptide inhibitor bound to aldolase: a
RT proposed mechanism for regulating binding by tyrosine
RT phosphorylation.";
RL Biochemistry 34:16574-16584(1995).
RN [27]
RP STRUCTURE BY NMR OF 1-16.
RX PubMed=9454576; DOI=10.1021/bi971445b;
RA Eisenmesser E.Z., Post C.B.;
RT "Insights into tyrosine phosphorylation control of protein-protein
RT association from the NMR structure of a band 3 peptide inhibitor bound
RT to glyceraldehyde-3-phosphate dehydrogenase.";
RL Biochemistry 37:867-877(1998).
RN [28]
RP STRUCTURE BY NMR OF 389-430.
RX PubMed=9765907;
RA Chambers E.J., Askin D., Bloomberg G.B., Ring S.M., Tanner M.J.;
RT "Studies on the structure of a transmembrane region and a cytoplasmic
RT loop of the human red cell anion exchanger.";
RL Biochem. Soc. Trans. 26:516-520(1998).
RN [29]
RP STRUCTURE BY NMR OF 803-835.
RX PubMed=9709005; DOI=10.1021/bi973158d;
RA Askin D., Bloomberg G.B., Chambers E.J., Tanner M.J.;
RT "NMR solution structure of a cytoplasmic surface loop of the human red
RT cell anion transporter, band 3.";
RL Biochemistry 37:11670-11678(1998).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1-379, AND SUBUNIT.
RX PubMed=11049968;
RA Zhang D., Kiyatkin A., Bolin J.T., Low P.S.;
RT "Crystallographic structure and functional interpretation of the
RT cytoplasmic domain of erythrocyte membrane band 3.";
RL Blood 96:2925-2933(2000).
RN [31]
RP VARIANT MEMPHIS GLU-56.
RX PubMed=1678289;
RA Yannoukakos D., Vasseur C., Driancourt C., Blouquit Y., Delauney J.,
RA Wajcman H., Bursaux E.;
RT "Human erythrocyte band 3 polymorphism (band 3 Memphis):
RT characterization of the structural modification (Lys 56-->Glu) by
RT protein chemistry methods.";
RL Blood 78:1117-1120(1991).
RN [32]
RP VARIANT EL4 400-ALA--ALA-408 DEL, AND VARIANT MEMPHIS GLU-56.
RX PubMed=1722314; DOI=10.1073/pnas.88.24.11022;
RA Jarolim P., Palek J., Amato D., Hassan K., Sapak P., Nurse G.T.,
RA Rubin H.L., Zhai S., Sahr K.E., Liu S.-C.;
RT "Deletion in erythrocyte band 3 gene in malaria-resistant Southeast
RT Asian ovalocytosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:11022-11026(1991).
RN [33]
RP VARIANT SPH4 ARG-327.
RX PubMed=1378323;
RA Jarolim P., Palek J., Rubin H.L., Prchal J.T., Korsgren C.,
RA Cohen C.M.;
RT "Band 3 Tuscaloosa: Pro-327-->Arg substitution in the cytoplasmic
RT domain of erythrocyte band 3 protein associated with spherocytic
RT hemolytic anemia and partial deficiency of protein 4.2.";
RL Blood 80:523-529(1992).
RN [34]
RP VARIANT EL4 400-ALA--ALA-408 DEL.
RX PubMed=1538405; DOI=10.1016/0022-2836(92)90254-H;
RA Schofield A.E., Tanner M.J.A., Pinder J.C., Clough B., Bayley P.M.,
RA Nash G.B., Dluzewski A.R., Reardon D.M., Cox T.M., Wilson R.J.M.,
RA Gratzer W.B.;
RT "Basis of unique red cell membrane properties in hereditary
RT ovalocytosis.";
RL J. Mol. Biol. 223:949-958(1992).
RN [35]
RP VARIANT ACANTHOCYTOSIS LEU-868.
RX PubMed=8343110;
RA Bruce L.J., Kay M.M., Lawrence C., Tanner M.J.;
RT "Band 3 HT, a human red-cell variant associated with acanthocytosis
RT and increased anion transport, carries the mutation Pro-868-->Leu in
RT the membrane domain of band 3.";
RL Biochem. J. 293:317-320(1993).
RN [36]
RP VARIANT HEMOLYTIC ANEMIA LYS-40.
RX PubMed=8471774;
RA Rybicki A.C., Qiu J.J.H., Musto S., Rosen N.L., Nagel R.L.,
RA Schwartz R.S.;
RT "Human erythrocyte protein 4.2 deficiency associated with hemolytic
RT anemia and a homozygous 40 glutamic acid-->lysine substitution in the
RT cytoplasmic domain of band 3 (band 3Montefiore).";
RL Blood 81:2155-2165(1993).
RN [37]
RP VARIANTS BLOOD GROUP DI(A)/MEMPHIS-II GLU-56 AND LEU-854.
RX PubMed=8206915;
RA Bruce L.J., Anstee D.J., Spring F.A., Tanner M.J.;
RT "Band 3 Memphis variant II. Altered stilbene disulfonate binding and
RT the Diego (Dia) blood group antigen are associated with the human
RT erythrocyte band 3 mutation Pro-854-->Leu.";
RL J. Biol. Chem. 269:16155-16158(1994).
RN [38]
RP VARIANT BLOOD GROUP WR(A) LYS-658.
RX PubMed=7812009;
RA Bruce L.J., Ring S.M., Anstee D.J., Reid M.E., Wilkinson S.,
RA Tanner M.J.;
RT "Changes in the blood group Wright antigens are associated with a
RT mutation at amino acid 658 in human erythrocyte band 3: a site of
RT interaction between band 3 and glycophorin A under certain
RT conditions.";
RL Blood 85:541-547(1995).
RN [39]
RP VARIANTS SPH4 GLN-760; TRP-760; CYS-808 AND TRP-870.
RX PubMed=7530501;
RA Jarolim P., Rubin H.L., Brabec V., Chrobak L., Zolotarev A.S.,
RA Alper S.L., Brugnara C., Wichterle H., Palek J.;
RT "Mutations of conserved arginines in the membrane domain of erythroid
RT band 3 lead to a decrease in membrane-associated band 3 and to the
RT phenotype of hereditary spherocytosis.";
RL Blood 85:634-640(1995).
RN [40]
RP VARIANTS SPH4 ASP-285; GLU-455; PRO-707; PRO-834 AND MET-837.
RX PubMed=8943874;
RA Jarolim P., Murray J.L., Rubin H.L., Taylor W.M., Prchal J.T.,
RA Ballas S.K., Snyder L.M., Chrobak L., Melrose W.D., Brabec V.,
RA Palek J.;
RT "Characterization of 13 novel band 3 gene defects in hereditary
RT spherocytosis with band 3 deficiency.";
RL Blood 88:4366-4374(1996).
RN [41]
RP VARIANTS SPH4 LYS-40; CYS-518 AND MET-663 DEL.
RX PubMed=8640229; DOI=10.1038/ng0696-214;
RA Eber S.W., Gonzalez J.M., Lux M.L., Scarpa A.L., Tse W.T.,
RA Dornwell M., Herbers J., Kugler W., Oezcan R., Pekrun A.,
RA Gallagher P.G., Schroeter W., Forget B.G., Lux S.E.;
RT "Ankyrin-1 mutations are a major cause of dominant and recessive
RT hereditary spherocytosis.";
RL Nat. Genet. 13:214-218(1996).
RN [42]
RP VARIANTS SPH4 SER-147 AND MET-488.
RX PubMed=9207478;
RA Alloisio N., Texier P., Vallier A., Ribeiro M.L., Morle L., Bozon M.,
RA Bursaux E., Maillet P., Goncalves P., Tanner M.J., Tamagnini G.,
RA Delaunay J.;
RT "Modulation of clinical expression and band 3 deficiency in hereditary
RT spherocytosis.";
RL Blood 90:414-420(1997).
RN [43]
RP VARIANT SPH4 ASN-783, AND VARIANTS ALA-38 AND MET-73.
RX PubMed=9012689; DOI=10.1046/j.1365-2141.1997.8732504.x;
RA Miraglia del Giudice E., Vallier A., Maillet P., Perrotta S.,
RA Cutillo S., Iolascon A., Tanner M.J., Delaunay J., Alloisio N.;
RT "Novel band 3 variants (bands 3 Foggia, Napoli I and Napoli II)
RT associated with hereditary spherocytosis and band 3 deficiency: status
RT of the D38A polymorphism within the EPB3 locus.";
RL Br. J. Haematol. 96:70-76(1997).
RN [44]
RP VARIANTS SPH4 CYS-490 AND MET-837.
RX PubMed=9233560; DOI=10.1046/j.1365-2141.1997.1893005.x;
RA Dhermy D., Galand C., Bournier O., Boulanger L., Cynober T.,
RA Schismanoff P.O., Bursaux E., Tchernia G., Boivin P., Garbarz M.;
RT "Heterogenous band 3 deficiency in hereditary spherocytosis related to
RT different band 3 gene defects.";
RL Br. J. Haematol. 98:32-40(1997).
RN [45]
RP ERRATUM.
RA Dhermy D., Galand C., Bournier O., Boulanger L., Cynober T.,
RA Schismanoff P.O., Bursaux E., Tchernia G., Boivin P., Garbarz M.;
RL Br. J. Haematol. 99:474-474(1997).
RN [46]
RP VARIANTS AD-DRTA CYS-589; HIS-589 AND PHE-613.
RX PubMed=9312167; DOI=10.1172/JCI119694;
RA Bruce L.J., Cope D.L., Jones G.K., Schofield A.E., Burley M.,
RA Povey S., Unwin R.J., Wrong O., Tanner M.J.;
RT "Familial distal renal tubular acidosis is associated with mutations
RT in the red cell anion exchanger (Band 3, AE1) gene.";
RL J. Clin. Invest. 100:1693-1707(1997).
RN [47]
RP VARIANTS BLOOD GROUPS RB(A); TR(A) AND WD(A).
RX PubMed=9191821; DOI=10.1046/j.1537-2995.1997.37697335155.x;
RA Jarolim P., Murray J.L., Rubin H.L., Smart E., Moulds J.M.;
RT "Blood group antigens Rb(a), Tr(a), and Wd(a) are located in the third
RT ectoplasmic loop of erythroid band 3.";
RL Transfusion 37:607-615(1997).
RN [48]
RP VARIANT SPH4 ALA-837.
RX PubMed=9973643; DOI=10.1159/000040904;
RA Iwase S., Ideguchi H., Takao M., Horiguchi-Yamada J., Iwasaki M.,
RA Takahara S., Sekikawa T., Mochizuki S., Yamada H.;
RT "Band 3 Tokyo: Thr837-->Ala837 substitution in erythrocyte band 3
RT protein associated with spherocytic hemolysis.";
RL Acta Haematol. 100:200-203(1998).
RN [49]
RP VARIANTS BLOOD GROUPS BOW; BP(A); ELO; HG(A); MO(A); VG(A) AND WU.
RX PubMed=9845551;
RA Jarolim P., Rubin H.L., Zakova D., Storry J., Reid M.E.;
RT "Characterization of seven low incidence blood group antigens carried
RT by erythrocyte band 3 protein.";
RL Blood 92:4836-4843(1998).
RN [50]
RP VARIANT DRTA-HA ASP-701.
RX PubMed=9854053; DOI=10.1172/JCI4836;
RA Tanphaichitr V.S., Sumboonnanonda A., Ideguchi H., Shayakul C.,
RA Brugnara C., Takao M., Veerakul G., Alper S.L.;
RT "Novel AE1 mutations in recessive distal renal tubular acidosis: loss-
RT of-function is rescued by glycophorin A.";
RL J. Clin. Invest. 102:2173-2179(1998).
RN [51]
RP VARIANTS AD-DRTA HIS-589 AND SER-589.
RX PubMed=9600966; DOI=10.1073/pnas.95.11.6337;
RA Karet F.E., Gainza F.J., Gyory A.Z., Unwin R.J., Wrong O.,
RA Tanner M.J.A., Nayir A., Alpay H., Santos F., Hulton S.A.,
RA Bakkaloglu A., Ozen S., Cunningham M.J., di Pietro A., Walker W.G.,
RA Lifton R.P.;
RT "Mutations in the chloride-bicarbonate exchanger gene AE1 cause
RT autosomal dominant but not autosomal recessive distal renal tubular
RT acidosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:6337-6342(1998).
RN [52]
RP VARIANTS BLOOD GROUP WU.
RX PubMed=9709782; DOI=10.1046/j.1537-2995.1998.38898375513.x;
RA Zelinski T., McManus K., Punter F., Moulds M., Coghlan G.;
RT "A Gly565-->Ala substitution in human erythroid band 3 accounts for
RT the Wu blood group polymorphism.";
RL Transfusion 38:745-748(1998).
RN [53]
RP VARIANT SPH4 HIS-490.
RX PubMed=10580570;
RA Lima P.R.M., Sales T.S.I., Costa F.F., Saad S.T.O.;
RT "Arginine 490 is a hot spot for mutation in the band 3 gene in
RT hereditary spherocytosis.";
RL Eur. J. Haematol. 63:360-361(1999).
RN [54]
RP VARIANTS DRTA-HA ASP-701 AND VAL-850 DEL, AND VARIANT AD-DRTA ASP-858.
RX PubMed=10926824; DOI=10.1042/0264-6021:3500041;
RA Bruce L.J., Wrong O., Toye A.M., Young M.T., Ogle G., Ismail Z.,
RA Sinha A.K., McMaster P., Hwaihwanje I., Nash G.B., Hart S., Lavu E.,
RA Palmer R., Othman A., Unwin R.J., Tanner M.J.A.;
RT "Band 3 mutations, renal tubular acidosis and South-East Asian
RT ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band
RT 3 transport in red cells.";
RL Biochem. J. 350:41-51(2000).
RN [55]
RP VARIANT SPH4 MET-488.
RX PubMed=10942416;
RA Ribeiro M.L., Alloisio N., Almeida H., Gomes C., Texier P., Lemos C.,
RA Mimoso G., Morle L., Bey-Cabet F., Rudigoz R.-C., Delaunay J.,
RA Tamagnini G.;
RT "Severe hereditary spherocytosis and distal renal tubular acidosis
RT associated with the total absence of band 3.";
RL Blood 96:1602-1604(2000).
RN [56]
RP VARIANTS SPH4 ARG-130; ARG-455; ARG-714; TRP-760; GLN-760; HIS-808;
RP ARG-837 AND MET-837, AND VARIANTS ALA-38; GLU-56; ASP-72 AND LEU-854.
RX PubMed=10745622;
RA Yawata Y., Kanzaki A., Yawata A., Doerfler W., Oezcan R., Eber S.W.;
RT "Characteristic features of the genotype and phenotype of hereditary
RT spherocytosis in the Japanese population.";
RL Int. J. Hematol. 71:118-135(2000).
RN [57]
RP CHARACTERIZATION OF VARIANTS PRO-707; GLN-760; TRP-760; CYS-808;
RP PRO-834; MET-837 AND TRP-870.
RX PubMed=11208088; DOI=10.1034/j.1600-0854.2000.011208.x;
RA Quilty J.A., Reithmeier R.A.;
RT "Trafficking and folding defects in hereditary spherocytosis mutants
RT of the human red cell anion exchanger.";
RL Traffic 1:987-998(2000).
RN [58]
RP VARIANTS BLOOD GROUP NFLD+ ASP-429 AND ALA-561, AND VARIANT BLOOD
RP GROUP BOW+ SER-561.
RX PubMed=10738034; DOI=10.1046/j.1537-2995.2000.40030325.x;
RA McManus K., Pongoski J., Coghlan G., Zelinski T.;
RT "Amino acid substitutions in human erythroid protein band 3 account
RT for the low-incidence antigens NFLD and BOW.";
RL Transfusion 40:325-329(2000).
RN [59]
RP VARIANT BLOOD GROUP FR(A+) LYS-480.
RX PubMed=11061863; DOI=10.1046/j.1537-2995.2000.40101246.x;
RA McManus K., Lupe K., Coghlan G., Zelinski T.;
RT "An amino acid substitution in the putative second extracellular loop
RT of RBC band 3 accounts for the Froese blood group polymorphism.";
RL Transfusion 40:1246-1249(2000).
RN [60]
RP VARIANTS BLOOD GROUP SW(A+) GLN-646 AND TRP-646.
RX PubMed=11155072; DOI=10.1159/000056733;
RA Zelinski T., Rusnak A., McManus K., Coghlan G.;
RT "Distinctive Swann blood group genotypes: molecular investigations.";
RL Vox Sang. 79:215-218(2000).
RN [61]
RP VARIANTS SPH4 LYS-90 AND TRP-870.
RX PubMed=11380459; DOI=10.1046/j.1365-2141.2001.02800.x;
RA Bracher N.A., Lyons C.A., Wessels G., Mansvelt E., Coetzer T.L.;
RT "Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in
RT combination with band 3 Prague III.";
RL Br. J. Haematol. 113:689-693(2001).
RN [62]
RP VARIANT DRTA-HA PRO-602, AND VARIANT DRTA-NRC PRO-773.
RX PubMed=15211439; DOI=10.1053/j.ajkd.2004.03.033;
RA Sritippayawan S., Sumboonnanonda A., Vasuvattakul S., Keskanokwong T.,
RA Sawasdee N., Paemanee A., Thuwajit P., Wilairat P., Nimmannit S.,
RA Malasit P., Yenchitsomanus P.T.;
RT "Novel compound heterozygous SLC4A1 mutations in Thai patients with
RT autosomal recessive distal renal tubular acidosis.";
RL Am. J. Kidney Dis. 44:64-70(2004).
RN [63]
RP VARIANT AD-DRTA ARG-609.
RX PubMed=14734552; DOI=10.1074/jbc.M400188200;
RA Rungroj N., Devonald M.A.J., Cuthbert A.W., Reimann F.,
RA Akkarapatumwong V., Yenchitsomanus P.-T., Bennett W.M., Karet F.E.;
RT "A novel missense mutation in AE1 causing autosomal dominant distal
RT renal tubular acidosis retains normal transport function but is
RT mistargeted in polarized epithelial cells.";
RL J. Biol. Chem. 279:13833-13838(2004).
RN [64]
RP VARIANT SPH4 LYS-663.
RX PubMed=15813913; DOI=10.1111/j.1600-0609.2004.00405.x;
RA Lima P.R.M., Baratti M.O., Chiattone M.L., Costa F.F., Saad S.T.O.;
RT "Band 3Tambau: a de novo mutation in the AE1 gene associated with
RT hereditary spherocytosis. Implications for anion exchange and
RT insertion into the red blood cell membrane.";
RL Eur. J. Haematol. 74:396-401(2005).
RN [65]
RP VARIANTS SPH4 PRO-687; TYR-705; PRO-731; ARG-734 AND GLN-760.
RX PubMed=16227998; DOI=10.1038/ng1656;
RA Bruce L.J., Robinson H.C., Guizouarn H., Borgese F., Harrison P.,
RA King M.-J., Goede J.S., Coles S.E., Gore D.M., Lutz H.U.,
RA Ficarella R., Layton D.M., Iolascon A., Ellory J.C., Stewart G.W.;
RT "Monovalent cation leaks in human red cells caused by single amino-
RT acid substitutions in the transport domain of the band 3 chloride-
RT bicarbonate exchanger, AE1.";
RL Nat. Genet. 37:1258-1263(2005).
CC -!- FUNCTION: Band 3 is the major integral glycoprotein of the
CC erythrocyte membrane. Band 3 has two functional domains. Its
CC integral domain mediates a 1:1 exchange of inorganic anions across
CC the membrane, whereas its cytoplasmic domain provides binding
CC sites for cytoskeletal proteins, glycolytic enzymes, and
CC hemoglobin.
CC -!- ENZYME REGULATION: Phenyl isothiocyanate inhibits anion transport
CC in vitro.
CC -!- SUBUNIT: A dimer in solution, in its membrane environment, it
CC exists primarily as a mixture of dimers and tetramers and spans
CC the membrane asymmetrically. Interacts (via cytoplasmic N-terminus
CC domain) with ANK1 (via N-terminus ANK repeats), tetramer formation
CC is critical for ankyrin association.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Erythrocytes.
CC -!- PTM: Phosphorylated on Tyr-8 and Tyr-21 most likely by SYK. PP1-
CC resistant phosphorylation that precedes Tyr-359 and Tyr-904
CC phosphorylation.
CC -!- PTM: Phosphorylated on Tyr-359 and Tyr-904 most likely by LYN.
CC PP1-inhibited phosphorylation that follows Tyr-8 and Tyr-21
CC phosphorylation.
CC -!- POLYMORPHISM: SLC4A1 is responsible for the Diego blood group
CC system. The molecular basis of the Di(a)=Di1/Di(b)/Di2 blood group
CC antigens is a single variation in position 854; Leu-854
CC corresponds to Di(a) and Pro-854 to Di(b). The molecular basis of
CC the Wr(a)=Di3/Wr(b)/Di4 blood group antigens is a single variation
CC in position 658; Lys-658 corresponds to Wr(a) and Glu-658 to
CC Wr(b). The blood group antigens Wd(a)=Di5 (Waldner-type) has Met-
CC 557; Rb(a)=Di6 has Leu-548 and WARR=Di7 has Ile-552.
CC -!- POLYMORPHISM: SLC4A1 is responsible for the Swann blood group
CC system (SW) [MIM:601550]. Sw(a+) has a Gln or a Trp at position
CC 646 and Sw(a-) has an Arg.
CC -!- POLYMORPHISM: SLC4A1 is responsible for the Froese blood group
CC system (FR) [MIM:601551]. FR(a+) has a Lys at position 480 and
CC FR(a-) has a Glu.
CC -!- POLYMORPHISM: Genetic variations in SLC4A1 are involved in
CC resistance to malaria [MIM:611162].
CC -!- DISEASE: Elliptocytosis 4 (EL4) [MIM:109270]: A Rhesus-unlinked
CC form of hereditary elliptocytosis, a genetically heterogeneous,
CC autosomal dominant hematologic disorder. It is characterized by
CC variable hemolytic anemia and elliptical or oval red cell shape.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Spherocytosis 4 (SPH4) [MIM:612653]: Spherocytosis is a
CC hematologic disorder leading to chronic hemolytic anemia and
CC characterized by numerous abnormally shaped erythrocytes which are
CC generally spheroidal. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Renal tubular acidosis, distal, autosomal dominant (AD-
CC dRTA) [MIM:179800]: An autosomal dominant disease characterized by
CC reduced ability to acidify urine, variable hyperchloremic
CC hypokalemic metabolic acidosis, nephrocalcinosis, and
CC nephrolithiasis. It is due to functional failure of alpha-
CC intercalated cells of the cortical collecting duct of the distal
CC nephron, where vectorial proton transport is required for urinary
CC acidification. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Renal tubular acidosis, distal, with hemolytic anemia
CC (dRTA-HA) [MIM:611590]: A disease characterized by the association
CC of hemolytic anemia with distal renal tubular acidosis, the
CC reduced ability to acidify urine resulting in variable
CC hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis,
CC and nephrolithiasis. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Renal tubular acidosis, distal, with normal red cell
CC morphology (dRTA-NRC) [MIM:611590]: A disease characterized by
CC reduced ability to acidify urine, variable hyperchloremic
CC hypokalemic metabolic acidosis, nephrocalcinosis, and
CC nephrolithiasis. It is due to functional failure of alpha-
CC intercalated cells of the cortical collecting duct of the distal
CC nephron, where vectorial proton transport is required for urinary
CC acidification. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the anion exchanger (TC 2.A.31) family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Band 3 entry;
CC URL="http://en.wikipedia.org/wiki/Band_3";
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene
CC mutation database;
CC URL="http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system;=diego";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC4A1";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/slc4a1/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SLC4A1ID42325ch17q21.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
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DR EMBL; X12609; CAA31128.1; -; mRNA.
DR EMBL; M27819; AAA35514.1; -; mRNA.
DR EMBL; DQ419529; ABD74692.1; -; mRNA.
DR EMBL; GQ981383; ADN39420.1; -; mRNA.
DR EMBL; GQ981384; ADN39421.1; -; mRNA.
DR EMBL; DQ072115; AAY57324.1; -; Genomic_DNA.
DR EMBL; CH471178; EAW51614.1; -; Genomic_DNA.
DR EMBL; BC096106; AAH96106.1; -; mRNA.
DR EMBL; BC096107; AAH96107.1; -; mRNA.
DR EMBL; BC099628; AAH99628.1; -; mRNA.
DR EMBL; BC099629; AAH99629.1; -; mRNA.
DR EMBL; BC101570; AAI01571.1; -; mRNA.
DR EMBL; BC101574; AAI01575.1; -; mRNA.
DR EMBL; S68680; AAC60608.2; -; mRNA.
DR PIR; A36218; B3HU.
DR RefSeq; NP_000333.1; NM_000342.3.
DR RefSeq; XP_005257649.1; XM_005257592.1.
DR UniGene; Hs.443948; -.
DR PDB; 1BH7; NMR; -; A=803-835.
DR PDB; 1BNX; NMR; -; A=389-430.
DR PDB; 1BTQ; NMR; -; A=405-424.
DR PDB; 1BTR; NMR; -; A=405-424.
DR PDB; 1BTS; NMR; -; A=436-456.
DR PDB; 1BTT; NMR; -; A=436-456.
DR PDB; 1BZK; NMR; -; A=389-430.
DR PDB; 1HYN; X-ray; 2.60 A; P/Q/R/S=1-379.
DR PDB; 2BTA; NMR; -; A=1-15.
DR PDB; 2BTB; NMR; -; A=1-15.
DR PDB; 3BTB; NMR; -; A=1-15.
DR PDB; 4KY9; X-ray; 2.23 A; A/P=51-356.
DR PDBsum; 1BH7; -.
DR PDBsum; 1BNX; -.
DR PDBsum; 1BTQ; -.
DR PDBsum; 1BTR; -.
DR PDBsum; 1BTS; -.
DR PDBsum; 1BTT; -.
DR PDBsum; 1BZK; -.
DR PDBsum; 1HYN; -.
DR PDBsum; 2BTA; -.
DR PDBsum; 2BTB; -.
DR PDBsum; 3BTB; -.
DR PDBsum; 4KY9; -.
DR ProteinModelPortal; P02730; -.
DR SMR; P02730; 55-356, 389-430, 803-835.
DR IntAct; P02730; 3.
DR MINT; MINT-1344291; -.
DR STRING; 9606.ENSP00000262418; -.
DR TCDB; 2.A.31.1.1; the anion exchanger (ae) family.
DR PhosphoSite; P02730; -.
DR DMDM; 114787; -.
DR PaxDb; P02730; -.
DR PRIDE; P02730; -.
DR Ensembl; ENST00000262418; ENSP00000262418; ENSG00000004939.
DR GeneID; 6521; -.
DR KEGG; hsa:6521; -.
DR UCSC; uc002igf.4; human.
DR CTD; 6521; -.
DR GeneCards; GC17M042337; -.
DR HGNC; HGNC:11027; SLC4A1.
DR HPA; HPA015584; -.
DR MIM; 109270; gene+phenotype.
DR MIM; 110500; phenotype.
DR MIM; 112010; phenotype.
DR MIM; 112050; phenotype.
DR MIM; 130600; phenotype.
DR MIM; 179800; phenotype.
DR MIM; 601550; phenotype.
DR MIM; 601551; phenotype.
DR MIM; 611162; phenotype.
DR MIM; 611590; phenotype.
DR MIM; 612653; phenotype.
DR neXtProt; NX_P02730; -.
DR Orphanet; 93608; Autosomal dominant distal renal tubular acidosis.
DR Orphanet; 93610; Distal renal tubular acidosis with anemia.
DR Orphanet; 822; Hereditary spherocytosis.
DR Orphanet; 98868; Southeast asian ovalocytosis.
DR PharmGKB; PA35895; -.
DR eggNOG; NOG268067; -.
DR HOVERGEN; HBG004326; -.
DR InParanoid; P02730; -.
DR KO; K06573; -.
DR OMA; WSLLELQ; -.
DR OrthoDB; EOG7TMZR0; -.
DR PhylomeDB; P02730; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR EvolutionaryTrace; P02730; -.
DR GeneWiki; Band_3; -.
DR GenomeRNAi; 6521; -.
DR NextBio; 25367; -.
DR PMAP-CutDB; P02730; -.
DR PRO; PR:P02730; -.
DR ArrayExpress; P02730; -.
DR Bgee; P02730; -.
DR Genevestigator; P02730; -.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:BHF-UCL.
DR GO; GO:0030018; C:Z disc; ISS:UniProtKB.
DR GO; GO:0015108; F:chloride transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005452; F:inorganic anion exchanger activity; TAS:Reactome.
DR GO; GO:0043495; F:protein anchor; TAS:BHF-UCL.
DR GO; GO:0015701; P:bicarbonate transport; TAS:Reactome.
DR GO; GO:0006873; P:cellular ion homeostasis; TAS:ProtInc.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.40.1100.10; -; 1.
DR InterPro; IPR001717; Anion_exchange.
DR InterPro; IPR002977; Anion_exchange_1.
DR InterPro; IPR018241; Anion_exchange_CS.
DR InterPro; IPR013769; Band3_cytoplasmic_dom.
DR InterPro; IPR011531; HCO3_transpt_C.
DR InterPro; IPR003020; HCO3_transpt_euk.
DR InterPro; IPR016152; PTrfase/Anion_transptr.
DR PANTHER; PTHR11453; PTHR11453; 1.
DR Pfam; PF07565; Band_3_cyto; 1.
DR Pfam; PF00955; HCO3_cotransp; 2.
DR PRINTS; PR00165; ANIONEXCHNGR.
DR PRINTS; PR01187; ANIONEXHNGR1.
DR PRINTS; PR01231; HCO3TRNSPORT.
DR SUPFAM; SSF55804; SSF55804; 1.
DR TIGRFAMs; TIGR00834; ae; 1.
DR PROSITE; PS00219; ANION_EXCHANGER_1; 1.
DR PROSITE; PS00220; ANION_EXCHANGER_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Anion exchange; Blood group antigen;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Elliptocytosis; Glycoprotein; Hereditary hemolytic anemia;
KW Ion transport; Lipoprotein; Membrane; Palmitate; Phosphoprotein;
KW Polymorphism; Reference proteome; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1 911 Band 3 anion transport protein.
FT /FTId=PRO_0000079209.
FT TOPO_DOM 1 403 Cytoplasmic.
FT TRANSMEM 404 424 Helical; (Potential).
FT TRANSMEM 437 456 Helical; (Potential).
FT TRANSMEM 460 479 Helical; (Potential).
FT TRANSMEM 491 510 Helical; (Potential).
FT TRANSMEM 523 541 Helical; (Potential).
FT TOPO_DOM 542 568 Extracellular (Potential).
FT TRANSMEM 569 588 Helical; (Potential).
FT TOPO_DOM 589 603 Cytoplasmic (Potential).
FT TRANSMEM 604 624 Helical; (Potential).
FT TOPO_DOM 625 660 Extracellular (Potential).
FT TRANSMEM 661 680 Helical; (Potential).
FT TRANSMEM 699 719 Helical; (Potential).
FT TRANSMEM 763 780 Helical; (Potential).
FT TRANSMEM 785 806 Helical; (Potential).
FT TRANSMEM 844 865 Helical; (Potential).
FT REGION 55 290 Globular.
FT REGION 176 185 Interaction with ANK1 (Probable).
FT REGION 304 357 Dimerization arm.
FT REGION 404 911 Membrane (anion exchange).
FT REGION 559 630 Involved in anion transport.
FT SITE 590 590 Important for anion transport.
FT SITE 681 681 Important for anion-proton cotransport.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 8 8 Phosphotyrosine.
FT MOD_RES 21 21 Phosphotyrosine.
FT MOD_RES 46 46 Phosphotyrosine.
FT MOD_RES 359 359 Phosphotyrosine.
FT MOD_RES 904 904 Phosphotyrosine.
FT LIPID 843 843 S-palmitoyl cysteine.
FT CARBOHYD 642 642 N-linked (GlcNAc...) (complex).
FT VARIANT 27 27 P -> H (in dbSNP:rs55777403).
FT /FTId=VAR_058035.
FT VARIANT 38 38 D -> A (in dbSNP:rs5035).
FT /FTId=VAR_014612.
FT VARIANT 40 40 E -> K (in hemolytic anemia; Montefiore;
FT dbSNP:rs45562031).
FT /FTId=VAR_000798.
FT VARIANT 45 45 D -> E (in dbSNP:rs34700496).
FT /FTId=VAR_036693.
FT VARIANT 56 56 K -> E (in Di(a)/Memphis-II antigen;
FT dbSNP:rs5036).
FT /FTId=VAR_000799.
FT VARIANT 68 68 E -> K (in dbSNP:rs13306787).
FT /FTId=VAR_039290.
FT VARIANT 72 72 E -> D (in dbSNP:rs13306788).
FT /FTId=VAR_058036.
FT VARIANT 73 73 L -> M.
FT /FTId=VAR_039291.
FT VARIANT 90 90 E -> K (in SPH4; Cape Town;
FT dbSNP:rs28929480).
FT /FTId=VAR_013784.
FT VARIANT 112 112 R -> S (in dbSNP:rs5037).
FT /FTId=VAR_014613.
FT VARIANT 130 130 G -> R (in SPH4; Fukoka).
FT /FTId=VAR_013785.
FT VARIANT 147 147 P -> S (in SPH4; Mondego).
FT /FTId=VAR_013786.
FT VARIANT 285 285 A -> D (in SPH4; Boston).
FT /FTId=VAR_013787.
FT VARIANT 327 327 P -> R (in SPH4; Tuscaloosa;
FT dbSNP:rs28931583).
FT /FTId=VAR_000800.
FT VARIANT 400 408 Missing (in EL4).
FT /FTId=VAR_000801.
FT VARIANT 429 429 E -> D (in NFLD+ antigen).
FT /FTId=VAR_058037.
FT VARIANT 432 432 R -> W (in ELO antigen).
FT /FTId=VAR_013788.
FT VARIANT 442 442 I -> F (in dbSNP:rs5018).
FT /FTId=VAR_014614.
FT VARIANT 455 455 G -> E (in SPH4; Benesov).
FT /FTId=VAR_013789.
FT VARIANT 455 455 G -> R (in SPH4; Yamagata).
FT /FTId=VAR_058038.
FT VARIANT 480 480 E -> K (in FR(a+) antigen).
FT /FTId=VAR_013790.
FT VARIANT 488 488 V -> M (in SPH4; Coimbra; also in AR-
FT dRTA; dbSNP:rs28931584).
FT /FTId=VAR_013791.
FT VARIANT 490 490 R -> C (in SPH4; Bicetre I).
FT /FTId=VAR_013792.
FT VARIANT 490 490 R -> H (in SPH4; Pinhal).
FT /FTId=VAR_058039.
FT VARIANT 508 508 E -> K (in dbSNP:rs45568837).
FT /FTId=VAR_025090.
FT VARIANT 518 518 R -> C (in SPH4; Dresden).
FT /FTId=VAR_000802.
FT VARIANT 548 548 P -> L (in RB(A) antigen).
FT /FTId=VAR_000803.
FT VARIANT 551 551 K -> N (in TR(A) antigen).
FT /FTId=VAR_013793.
FT VARIANT 552 552 T -> I (in WARR antigen).
FT /FTId=VAR_000804.
FT VARIANT 555 555 Y -> H (in VG(a) antigen).
FT /FTId=VAR_013794.
FT VARIANT 557 557 V -> M (in WD(a) antigen).
FT /FTId=VAR_000805.
FT VARIANT 561 561 P -> A (in NFLD+ antigen).
FT /FTId=VAR_058040.
FT VARIANT 561 561 P -> S (in BOW antigen).
FT /FTId=VAR_013795.
FT VARIANT 565 565 G -> A (in WU antigen).
FT /FTId=VAR_013796.
FT VARIANT 566 566 P -> A (in KREP antigen).
FT /FTId=VAR_013797.
FT VARIANT 566 566 P -> S (in PN(a) antigen).
FT /FTId=VAR_013798.
FT VARIANT 569 569 N -> K (in BP(a) antigen).
FT /FTId=VAR_013799.
FT VARIANT 586 586 M -> L (in dbSNP:rs5019).
FT /FTId=VAR_014615.
FT VARIANT 589 589 R -> C (in AD-dRTA; reduced red cell
FT sulfate transport and altered
FT glycosylation of the red cell band 3 N-
FT glycan chain).
FT /FTId=VAR_015104.
FT VARIANT 589 589 R -> H (in AD-dRTA).
FT /FTId=VAR_015105.
FT VARIANT 589 589 R -> S (in AD-dRTA).
FT /FTId=VAR_015106.
FT VARIANT 602 602 R -> P (in dRTA-HA).
FT /FTId=VAR_039292.
FT VARIANT 609 609 G -> R (in AD-dRTA; detected subapically
FT and at the apical membrane as well as at
FT the basolateral membrane in contrast to
FT the normal basolateral appearance of
FT wild-type protein).
FT /FTId=VAR_058041.
FT VARIANT 613 613 S -> F (in AD-dRTA; markedly increased
FT red cell sulfate transport but almost
FT normal red cell iodide transport).
FT /FTId=VAR_015107.
FT VARIANT 646 646 R -> Q (in SW(a+) antigen).
FT /FTId=VAR_013800.
FT VARIANT 646 646 R -> W (in SW(a+) antigen).
FT /FTId=VAR_013801.
FT VARIANT 656 656 R -> C (in HG(a) antigen).
FT /FTId=VAR_013802.
FT VARIANT 656 656 R -> H (in MO(a) antigen).
FT /FTId=VAR_013803.
FT VARIANT 658 658 E -> K (in WR(a) antigen).
FT /FTId=VAR_000806.
FT VARIANT 663 663 M -> K (in SPH4; Tambau).
FT /FTId=VAR_058042.
FT VARIANT 663 663 Missing (in SPH4; Osnabruck II).
FT /FTId=VAR_000807.
FT VARIANT 687 687 L -> P (in SPH4).
FT /FTId=VAR_039293.
FT VARIANT 688 688 I -> V (in dbSNP:rs5022).
FT /FTId=VAR_014616.
FT VARIANT 690 690 S -> G (in dbSNP:rs5023).
FT /FTId=VAR_014617.
FT VARIANT 701 701 G -> D (in dRTA-HA; dbSNP:rs121912748).
FT /FTId=VAR_015171.
FT VARIANT 705 705 D -> Y (in SPH4).
FT /FTId=VAR_039294.
FT VARIANT 707 707 L -> P (in SPH4; Most).
FT /FTId=VAR_013804.
FT VARIANT 714 714 G -> R (in SPH4; Okinawa).
FT /FTId=VAR_013805.
FT VARIANT 731 731 S -> P (in SPH4).
FT /FTId=VAR_039295.
FT VARIANT 734 734 H -> R (in SPH4).
FT /FTId=VAR_039296.
FT VARIANT 760 760 R -> Q (in SPH4; Prague II).
FT /FTId=VAR_013806.
FT VARIANT 760 760 R -> W (in SPH4; Hradec Kralove).
FT /FTId=VAR_013807.
FT VARIANT 771 771 G -> D (in SPH4; Chur).
FT /FTId=VAR_013808.
FT VARIANT 773 773 S -> P (in dRTA-NRC).
FT /FTId=VAR_039297.
FT VARIANT 783 783 I -> N (in SPH4; Napoli II).
FT /FTId=VAR_013809.
FT VARIANT 808 808 R -> C (in SPH4; Jablonec).
FT /FTId=VAR_013810.
FT VARIANT 808 808 R -> H (in SPH4; Nara).
FT /FTId=VAR_013811.
FT VARIANT 832 832 R -> H (in dbSNP:rs5025).
FT /FTId=VAR_014618.
FT VARIANT 834 834 H -> P (in SPH4; Birmingham).
FT /FTId=VAR_013812.
FT VARIANT 837 837 T -> A (in SPH4; Tokyo).
FT /FTId=VAR_013813.
FT VARIANT 837 837 T -> M (in SPH4; Philadelphia).
FT /FTId=VAR_013814.
FT VARIANT 837 837 T -> R (in SPH4; Nagoya).
FT /FTId=VAR_058043.
FT VARIANT 850 850 Missing (in dRTA-HA).
FT /FTId=VAR_015109.
FT VARIANT 854 854 P -> L (in Di(a)/Memphis-II antigen;
FT dbSNP:rs2285644).
FT /FTId=VAR_000808.
FT VARIANT 858 858 A -> D (in AD-dRTA).
FT /FTId=VAR_015108.
FT VARIANT 862 862 V -> I (in dbSNP:rs5026).
FT /FTId=VAR_014619.
FT VARIANT 868 868 P -> L (in acanthocytosis; due to band 3
FT high transport).
FT /FTId=VAR_013815.
FT VARIANT 870 870 R -> W (in SPH4; Prague III;
FT dbSNP:rs28931585).
FT /FTId=VAR_013816.
FT CONFLICT 11 11 M -> D (in Ref. 9; AA sequence).
FT CONFLICT 68 68 E -> EE (in Ref. 9; AA sequence).
FT CONFLICT 759 759 Q -> H (in Ref. 3; ABD74692).
FT STRAND 9 12
FT STRAND 58 67
FT TURN 68 70
FT STRAND 73 88
FT HELIX 104 115
FT STRAND 118 123
FT HELIX 128 141
FT HELIX 147 149
FT HELIX 150 157
FT HELIX 164 170
FT STRAND 173 175
FT HELIX 195 200
FT HELIX 212 219
FT STRAND 226 234
FT STRAND 241 251
FT STRAND 256 258
FT STRAND 262 270
FT HELIX 278 289
FT HELIX 292 300
FT HELIX 304 316
FT STRAND 319 321
FT HELIX 328 333
FT HELIX 335 346
FT TURN 392 394
FT HELIX 395 399
FT HELIX 409 422
FT HELIX 437 453
FT TURN 806 809
FT HELIX 829 833
SQ SEQUENCE 911 AA; 101792 MW; 35EC3EE7AFF27D2F CRC64;
MEELQDDYED MMEENLEQEE YEDPDIPESQ MEEPAAHDTE ATATDYHTTS HPGTHKVYVE
LQELVMDEKN QELRWMEAAR WVQLEENLGE NGAWGRPHLS HLTFWSLLEL RRVFTKGTVL
LDLQETSLAG VANQLLDRFI FEDQIRPQDR EELLRALLLK HSHAGELEAL GGVKPAVLTR
SGDPSQPLLP QHSSLETQLF CEQGDGGTEG HSPSGILEKI PPDSEATLVL VGRADFLEQP
VLGFVRLQEA AELEAVELPV PIRFLFVLLG PEAPHIDYTQ LGRAAATLMS ERVFRIDAYM
AQSRGELLHS LEGFLDCSLV LPPTDAPSEQ ALLSLVPVQR ELLRRRYQSS PAKPDSSFYK
GLDLNGGPDD PLQQTGQLFG GLVRDIRRRY PYYLSDITDA FSPQVLAAVI FIYFAALSPA
ITFGGLLGEK TRNQMGVSEL LISTAVQGIL FALLGAQPLL VVGFSGPLLV FEEAFFSFCE
TNGLEYIVGR VWIGFWLILL VVLVVAFEGS FLVRFISRYT QEIFSFLISL IFIYETFSKL
IKIFQDHPLQ KTYNYNVLMV PKPQGPLPNT ALLSLVLMAG TFFFAMMLRK FKNSSYFPGK
LRRVIGDFGV PISILIMVLV DFFIQDTYTQ KLSVPDGFKV SNSSARGWVI HPLGLRSEFP
IWMMFASALP ALLVFILIFL ESQITTLIVS KPERKMVKGS GFHLDLLLVV GMGGVAALFG
MPWLSATTVR SVTHANALTV MGKASTPGAA AQIQEVKEQR ISGLLVAVLV GLSILMEPIL
SRIPLAVLFG IFLYMGVTSL SGIQLFDRIL LLFKPPKYHP DVPYVKRVKT WRMHLFTGIQ
IICLAVLWVV KSTPASLALP FVLILTVPLR RVLLPLIFRN VELQCLDADD AKATFDEEEG
RDEYDEVAMP V
//

MIM 109270
*RECORD*
*FIELD* NO
109270
*FIELD* TI
+109270 SOLUTE CARRIER FAMILY 4 (ANION EXCHANGER), MEMBER 1; SLC4A1
;;BAND 3 OF RED CELL MEMBRANE; BND3;;
read moreERYTHROCYTE MEMBRANE PROTEIN BAND 3; EMPB3;;
ERYTHROID PROTEIN BAND 3; EPB3;;
ANION EXCHANGE PROTEIN 1; AE1
ACANTHOCYTOSIS, ONE FORM OF, INCLUDED;;
OVALOCYTOSIS, MALAYSIAN-MELANESIAN-FILIPINO TYPE, INCLUDED;;
OVALOCYTOSIS, SOUTHEAST ASIAN, INCLUDED; SAO, INCLUDED;;
ELLIPTOCYTOSIS 4, INCLUDED; EL4, INCLUDED;;
ELLIPTOCYTOSIS, STOMATOCYTIC HEREDITARY, INCLUDED;;
HE, STOMATOCYTIC, INCLUDED
*FIELD* TX

DESCRIPTION

Band 3 is the major glycoprotein of the erythrocyte membrane. It
mediates exchange of chloride and bicarbonate across the phospholipid
bilayer and plays a central role in respiration of carbon dioxide. It is
a 93,000-Da protein composed of 2 distinct domains that function
independently. The 50,000-Da C-terminal polypeptide codes for the
transmembrane domain that is involved in anion transport. The 43,000-Da
cytoplasmic domain anchors the membrane cytoskeleton to the membrane
through an ankyrin-binding site (band 2.1) and also contains binding
sites for hemoglobin and several glycolytic enzymes. Proteins related to
red cell band 3 have been identified in several types of nucleated
somatic cells (reviewed by Palumbo et al., 1986).

CLONING

Lux et al. (1989) cloned human band 3 from a fetal liver cDNA library.
The deduced 911-amino acid protein is similar in structure to other
anion exchangers and is divided into 3 regions: a hydrophobic,
cytoplasmic domain that interacts with a variety of membrane and
cytoplasmic proteins (residues 1-403); a hydrophobic, transmembrane
domain that forms the anion antiporter (residues 404-882); and an
acidic, C-terminal domain (residues 883-911). Lux et al. (1989)
presented a model in which the protein crosses the membrane 14 times.

GENE FUNCTION

Langdon and Holman (1988) concluded that band 3 constitutes the major
glucose transporter of human erythrocytes. A monoclonal antibody to band
3 specifically removed band 3 and more than 90% of the reconstitutable
glucose transport activity from extracts of erythrocyte membranes;
nonimmune serum removed neither. Band 3 is probably a multifunctional
transport protein responsible for transport of glucose, anions, and
water.

Senescent cell antigen (SCA), an aging antigen, is a protein that
appears on old cells and marks them for removal by the immune system.
The aging antigen is generated by the degradation of protein band 3.
Besides its role in the removal of senescent and damaged cells, SCA also
appears to be involved in the removal of erythrocytes in hemolytic
anemias and the removal of malaria-infected erythrocytes. Band 3 is
found in diverse cell types and tissues besides erythrocytes, including
hepatocytes, squamous epithelial cells, lung alveolar cells,
lymphocytes, kidney, neurons, and fibroblasts. It is also present in
nuclear, Golgi, and mitochondrial membranes. Kay et al. (1990) used
synthetic peptides to identify antigenic sites on band 3 recognized by
the IgG that binds to old cells.

Tanner (1993) discussed the molecular and cellular biology of the
erythrocyte anion exchanger, band 3. It permits the high rate of
exchange of chloride ion by bicarbonate ion across the red cell
membrane: the efflux of bicarbonate from the cell in exchange for plasma
chloride ion in the capillaries of the tissues (the Hamburger shift, or
chloride ion shift) and the reverse process in lung capillaries. At
least 2 nonerythroid anion exchange genes have been characterized, AE2
(109280) and AE3 (106195), and tentative evidence for a fourth member of
the class, AE4 (SLC4A9; 610207), was mentioned. The ability of AE2 and
AE3 to mediate anion transport has been confirmed. As outlined by Tanner
(1993), it is not strictly accurate to refer to the AE1 gene as being
that for the erythroid anion exchanger because the AE1 gene is expressed
in some nonerythroid tissues, where it appears to be transcribed from
different tissue-specific promoters.

Watts et al. (1996) determined that both ZAP70 (176947) and LCK (153390)
can phosphorylate the cytoplasmic fragment of BND3. However, these 2
protein tyrosine kinases act on different sites of the BND3 protein.

Pawloski et al. (2001) demonstrated that in human erythrocytes
hemoglobin-derived S-nitrosothiol (SNO), generated from imported nitric
acid (NO), is associated predominantly with the red blood cell membrane,
and principally with cysteine residues in the hemoglobin-binding
cytoplasmic domain of the anion exchanger AE1. Interaction with AE1
promotes the deoxygenated structure in SNO-hemoglobin, which subserves
NO group transfer to the membrane. Furthermore, Pawloski et al. (2001)
showed that vasodilatory activity is released from this membrane
precinct by deoxygenation. Thus, the oxygen-regulated cellular mechanism
that couples the synthesis and export of hemoglobin-derived NO
bioactivity operates, at least in part, through formation of AE1-SNO at
the membrane-cytosol interface.

Goel et al. (2003) identified a sialic acid-independent host-parasite
interaction involved in the Plasmodium falciparum malaria parasite
invasion of red blood cells. They showed that 2 nonglycosylated
extracellular regions of band 3 function as a crucial host receptor.
They identified 2 processing products of merozoite surface protein-1
(MSP1) as major parasite ligands binding to the band 3 receptor.

Bruce et al. (2004) studied the properties of band 3 in red cells
lacking glycophorin A (GPA; 111340) and found that sulfate, iodide, and
chloride transport were reduced. Increased flexibility of the membrane
domain of band 3 was associated with reduced anion transport activity.
Bruce et al. (2004) suggested that band 3 in the red cell can take up 2
different structures: one with high anion transport activity when GPA is
present and one with lower anion transport activity when GPA is absent.

GENE STRUCTURE

Schofield et al. (1994) demonstrated that the EPB3 gene extends over 18
kb and consists of 20 exons. The cDNA sequence comprises 4,906
nucleotides, excluding the poly(A) tail. They found extensive similarity
between the human and mouse genes, although the latter covers 17 kb. The
additional length of the human gene is mainly caused by the presence of
6 Alu repetitive units in the human gene between intron 13 and exon 20.
Two potential promoter regions are positioned so that they could give
rise to the different transcripts found in erythroid cells and in the
kidney. The kidney transcript would lack exons 1 through 3 of the
erythroid transcript. The translation initiator downstream to the human
kidney promoter would give rise to a protein with a 20-amino acid
section at the N-terminus that is not present in the erythroid protein.
Sahr et al. (1994) concluded that the AE1 gene spans approximately 20 kb
and consists of 20 exons separated by 19 introns. Its structure showed
close similarity to that of the mouse AE1 gene. Sahr et al. (1994)
described the upstream and internal promoter sequences of the human AE1
gene used in erythroid and kidney cells, respectively.

MAPPING

Showe et al. (1987) localized the gene for BND3 to 17q21-qter by
Southern blot analysis of DNA from somatic cell hybrids.

Lux et al. (1989) confirmed assignment of the BND3 gene to chromosome
17.

According to HGM10, EPB3 is in the same large restriction fragment as
RNU2 (180690), which narrows the localization to 17q21-q22. Using RFLPs
of both loci, Stewart et al. (1989) showed that EPB3 is closely linked
to NGFR (162010) (maximum lod = 11.40 at theta = 0.00, with a confidence
limit of 0.00 to 0.04).

MOLECULAR GENETICS

Mueller and Morrison (1977) and Hsu and Morrison (1985) reported variant
forms of band 3 with an elongated N terminus. Both variants are
hematologically normal with normal red cell morphologic features; the
red cells do not appear to be resistant to invasion by malaria parasites
in vitro (Ranney et al., 1990; Schulman et al., 1990).

Palatnik et al. (1990) described 3 phenotypes based on the polymorphism
of band-3 protein from human red cells. Limited proteolysis of intact
red cells from most individuals (homozygotes) yields a peptide of 60 kD,
but in some persons (heterozygotes), there is also a 63-kD peptide, and
rarely only the single peptide of 63 kD is found. This was the first
description of the 63-kD homozygote. The frequency of the p63 allele was
estimated to be 0.041 +/- 0.0068 in Caucasoids and 0.125 +/- 0.0121 in
Negroids.

- Acanthocytosis

Kay et al. (1987, 1988) reported 2 sibs with acanthocytosis whose red
cells showed markedly increased anion transport activity. The sibs were
clinically normal, the abnormality having been detected through the
acanthocytosis found on blood studies for unrelated reasons. Kay et al.
(1987, 1988) concluded that the 'disorder' was recessive. Bruce et al.
(1993) studied the red cells of one of the sibs reported by Kay et al.
(1988) and identified band 3 HT (109270.0032).

- Ovalocytosis/Elliptocytosis

Elliptocytosis (or ovalocytosis, as it is called by some) occurs in
polymorphic frequency in aborigines of Malaysia and Melanesia. Lie-Injo
(1965) first pointed out the high frequency in studies of Malaysian
Orang Asli. Lie-Injo et al. (1972), Ganesan et al. (1975), and Baer et
al. (1976) extended the observations in Malaysia, where frequencies as
high as 39% were found. Ganesan et al. (1975) reported an
extraordinarily high frequency of 'ovalocytosis' among the Land Dayaks
(12.7%) and Sea Dayaks (9.0%), the indigenous people of Sarawak. Amato
and Booth (1977), Booth et al. (1977) and Holt et al. (1981) identified
another focus of high frequency of elliptocytosis in Melanesia (Papua
New Guinea, Sarawak) where the phenotype was thought to be recessive.
The morphologic change in the red cells was apparently responsible for a
previously described depression of blood group antigens (Booth, 1972),
e.g., Gerbich blood group (110750), which was also thought to be
recessively inherited. Red cells in this condition are ovalocytes, which
are often macrocytic; some, called stomatocytes, have a longitudinal
slit in the middle. Indeed, stomatocytic hereditary elliptocytosis, or
stomatocytic HE, is a synonym.

Fix et al. (1982) reported the findings in studies of Malaysian Orang
Asli families and concluded that inheritance is autosomal dominant. They
quoted Kidson et al. (1981) as stating that 'in 3 of 4 families
involving the marriage of a Melanesian ovalocytic and a Caucasian
normocytic person, we have found ovalocytic children.' Kidson et al.
(1981) found that ovalocytic erythrocytes from Melanesians are resistant
to invasion by malaria parasites, thus providing a plausible explanation
for the polymorphism (also see Serjeantson et al., 1977). This may be a
mutation of a structural protein of the red cell that endows the bearer
with a selective advantage. Baer (1988) suggested that Malaysian
elliptocytosis may be a balanced polymorphism, i.e., that individuals
homozygous for the elliptocytosis allele, not clearly identifiable by
any assay, may be differentially susceptible to mortality, whereas the
heterozygote is at an advantage. See 110750 for evidence that this form
of elliptocytosis is indeed caused by a selective advantage of
heterozygotes (vis-a-vis falciparum malaria). Hadley et al. (1983)
showed that Melanesian elliptocytes are highly resistant to invasion by
Plasmodium knowlesi and P. falciparum in vitro. This is the only human
red cell variant known to be resistant to both.

Liu et al. (1990) found a structurally and functionally abnormal band 3
protein in Southeast Asian ovalocytosis. The abnormal protein binds
tightly to ankyrin, thus leading to increased rigidity of the red cells,
and in some way is responsible for the resistance of the red cells to
invasion by malaria parasites. Linkage studies in 14 families showed a
lod score of 7.0 for linkage between the molecular defect in the band 3
protein and ovalocytosis. One of the patients they studied was Filipino.

Jones et al. (1990) concluded that the markedly increased
phosphorylation of band 3 protein in whole red cells or isolated ghosts
from ovalocytic individuals might be explained by the following
findings. The cytoplasmic domain of the ovalocyte band 3 was found to be
approximately 3 kD larger than the normocytic protein. The N-terminal
sequence of the ovalocytic band 3 was different from the reported
sequence, suggesting that the increased size resulted from an N-terminal
extension. This is the region of band 3 that is phosphorylated and
interacts with the red cell cytoskeleton. Liu et al. (1994) suggested
that the homozygous state for the BND3 mutation in Southeast Asian
ovalocytosis (109270.0002) may be lethal. In a group of 6 families in
which both parents were heterozygous for the SAO and band 3-Memphis
mutations, there were 35 offspring; 12 of these were available for
testing and 10 were found to be heterozygous for the 2 mutations,
whereas the other 2 did not carry either. Specifically, none was
homozygous for the SAO band 3 mutation. They suggested that there was an
increased frequency of miscarriages in these families.

Coetzer et al. (1996) described a 4-generation South African kindred
with dominantly inherited ovalocytosis and hemolytic anemia. All
affected subjects exhibited varying degrees of hemolytic anemia.
Additionally, there was evidence for independent segregation of the band
3 Memphis I polymorphism (109270.0001) and the 27-bp deletion in BND3,
which constitutes the Southeast Asian ovalocytosis (SAO) mutation
(109270.0002). Six SAO subjects and all 3 normal family members were
heterozygous for the band 3 Memphis I polymorphism and one SAO subject
was homozygous for this mutation.

- Spherocytosis Type 4

In a 28-year-old female with congenital spherocytic hemolytic anemia
(SPH4; 612653), Jarolim et al. (1991) identified a missense mutation in
the SLC4A1 gene (109270.0003).

Bruce et al. (2005) identified 11 human pedigrees with dominantly
inherited hemolytic anemias in both the hereditary stomatocytosis and
spherocytosis classes. Affected individuals in these families had an
increase in membrane permeability to sodium and potassium ion that was
particularly marked at zero degree centigrade. They found that disease
in these pedigrees was associated with a series of single amino acid
substitutions in the intramembrane domain of the band 3 anion exchanger,
AE1. Anion movements were reduced in the abnormal red cells. The 'leak'
cation fluxes were inhibited by chemically diverse inhibitors of band 3.
Expression of the mutated genes in Xenopus laevis oocytes induced
abnormal NA and K fluxes in the oocytes, and the induced chloride
transport was low. These data were considered consistent with the
suggestion that the substitutions convert the protein from an anion
exchanger into an unregulated cation channel. Only 1 of the gene
changes, R760Q (109270.0028), had previously been reported. All the
mutations were in exon 17 of the SLC4A1 gene.

- Choreoacanthocytosis

Tanner (1993) reviewed the evidence that mutations in the AE1 gene can
cause choreoacanthocytosis (200150; see Kay, 1991). Kay et al. (1989)
reported a band 3 alteration in association with anemia as determined by
a reticulocyte count of 20%. The erythrocyte defect was reflected in
increased IgG binding, increased breakdown products of band 3, and
altered anion- and glucose-transport activity in middle-aged cells. IgG
eluted from the red cells of the propositus appeared to have a
specificity for senescent cell antigen. This and other studies suggested
that band 3 was aging prematurely in erythrocytes of the subject, and
that the senescent cell antigen appeared on the middle-aged red cells.
Two sibs were affected. Both parents were thought to show 'subtle band 3
changes.' Autosomal recessive inheritance was postulated.

- Distal Renal Tubular Acidosis, Autosomal Dominant

Bruce et al. (1997) found that all affected members of 4 families with
autosomal dominant familial renal tubular acidosis (RTA; 179800) were
heterozygous for mutations in the SLC4A1 gene; these mutations were not
found in any of the 9 normal family members studied. In 2 families the
mutation was arg589 to his (109270.0012); arg589-to-cys (109270.0013)
and ser613-to-phe (109270.0014) changes were found in the other
families. Linkage studies confirmed the cosegregation of the disease
with a genetic marker close to SLC4A1. Affected individuals with the
mutations in arg589 had reduced red cell sulfate transport and altered
glycosylation of the red cell band 3 N-glycan chain. The red cells of
individuals with the ser613-to-phe mutation had markedly increased red
cell sulfate transport but almost normal red cell iodide transport. The
erythroid and kidney isoforms of the mutant band 3 protein were
expressed in Xenopus oocytes and all showed significant chloride
transport activity. Bruce et al. (1997) concluded that dominantly
inherited RTA is associated with mutations in band 3; however, both the
disease and its autosomal dominant inheritance are not related simply to
the anion transport activity of the mutant proteins. Arg589 is located
in the cytoplasmic loop between transmembrane segments 6 and 7 of band
3. This arginine is conserved in all known vertebrate sequences of AE1,
AE2, and AE3, suggesting that it is functionally important. Arg589 is
located in a cluster of basic residues which may form part of the
cytoplasmic anion binding site of band 3. The mechanism by which the
S613F mutation increases the affinity of the protein for sulfate was not
clear. One possibility was that the mutation, which is located near the
center of membrane span 7 and results in a substitution of serine by a
bulky phenylalanine residue, altered the orientation of membrane span 7
relative to span 6. This may distort the conformation of the cytoplasmic
loop between spans 6 and 7 which contains the putative anion binding
site so that the clustered basic residues bind sulfate more tightly than
the wildtype protein.

Bruce et al. (1997) were prompted to undertake this study because of a
possible association between dominant RTA and hereditary ovalocytosis
(Baehner et al., 1968). Mutations in the families with dominant RTA were
different from those affecting band 3 in Southeast Asian ovalocytosis.
Complete absence of band 3 was found by Inaba et al. (1996) to result in
defective renal acid secretion in cattle.

Most of the patients in the 4 families studied by Bruce et al. (1997)
presented clinically with renal stones, and the majority had
nephrocalcinosis. One patient in a family with the arg589-to-his
mutation had rickets when initially seen at age 10 years and developed
osteomalacia at the age of 31 after she stopped taking alkali therapy,
but no other patient had bone disease. Eight patients were not acidotic
when first seen, and were diagnosed as 'incomplete' dominant RTA because
they were unable to excrete a urine more acid than pH 5.3 after oral
acute ammonium chloride challenge. Compared with acidotic cases, these
patients tended to be younger, with lower plasma creatinines, better
preservation of urinary concentrating ability, and less (or no)
nephrocalcinosis; over a 10-year period, 2 of the patients spontaneously
developed acidosis. Acidotic patients were treated with oral alkalis,
usually 6 gm of sodium bicarbonate daily, and had normal acid-base
status at the time of the study; nonacidotic patients were not treated.

Karet et al. (1998) screened 26 kindreds with primary distal renal
tubular acidosis (dRTA; 179800) for mutations in the AE1 gene.
Inheritance was autosomal recessive in 17, autosomal dominant in 1, and
uncertain due to unknown parental phenotype or sporadic disease in 8. No
mutations in AE1 were detected in any of the autosomal recessive
kindreds, and analysis of linkage showed no evidence of linkage of
recessive distal RTA to AE1. In contrast, heterozygous mutations in AE1
were identified in the 1 known dominant distal RTA kindred, in 1
sporadic case, and in 1 kindred with 2 affected brothers. In the
dominant kindred, an arg589-to-ser mutation (109270.0015) cosegregated
with distal RTA in the extended pedigree. In the sporadic case, an
arg589-to-his mutation (109270.0012) proved to be a de novo change. In
the third kindred, both affected brothers had an intragenic 13-bp
duplication resulting in deletion of the last 11 amino acids of AE1
(band 3 Walton; 109270.0025). Parental consanguinity was identified in
14 of the 17 recessive pedigrees. In the recessive kindreds, 19 of 25
patients were diagnosed at 1 year of age or less, and the remainder
presented at 6 years or younger. All index cases presented either
acutely with vomiting and dehydration, or with failure to thrive or
delayed growth. Younger affected sibs were often diagnosed
prospectively. All patients with the recessive disease were found to
have nephrocalcinosis, nephrolithiasis, or both, and several had
rickets. Nine of these patients from 6 families also had bilateral
sensorineural deafness confirmed by audiometry; see renal tubular
acidosis with progressive nerve deafness (267300). In contrast, in the 1
dominant kindred (with the arg589-to-ser mutation), 2 propositae were
diagnosed because of nephrolithiasis at ages 56 and 36 years.
Prospective screening identified other affected family members who were
all asymptomatic, and most were diagnosed in adulthood. None of the 6
affected members of this family had radiologic evidence of
nephrocalcinosis.

The chloride-bicarbonate exchanger AE1, which is mutant in autosomal
dominant distal renal tubular acidosis, is normally expressed at the
basolateral surface of alpha-intercalated cells in the distal nephron.
Devonald et al. (2003) demonstrated that AE1 is aberrantly targeted to
the apical surface in this disorder, in contrast with many disorders
where mutant membrane proteins are retained intracellularly and
degraded.

- Distal Renal Tubular Acidosis with Hemolytic Anemia

Tanphaichitr et al. (1998) described novel AE1 mutations in a Thai
family with a recessive syndrome of dRTA and hemolytic anemia in which
red cell anion transport was normal (611590). A brother and sister were
triply homozygous for 2 benign mutations, M31T and K56E (109270.0001),
and for a loss-of-function mutation, G701D (109270.0016). The AE1 G701D
loss-of-function mutation was accompanied by impaired trafficking to the
Xenopus oocyte surface. Coexpression of the erythroid AE1 chaperonin,
glycophorin A, along with the AE1 G701D mutation, rescued both
AE1-mediated chloride ion transport and AE1 surface expression in
oocytes. The genetic and functional data suggested that the homozygous
AE1 G701D mutation causes recessively transmitted dRTA in this kindred
with apparently normal erythroid anion transport.

Bruce et al. (2000) studied 3 Malaysian and 6 Papua New Guinean families
with dRTA and Southeast Asian ovalocytosis (SAO). The SAO deletion
mutation (109270.0002) occurred in many of the families but did not
itself result in distal renal tubular acidosis. Compound heterozygotes
of each of the 3 dRTA mutations (G701D, 109270.0016; A858D, 109270.0020;
delV850 109270.0021) with SAO all had dRTA, evidence of hemolytic
anemia, and abnormal red cell properties. The A858D mutation showed
dominant inheritance and the recessive delV850 and G701D mutations
showed a pseudodominant phenotype when the transport-inactive SAO allele
was also present. Red cell and Xenopus oocyte expression studies showed
that the delV850 and A858D mutant proteins had greatly decreased anion
transport when present as compound heterozygotes with each other or with
SAO. Red cells with A858D/SAO had only 3% of the sulfite ion efflux of
normal cells, the lowest anion transport activity reported for human red
cells to that time. Bruce et al. (2000) confirmed that the G701D mutant
protein has an absolute requirement for glycophorin A for movement to
the cell surface.

Sritippayawan et al. (2004) reported 2 Thai families with recessive dRTA
due to different compound heterozygous mutations of the SLC4A1 gene. In
the first family, the patient with dRTA had compound heterozygous
G701D/S773P (109270.0026) mutations. In the second family, the patient
and his sister had dRTA and SAO, and were compound heterozygotes for the
SAO deletion mutation and an R602H mutation (109270.0027). Sritippayawan
et al. (2004) noted that the second patient had a severe form of dRTA
whereas his sister had only mild metabolic acidosis, indicating that
other modifying factors or genes might play a role in governing the
severity of the disease.

Kittanakom et al. (2004) transiently transfected human embryonic kidney
HEK293 cells with the renal isoform of SLC4A1 containing the S773P
mutation, alone or in combination with wildtype SLC4A1 or with the G701D
mutant. The S773P mutant was expressed at a 3-fold lower level than
wildtype, had a 2-fold decrease in its half-life, and was targeted for
degradation by the proteasome. Both S773P and G701D exhibited defective
trafficking to the plasma membrane, providing an explanation for the
dysfunction found in dRTA.

- Blood Groups

Diego blood group (110500) Di(a) is a low-incidence blood group antigen
in Caucasians that is antithetical to Di(b). Prevalence of Di(a) is much
higher in American Indians, reaching up to 54% in some groups of South
American Indians. Bruce et al. (1994) demonstrated that the Diego blood
group polymorphism is the result of a single amino acid substitution at
position 854 of the AE1 molecule, with proline of the wildtype band 3
corresponding to the Di(b) antigen and leucine to the Di(a) antigen.
Subsequently, Bruce et al. (1995) mapped the low-incidence blood group
antigen Wr(a) (109270.0011) to the C-terminal end of the fourth
ectoplasmic loop and defined a single amino acid substitution in Wr(b)
(109270.0006). Jarolim et al. (1998) studied the molecular basis of 7
low-incidence blood group antigens that likewise are due to variation in
AE1.

McManus et al. (2000) demonstrated that the Froese blood group
polymorphism (601551) is the result of change in the SLC4A1 gene
(109270.0029).

Zelinski et al. (2000) demonstrated that the Swann blood group (601550)
is due to molecular changes in the SLC4A1 gene (109270.0030).

ANIMAL MODEL

Inaba et al. (1996) studied a moderately uncompensated bovine anemia
associated with spherocytosis inherited in an autosomal incompletely
dominant mode and retarded growth. Using biochemical methods they showed
that the bovine red cells lacked the band 3 protein completely. Sequence
analysis of EPB3 cDNA and genomic DNA showed a C-to-T transition
resulting in a missense mutation: CGA-to-TGA; arg646-to-ter. The
location of the mutation was at the position corresponding to codon 646
in human EPB3 cDNA. The animal red cells were deficient in spectrin,
ankyrin, actin (see 102630), and protein 4.2 (177070), resulting in a
distorted and disrupted membrane skeletal network with decreased
density. Therefore, the animal's red cell membranes were extremely
unstable and showed the loss of surface area in several distinct ways
such as invagination, vesiculation, and extrusion of microvesicles,
leading to the formation of spherocytes. Inaba et al. (1996) also found
that total deficiency of bovine band 3 also resulted in defective
chloride/bicarbonate exchange, causing mild acidosis with decreases in
bicarbonate concentration and total CO(2) in the animal's blood. The
results demonstrated to the authors that bovine band 3 contributes to
red cell membrane stability, CO(2) transport, and acid-base homeostasis,
but is not always essential to the survival of this mammal.

Erythroid band 3 (AE1) is one of 3 anion exchanges that are encoded by
separate genes. The AE1 gene is transcribed by 2 promoters: the upstream
promoter is used for erythroid band 3, whereas the downstream promoter
initiates transcription of the band 3 isoform in kidney. To assess the
biologic consequences of band 3 deficiency, Southgate et al. (1996)
selectively inactivated erythroid but not kidney band 3 by gene
targeting in mice. Although no death in utero occurred, most homozygous
mice died within 2 weeks after birth. The erythroid band 3-null mice
showed retarded growth, spherocytic red blood cell morphology, and
severe hemolytic anemia. Remarkably, the band 3 -/- red blood cells
assembled normal membrane skeleton, thus challenging the notion that the
presence of band 3 is required for stable biogenesis of the membrane
skeleton. Similarly, Peters et al. (1996) used targeted mutagenesis in
the mouse to assess AE1 function in vivo. RBCs lacking AE1 spontaneously
shed membrane vesicles and tubules, leading to severe spherocytosis and
hemolysis, but the levels of the major skeleton components, the
synthesis of spectrin in mutant erythroblasts, and skeletal architecture
were normal or nearly normal. Their results indicated that AE1 does not
regulate RBC membrane skeleton assembly in vivo but is essential for
membrane stability. Peters et al. (1996) postulated that stabilization
is achieved through AE1-lipid interactions and that loss of these
interactions is a key pathogenic event in hereditary spherocytosis. Jay
(1996) reviewed the role of band 3 in red cell homeostasis and cell
shape.

Paw et al. (2003) characterized a zebrafish mutant called retsina (ret)
that exhibits an erythroid-specific defect in cell division with marked
dyserythropoiesis similar to human congenital dyserythropoietic anemia
(see 224100). Erythroblasts from ret fish show binuclearity and undergo
apoptosis due to a failure in the completion of chromosome segregation
and cytokinesis. Through positional cloning, Paw et al. (2003)
demonstrated that the ret mutation is in the Slc4a1 gene, encoding the
anion exchanger-1 (also called band 3 and AE1), an erythroid-specific
cytoskeletal protein. They further showed an association between
deficiency in Slc4a1 and mitotic defects in the mouse. Rescue
experiments in ret zebrafish embryos expressing transgenic Slc4a1 with a
variety of mutations showed that the requirement for band 3 in normal
erythroid mitosis is mediated through its protein 4.1R-binding domains.
Paw et al. (2003) concluded that their report established an
evolutionarily conserved role for band 3 in erythroid-specific cell
division and illustrated the concept of cell-specific adaptation for
mitosis.

*FIELD* AV
.0001
BAND 3 MEMPHIS
SLC4A1, LYS56GLU

In addition to the variants of band 3 leading to abnormalities of
erythrocyte shape (Liu et al., 1990), Mueller and Morrison (1977)
identified a polymorphism tentatively described as an elongation of the
cytoplasmic domain, whose structure was still to be defined. Ranney et
al. (1990) found a silent band 3 polymorphism, called band 3 Memphis, in
all human populations with a frequency varying from one population to
another. Yannoukakos et al. (1991) demonstrated that this
electrophoretic variant is due to substitution of glutamic acid for
lysine at position 56. An A-to-G substitution in the first base of codon
56 is responsible for the change.

Ideguchi et al. (1992) showed that the prevalence of the Memphis variant
is particularly high in Japanese; the calculated gene frequency was
0.156, about 4 times higher than in Caucasians. They found that the
transport rate of phosphoenolpyruvate in erythrocytes of homozygotes was
decreased to about 80% of that in control cells and the rate in
heterozygotes was at an intermediate level. They interpreted this as
indicating that some structural changes in the cytoplasmic domain of
band 3 influence the conformation of the anion transport system. The
band 3 Memphis variant is characterized by a reduced mobility of
proteolytic fragments derived from the N-terminus of the cytoplasmic
domain of band 3 (cdb3).

Jarolim et al. (1992) found the AAG-to-GAG transition at codon 56
resulting in the lys56-to-glu substitution in all of 12 heterozygotes
including 1 white, 1 black, 1 Chinese, 1 Filipino, 1 Malay, and 7
Melanesian subjects. Since most of the previously cloned mouse, rat, and
chicken band 3 and band 3-related proteins contain glutamic acid in the
position corresponding to amino acid 56 in the human band 3, Jarolim et
al. (1992) proposed that the Memphis variant is the evolutionarily older
form of band 3.

The Memphis polymorphism is also referred to as dbSNP rs5036. Wilder et
al. (2009) found that all 4 Indonesian chromosomes with the 27-bp
deletion (109270.0002) also carried the Memphis polymorphism, suggesting
that it is a target of recent natural seletion.

.0002
OVALOCYTOSIS, SOUTHEAST ASIAN
MALARIA, CEREBRAL, RESISTANCE TO
SLC4A1, 27-BP DEL, CODONS 400-408

Following up on the demonstration by Liu et al. (1990) that a
structurally and functionally abnormal band 3 protein shows absolute
linkage with the SAO phenotype, Jarolim et al. (1991) demonstrated that
the EPB3 gene in these cases contains a 27-bp deletion, resulting in
deletion of 9 amino acids (codons 400-408) in the boundary of
cytoplasmic and membrane domains of the band 3 protein. The defect was
detected in all 30 ovalocytic subjects from Malaysia, the Philippines,
and 2 unrelated coastal regions of Papua New Guinea, whereas it was
absent in all 30 controls from Southeast Asia and 20 subjects of
different ethnic origin from the United States. The lys56-to-glu
mutation (109270.0001) was also found in all SAO subjects; however, it
was detected in 5 of 50 control subjects as well, suggesting that it
represents a linked polymorphism.

Mohandas et al. (1992) likewise demonstrated the deletion of amino acids
400-408 in the boundary between the cytoplasmic and the first
transmembrane domains of band 3. The biophysical consequences of the
mutation was a marked decrease in lateral mobility of band 3 and an
increase in membrane rigidity. Mohandas et al. (1992) suggested that the
mutation induces a conformational change in the cytoplasmic domain of
band 3, leading to its entanglement in the skeletal protein network.
This entanglement inhibits the normal unwinding and stretching of the
spectrin tetramers necessary for membrane extension, leading to
increased rigidity.

The same deletion of 9 amino acids was found by Tanner et al. (1991) in
a Mauritian Indian and by Ravindranath et al. (1994) in an African
American mother and daughter. All cases of SAO had been associated with
the Memphis-1 polymorphism (109270.0001), which is found in all
populations but is present at higher frequency in American Indian and
African American populations. However, SAO had not previously been
identified in African Americans.

The band 3 variant in southeast Asian ovalocytosis may prevent cerebral
malaria (611162), but it exacerbates malarial anemia and may also
increase acidosis, a major determinant of mortality in malaria. Allen et
al. (1999) undertook a case-control study of children admitted to
hospital in a malarious area of Papua New Guinea. The 24-bp deletion,
detected by PCR, was present in 0 of 68 children with cerebral malaria,
compared with 6 (8.8%) of 68 matched community controls. Median
hemoglobin levels were 1.2 g/dl lower in malaria cases with southeast
Asian ovalocytosis than in controls (P = 0.035), but acidosis was not
affected. The band 3 protein mediates the cytoadherence of parasitized
erythrocytes in vitro. The remarkable protection that the SAO variant
affords against cerebral malaria may offer a valuable approach to a
better understanding of the mechanisms of adherence of parasitized
erythrocytes to vascular endothelium and the pathogenesis of cerebral
malaria.

The abnormal SAO protein does not mediate chloride transport (Groves et
al., 1993), and homozygosity for the 9-amino acid deletion is apparently
lethal (Liu et al., 1994).

Yusoff et al. (2003) examined the incidence of SAO in Malays in
Kelantan, Malaysia, who had distal renal tubular acidosis (179800). SAO
was identified in 18 of the 22 distal renal tubular acidosis patients
(81.8%), but in only 2 of the 50 controls (4%). Yusoff et al. (2003)
referred to the band 3 variant as a 27-nt deletion.

In a population-based study of 19 individuals each from Japan, Taiwan,
and Indonesia, Wilder et al. (2009) found the 27-bp deletion associated
with the SAO trait in 4 of the Indonesian samples only. These 4 SAO
chromosomes also carried the Memphis variant (109270.0001). The
haplotype associated with the 27-bp deletion was also found in Japanese
samples, but not in Taiwanese samples, which was a surprising finding
since Taiwan was thought to be part of the Austronesian population
expansion. The findings indicated that chromosomes related to Indonesian
SAO alleles are not a major component of genetic diversity among
aboriginal Taiwanese, and suggested that the SLC4A1 gene is subject to
natural selection.

.0003
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 TUSCALOOSA
SLC4A1, PRO327ARG

Jarolim et al. (1991) studied a 28-year-old black female with congenital
spherocytic hemolytic anemia (612653). Splenectomy corrected the anemia
but only partially normalized the reticulocyte count. Although there was
partial deficiency of protein 4.2 (177070), other findings suggested a
primary defect in band 3. By study of a PCR-amplified cDNA segment from
the EPB3 gene, Jarolim et al. (1991) demonstrated a CCC-to-CGC
transversion converting pro327 to arginine. Proline-327 is located in a
highly conserved region of band 3 and its substitution by the basic
arginine was expected to change both the secondary and tertiary
structure of the cytoplasmic domain of band 3. The same allele carried a
lys56-to-glu substitution, a common asymptomatic polymorphism designated
band 3 Memphis (109270.0001). Direct sequencing of genomic DNA from the
patient's unaffected mother and 2 sibs revealed neither of the 2
substitutions. Thus, the patient presumably represented a new mutation.

.0004
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 MONTEFIORE
SLC4A1, GLU40LYS

In a 33-year-old female with episodes of clinically apparent hemolytic
anemia coincident with pregnancies and associated with splenomegaly and
spherocytosis (612653), Rybicki et al. (1993) found a glu40-to-lys
mutation in the cytoplasmic domain of the EPB3 gene. The mutation was
homozygous; the proposita was the offspring of first-cousin parents born
in the Dominican Republic, largely of Spanish origin with some black
admixture. A striking feature was decreased RBC membrane content of
protein 4.2 (177070) which was thought to be a secondary phenomenon
resulting from defective interactions with band 3.

.0005
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 PRAGUE
SLC4A1, 10-BP DUP

Jarolim et al. (1994) described duplication of 10 nucleotides
(2455-2464) in the EPB3 gene in a family from Prague, Czech Republic,
with 5 individuals affected by spherocytosis (612653) in 3 generations.
Before splenectomy, the affected subjects had a compensated hemolytic
disease with reticulocytosis, hyperbilirubinemia, and increased osmotic
fragility. There was a partial deficiency of the band 3 protein that was
reflected by decreased rate of transmembrane sulfate flux and decreased
density of intramembrane particles. The mutant allele potentially
encoded an abnormal band 3 protein with a 3.5-kD COOH-terminal
truncation; however, they did not detect the mutant protein in the
membrane of mature red blood cells. Since the mRNA levels for the mutant
and normal alleles were similar and since the band 3 content was the
same in the light and dense red cell fractions, Jarolim et al. (1994)
concluded that the mutant band 3 was either not inserted into the plasma
membrane or was lost from the membrane before release of red cells into
the circulation.

.0006
WRIGHT BLOOD GROUP ANTIGEN
SLC4A1, GLU658LYS

Bruce et al. (1995) demonstrated that the blood group Wright antigens
(112050) are determined by mutation at amino acid residue 658 of
erythrocyte band-3.

.0007
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 CHUR
SLC4A1, GLY771ASP

In a large Swiss family with dominantly inherited spherocytosis and
deficiency of band-3 (612653), Maillet et al. (1995), by single-strand
conformation polymorphism analysis and nucleotide sequencing,
demonstrated a gly771-to-asp (G771D) (GGC-to-GAC) mutation in the EPB3
gene. Change was present in all 8 affected members of the family studied
but absent in 4 healthy members. It was located at a highly conserved
position in the middle of transmembrane segment 11, introducing a
negative charge in a stretch of 16 apolar or neutral residues.

.0008
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 NOIRTERRE
SLC4A1, GLN330TER

In a French kindred with typical autosomal dominant hereditary
spherocytosis (612653), Jenkins et al. (1996) found a 15 to 20%
deficiency of band-3, as well as abnormal erythrocyte membrane
mechanical stability. Anion transport studies of red cells from 2
affected individuals demonstrated decreased sulfate flux. A sequence
analysis of genomic DNA demonstrated a nonsense mutation of the EPB3
gene, gln330 to ter (Q330X), near the end of the band-3 cytoplasmic
domain. The mutation was present in genomic DNA of all HS family members
and absent in DNA of all unaffected family members. The variant was
named band-3 Noirterre after the village of residence of the family in
France. The change in codon 330 was from CAG to TAG.

.0009
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 LYON
SLC4A1, ARG150TER

Alloisio et al. (1996) described an 18-year-old man with moderate
hereditary spherocytosis (612653). The condition was associated with a
35% decrease in erythrocyte band-3. The underlying mutation was arg150
to ter (R150X) due to a CGA-to-TGA transition in codon 150. They
designated the new allele band-3 Lyon. The inheritance was dominant;
however, the mother, who also carried the allele Lyon, had a milder
clinical presentation and only a 16% decrease of band-3. They suspected
the father had transmitted a modifying mutation that remained silent in
the heterozygous state in him. Nucleotide sequencing after SSCP analysis
of the band-3 cDNA and promoter region revealed a G-to-A substitution at
position 89 from the cap site in the 5-prime untranslated region of the
EPB3 gene (designated 89G-to-A), an allele they referred to as band-3
Genas (109270.0010). A ribonuclease protection assay showed that (1) the
allele Genas from the father resulted in a 33% decrease in the amount of
band-3 mRNA; (2) the reduction caused by the allele Lyon (mother) was
42%; and (3) the compound heterozygous state for both alleles (proband)
resulted in a 58% decrease. These results suggested that some mildly
deleterious alleles of the EPB3 gene are compensated for by the normal
allele in the heterozygous state. They become manifest, however, through
the aggravation of the clinical picture, based on molecular alterations
when they occur in 'trans' to an allele causing a manifest reduction of
band-3 membrane protein concentration.

.0010
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 GENAS
SLC4A1, 89G-A

See 109270.0009 and Alloisio et al. (1996).

.0011
WALDNER BLOOD GROUP ANTIGEN
SLC4A1, VAL557MET

Bruce et al. (1995) demonstrated that the low-incidence blood group
antigen Wd(a) (112010) is associated with a val557-to-met substitution
in erythrocyte band-3.

.0012
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL DOMINANT
SLC4A1, ARG589HIS

Bruce et al. (1997) found an arg589-to-his mutation in affected members
of 2 Irish families with autosomal dominant distal renal tubular
acidosis (179800). The same mutation was on a different haplotype in the
2 families. These families had previously been reported in part by
Richards and Wrong (1972) and Wrong et al. (1993). The same
arg589-to-his mutation was found in a sporadic case of distal RTA by
Karet et al. (1998). The mutation was absent in both parents and the
unaffected sibs of the index case.

.0013
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL DOMINANT
SLC4A1, ARG589CYS

In a family with autosomal dominant distal renal tubular acidosis
(179800), Bruce et al. (1997) found an arg589-to-cys mutation in the
SLC4A1 gene.

.0014
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL DOMINANT
SLC4A1, SER613PHE

In a family with autosomal dominant distal renal tubular acidosis
(179800), Bruce et al. (1997) found a ser613-to-phe mutation in the
SLC4A1 gene.

.0015
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL DOMINANT
SLC4A1, ARG589SER

In a family with autosomal dominant distal renal tubular acidosis
(179800), Karet et al. (1998) found an arg589-to-ser mutation in the
SLC4A1 gene. This was the third substitution in the arg589 codon to be
identified as the cause of dominant distal RTA. In this family, RTA was
diagnosed in 2 propositae because of nephrolithiasis at ages 56 and 36
years. Prospective screening identified other affected family members
who were all asymptomatic.

.0016
RENAL TUBULAR ACIDOSIS, DISTAL, WITH HEMOLYTIC ANEMIA
SLC4A1, GLY701ASP

Tanphaichitr et al. (1998) described homozygosity for a gly701-to-asp
(G701D) loss-of-function mutation in the SLC4A1 gene in a Thai brother
and sister with autosomal recessive distal RTA and hemolytic anemia
(611590). The male proband presented at age 3.5 years with a history of
lethargy, anorexia, and slow growth. Physical examination showed height
and weight less than the third percentile, pallor, and
hepatosplenomegaly. Hypokalemia, hyperchloremic metabolic acidosis, and
normal creatinine were accompanied by isosthenuria and alkaline urinary
pH, bilateral nephrocalcinosis, and rachitic bone changes. Mild anemia
(hematocrit 11 g/dl) with microcytosis, reticulocytosis, and a
peripheral smear consistent with a xerocytic type of hemolytic anemia
were accompanied by homozygosity for hemoglobin E, a clinically benign
hemoglobin frequently encountered in Southeast Asia. The sister showed
similar findings.

Bruce et al. (2000) found the G701D mutation as 1 of 3 associated with
distal renal tubular acidosis and hemolytic anemia in families from
Malaysia and Papua New Guinea. The other 2 mutations were ala858 to asp
(A858D; 109270.0020) and deletion of val850 (delV850; 109270.0021).

Yenchitsomanus et al. (2002) found that all Thai patients with autosomal
recessive distal RTA caused by homozygosity for the G701D mutation
originated from northeastern Thailand. Yenchitsomanus et al. (2003)
confirmed the higher allele frequency of the G701D mutation in this
population. This suggested that the G701D allele might have arisen in
northeastern Thailand. The presence of patients with distal RTA who were
compound heterozygotes for the Southeast Asian ovalocytosis mutation
(109270.0002) and G701D in southern Thailand and Malaysia and their
apparent absence in northeastern Thailand indicated that the G701D
allele may have migrated to the southern peninsula region where SAO is
common, resulting in pathogenic allelic interaction.

.0017
DIEGO BLOOD GROUP ANTIGEN
SLC4A1, PRO854LEU

Bruce et al. (1994) demonstrated that the blood group Diego antigens
(110500) Di(a) and Di(b) are determined by a single amino acid
substitution at position 854 of the SLC4A1 gene, with proline
corresponding to the Di(b) antigen and leucine to the Di(a) antigen.

.0018
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 FUKUOKA
SLC4A1, GLY130ARG

Inoue et al. (1998) described a Japanese family with hereditary
spherocytosis (612653) associated with a homozygous missense mutation of
the band-3 gene, gly130 to arg. The homozygous unsplenectomized proband
was a 29-year-old male with compensated hemolytic anemia.

.0019
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 TOKYO
SLC4A1, THR837ALA

Iwase et al. (1998) reported the case of a 22-year-old Japanese man who
was admitted to hospital with cholelithiasis and hemolysis. He had been
icteric since early childhood. SDS-PAGE of erythrocyte membrane proteins
showed that the patient's band-3 was reduced to about 80% of the control
level. Molecular analysis demonstrated a change of codon 837 from ACG
(thr) to GCG (ala) in the AE1 gene. In bone marrow mononuclear cells,
both mutant and wildtype mRNA were comparably detected, suggesting that
this mutation interfered with band-3 processing or assembly, leading to
impaired accumulation of mutant band-3 in the plasma membrane. There was
no history suggesting other cases in the family; this appeared to be an
instance of heritable spherocytosis, but not hereditary spherocytosis.

.0020
RENAL TUBULAR ACIDOSIS, AUTOSOMAL DOMINANT
SLC4A1, ALA858ASP

Bruce et al. (2000) identified an ala858-to-asp mutation of the SLC4A1
gene as the cause of autosomal dominant renal tubular acidosis (179800)
in families in Malaysia and Papua New Guinea. Red cells with compound
heterozygosity for A858D and the Southeast Asian ovalocytosis mutation
(109270.0002) had the lowest anion transport activity reported for human
red cells to that time. Bruce et al. (2000) suggested that the dominant
A858D mutant protein is possibly mistargeted to an inappropriate plasma
membrane domain in the renal tubular cell.

.0021
RENAL TUBULAR ACIDOSIS, DISTAL, WITH HEMOLYTIC ANEMIA
SLC4A1, VAL850DEL

Bruce et al. (2000) observed autosomal recessive renal tubular acidosis
with hemolytic anemia (611590) due to deletion of valine-850 of the
SLC4A1 gene in families from Malaysia and Papua New Guinea. In
combination with the Southeast Asian ovalocytosis mutation
(109270.0002), the renal tubular acidosis displayed a pseudodominant
pedigree pattern. Bruce et al. (2000) suggested that the recessive
delV850 mutation may give rise to dRTA because of its decreased anion
transport activity in the kidney.

.0022
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 COIMBRA
RENAL TUBULAR ACIDOSIS, DISTAL, WITH HEMOLYTIC ANEMIA, INCLUDED
SLC4A1, VAL488MET

In the heterozygous state, band-3 Coimbra causes typical hereditary
spherocytosis (612653) and is associated with partial deficiency of
band-3 and, as a secondary phenomenon, of protein 4.2 (177070) (Alloisio
et al., 1997). Band 3 Coimbra is caused by a GTG-to-ATG change in exon
13 of the SLC4A1 gene, resulting in a val488-to-met substitution.

Ribeiro et al. (2000) reported severe hereditary spherocytosis and renal
tubular acidosis (611590) associated with total absence of band-3 in an
infant homozygous for the Coimbra mutation. Because the fetus stopped
moving near term, an emergency cesarean section was performed and a
severely anemic, hydropic female baby was delivered. She was
resuscitated and initially kept alive with respiratory assistance and
hypertransfusion therapy. Band 3 and protein 4.2 were absent; spectrin,
ankyrin, and glycophorin A were significantly reduced. Renal tubular
acidosis was detected by the age of 3 months. Nephrocalcinosis appeared
soon thereafter. With regular blood transfusions and daily bicarbonate
supplements, the child was doing 'reasonably well' at the age of 3
years.

.0023
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 CAPE TOWN
SLC4A1, GLU90LYS

Bracher et al. (2001) described a child with severe spherocytosis
(612653) who was compound heterozygous for 2 defects of band-3: a novel
GAG-to-AAG point mutation in exon 5, resulting in a glu90-to-lys (E90K)
substitution, which they designated band-3 Cape Town, and, in trans, a
previously described mutation, band-3 Prague III (109270.0024). The
patient was a Cape Coloured female child who presented at the age of 17
months.

.0024
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 PRAGUE III
SLC4A1, ARG870TRP

Bracher et al. (2001) described a case of severe spherocytosis (612653)
due to compound heterozygosity for an E90K mutation (109270.0023) and
the CGG-to-TGG band-3 Prague III mutation in exon 19 of the SLC4A1 gene,
arg870 to trp (R870W), previously described by Jarolim et al. (1995).
The mother had a normal blood count, osmotic fragility, and peripheral
blood smear; the father was unknown. The child displayed no jaundice and
did not have splenomegaly.

.0025
RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL DOMINANT
SLC4A1, 13-BP INS, 9-BP DEL

Toye et al. (2002) reported studies of band-3 Walton, a C-terminal
deletion associated with distal renal tubular acidosis (179800), in 2
brothers (Karet et al., 1998). The insertion-deletion underlying band-3
Walton consisted of a 13-bp insertion after the first base of amino acid
900 in exon 20. In addition, deletion of 9 bp over the sequence that
would have coded for amino acids tyr904 to glu906 of normal band-3 was
also present. The net effect was a premature stop codon and deletion of
the 11 COOH-terminal amino acids of the protein. The brothers were
heterozygous for the mutation. They had thirst, polyuria, and occasional
renal colic since childhood and were diagnosed as having distal renal
tubular acidosis on the basis of acidosis and hypokalemia at ages 37 and
25 years, respectively. Red cell morphology was normal, but both
patients had a tendency to erythremia, a recognized complication of
nephrocalcinosis from various causes (Feest et al., 1978). The parents
were dead, and there were no known living relatives for study. Toye et
al. (2002) demonstrated that the band-3 Walton protein is expressed in
the red cell membrane but retained internally in kidney cells.

Quilty et al. (2002) examined the effect of the 11-amino acid C-terminal
deletion, which they called 901-stop, on the biosynthesis, folding, and
trafficking of AE1 in transfected human embryonic kidney cells. The
901-stop mutation did not effect the folding of AE1, but it did alter
its trafficking to the plasma membrane. Coexpression of wildtype and
mutant proteins, mimicking the heterozygous state of the patients
carrying the mutation (Karet et al., 1998), resulted in heterooligomer
formation and impaired trafficking of the wildtype protein to the medial
Golgi. Quilty et al. (2002) concluded that the altered trafficking of
the mutant protein and its dominant-negative effect could explain both
its effect on urine acidification and its dominant inheritance pattern.

.0026
RENAL TUBULAR ACIDOSIS, DISTAL, WITH NORMAL RED CELL MORPHOLOGY
SLC4A1, SER773PRO

In a Thai patient with dRTA and normal red cell morphology (see 611590),
Sritippayawan et al. (2004) identified compound heterozygosity for the
G701D (109270.0016) mutation and a T-to-C transition in exon 18 of the
SLC4A1 gene, resulting in a ser773-to-pro (S773P) substitution. The
patient's clinically normal mother and father were heterozygous for
these mutations, respectively.

.0027
RENAL TUBULAR ACIDOSIS, DISTAL, WITH HEMOLYTIC ANEMIA
SLC4A1, ARG602PRO

In a Thai brother and sister with dRTA and Southeast Asian ovalocytosis
(SAO) (see 611590), Sritippayawan et al. (2004) identified compound
heterozygosity for the SAO deletion mutation (109270.0002) and a G-to-A
transition in exon 15, resulting in an arg602-to-pro (R602P)
substitution. Their mother had SAO and an unaffected brother was
heterozygous for the R602P mutation. The patient had a severe form of
dRTA whereas his sister had only mild metabolic acidosis, indicating
that other modifying factors or genes might play a role in governing the
severity of the disease.

.0028
SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 PRAGUE II
SLC4A1, ARG760GLN

Bruce et al. (2005) reported spherocytosis (612653) in 2 families due to
an arg760-to-gln (R760Q) mutation in the SLC4A1 gene. Jarolim et al.
(1995) had noted this variant, designated band 3 Prague II, in 2
subjects with hereditary spherocytosis.

.0029
FROESE BLOOD GROUP ANTIGEN
SLC4A1, GLU480LYS

McManus et al. (2000) demonstrated that the Froese blood group
polymorphism is due to a missense mutation glu480-to-lys (E480K) in RBC
band-3.

.0030
SWANN BLOOD GROUP ANTIGEN
SLC4A1, ARG646GLN

Zelinski et al. (2000) demonstrated that DNA from Sw(a+) (601550)
individuals showed one or the other of 2 mutations in exon 16 of the
SLC4A1 gene, CGG to CAG or CGG to TGG, resulting in an arg646-to-gln or
arg646-to-trp substitution, respectively.

.0031
SWANN BLOOD GROUP ANTIGEN
SLC4A1, ARG646TRP

See 109270.0030 and Zelinski et al. (2000).

.0032
ACANTHOCYTOSIS DUE TO BAND 3 HT
SLC4A1, PRO878LEU

In 1 of the 2 sibs with acanthocytosis and increased anion transport
activity of red cells, originally described by Kay et al. (1987, 1988),
Bruce et al. (1993) identified a pro868-to-leu (P868L) substitution in
the putative last membrane-spanning segment of the SLC4A1 protein. They
designated this mutation band 3 HT (high transport). The red cells of
the parents of the sibs also showed increased anion transport, but the
V(max) was not increased to the same degree as in the affected children,
suggesting that the children were homozygous for the mutation (Kay et
al., 1988).

*FIELD* SA
Mueller and Morrison (1977); Reinhart et al. (1994)
*FIELD* RF
1. Allen, S. J.; O'Donnell, A.; Alexander, N. D. E.; Mgone, C. S.;
Peto, T. E. A.; Clegg, J. B.; Alpers, M. P.; Weatherall, D. J.: Prevention
of cerebral malaria in children in Papua New Guinea by southeast Asian
ovalocytosis band 3. Am. J. Trop. Med. Hyg. 60: 1056-1060, 1999.

2. Alloisio, N.; Maillet, P.; Carre, G.; Texier, P.; Vallier, A.;
Baklouti, F.; Philippe, N.; Delaunay, J.: Hereditary spherocytosis
with band 3 deficiency: association with a nonsense mutation of the
band 3 gene (allele Lyon), and aggravation by a low-expression allele
occurring in trans (allele Genas). Blood 88: 1062-1069, 1996.

3. Alloisio, N.; Texier, P.; Vallier, A.; Ribeiro, M. L.; Morle, L.;
Bozon, M.; Bursaux, E.; Maillet, P.; Goncalves, P.; Tanner, M. J.
A.; Tamagnini, G.; Delaunay, J.: Modulation of clinical expression
and band 3 deficiency in hereditary spherocytosis. Blood 90: 414-420,
1997.

4. Amato, D.; Booth, P. B.: Hereditary ovalocytosis in Melanesians. Papua
New Guinea Med. J. 20: 26-32, 1977.

5. Baehner, R. L.; Gilchrist, G. S.; Anderson, E. J.: Hereditary
elliptocytosis and primary renal tubular acidosis in a single family. Am.
J. Dis. Child. 115: 414-419, 1968.

6. Baer, A.: Elliptocytosis, malaria, and fertility in Malaysia. Hum.
Biol. 60: 909-915, 1988.

7. Baer, A.; Lie-Injo, L. E.; Welch, Q. B.; Lewis, A. N.: Genetic
factors and malaria in the Temuan. Am. J. Hum. Genet. 28: 179-188,
1976.

8. Booth, P. B.: The occurrence of weak I(T) red cell antigen among
Melanesians. Vox Sang. 22: 64-72, 1972.

9. Booth, P. B.; Serjeantson, S.; Woodfield, D. G.; Amato, D.: Selective
depression of blood group antigens associated with hereditary ovalocytosis
among Melanesians. Vox Sang. 32: 99-110, 1977.

10. Bracher, N. A.; Lyons, C. A.; Wessels, G.; Mansvelt, E.; Coetzer,
T. L.: Band 3 Cape Town (E90K) causes severe hereditary spherocytosis
in combination with band 3 Prague III. Brit. J. Haemat. 113: 689-693,
2001.

11. Bruce, L. J.; Anstee, D. J.; Spring, F. A.; Tanner, M. J. A.:
Band 3 Memphis variant. II. Altered stilbene disulfonate binding and
the Diego (Di(a)) blood group antigen are associated with the human
erythrocyte band 3 mutation pro854-to-leu. J. Biol. Chem. 269: 16155-16158,
1994.

12. Bruce, L. J.; Cope, D. L.; Jones, G. K.; Schofield, A. E.; Burley,
M.; Povey, S.; Unwin, R. J.; Wrong, O.; Tanner, M. J. A.: Familial
distal renal tubular acidosis is associated with mutations in the
red cell anion exchanger (band 3, AE1) gene. J. Clin. Invest. 100:
1693-1707, 1997.

13. Bruce, L. J.; Kay, M. M. B.; Lawrence, C.; Tanner, M. J. A.:
Band 3 HT, a human red-cell variant associated with acanthocytosis
and increased anion transport, carries the mutation pro868-to-leu
in the membrane domain of band 3. Biochem. J. 293: 317-320, 1993.

14. Bruce, L. J.; Pan, R.; Cope, D. L.; Uchikawa, M.; Gunn, R. B.;
Cherry, R. J.; Tanner, M. J. A.: Altered structure and anion transport
properties of band 3 (AE1, SLC4A1) in human red cells lacking glycophorin
A. J. Biol. Chem. 279: 2414-2420, 2004.

15. Bruce, L. J.; Ring, S. M.; Anstee, D. J.; Reid, M. E.; Wilkinson,
S.; Tanner, M. J. A.: Changes in the blood group Wright antigens
are associated with a mutation at amino acid 658 in human erythrocyte
band 3: a site of interaction between band 3 and glycophorin A under
certain conditions. Blood 85: 541-547, 1995.

16. Bruce, L. J.; Robinson, H. C.; Guizouarn, H.; Borgese, F.; Harrison,
P.; King, M.-J.; Goede, J. S.; Coles, S. E.; Gore, D. M.; Lutz, H.
U.; Ficarella, R.; Layton, D. M.; Iolascon, A.; Ellory, J. C.; Stewart,
G. W.: Monovalent cation leaks in human red cells caused by single
amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate
exchanger, AE1. Nature Genet. 37: 1258-1263, 2005.

17. Bruce, L. J.; Tanner, M. J.; Zelinski, T.: The low incidence
blood group antigen, Wd(a), is associated with the substitution val557-to-met
in human erythrocyte band 3. (Abstract) Transfusion 35 (suppl.):
52S only, 1995.

18. Bruce, L. J.; Wrong, O.; Toye, A. M.; Young, M. T.; Ogle, G.;
Ismail, Z.; Sinha, A. K.; McMaster, P.; Hwaihwanje, I.; Nash, G. B.;
Hart, S.; Lavu, E.; Palmer, R.; Othman, A.; Unwin, R. J.; Tanner,
M. J. A.: Band 3 mutations, renal tubular acidosis and South-East
Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to
95% band 3 transport in red cells. Biochem. J. 350: 41-51, 2000.

19. Coetzer, T. L.; Beeton, L.; van Zyl, D.; Field, S. P.; Smart,
E.; Daniels, G. L.: Southeast Asian ovalocytosis in a South African
kindred with hemolytic anemia. Blood 87: 1656-1658, 1996.

20. Devonald, M. A. J.; Smith, A. N.; Poon, J. P.; Ihrke, G.; Karet,
F. E.: Non-polarized targeting of AE1 causes autosomal dominant distal
renal tubular acidosis. Nature Genet. 33: 125-127, 2003.

21. Feest, T. G.; Proctor, S.; Brown, R.; Wrong, O. M.: Nephrocalcinosis:
another cause of renal erythrocytosis. Brit. Med. J. 2: 605 only,
1978.

22. Fix, A. G.; Baer, A. S.; Lie-Injo, L. E.: The mode of inheritance
of ovalocytosis/elliptocytosis in Malaysian Orang Asli families. Hum.
Genet. 61: 250-253, 1982.

23. Ganesan, J.; Lie-Injo, L. E.; Ong, B. P.: Abnormal hemoglobins,
glucose-6-phosphate dehydrogenase deficiency and hereditary ovalocytosis
in the Dayaks of Sarawak. Hum. Hered. 25: 258-262, 1975.

24. Goel, V. K.; Li, X.; Chen, H.; Liu, S.-C.; Chisti, A. H.; Oh,
S. S.: Band 3 is a host receptor binding merozoite surface protein
1 during the Plasmodium falciparum invasion of erythrocytes. Proc.
Nat. Acad. Sci. 100: 5164-5169, 2003. Note: Erratum: Proc. Nat. Acad.
Sci. 100: 11184 only, 2003.

25. Groves, J. D.; Ring, S. M.; Schofield, A. E.; Tanner, M. J. A.
: The expression of the abnormal human red cell anion transporter
from South-East Asian ovalocytes (band 3 SAO) in Xenopus oocytes. FEBS
Lett. 330: 186-190, 1993.

26. Hadley, T.; Saul, A.; Lamont, G.; Hudson, D. E.; Miller, L. H.;
Kidson, C.: Resistance of Melanesian elliptocytes (ovalocytes) to
invasion by Plasmodium knowlesi and Plasmodium falciparum malaria
parasites in vitro. J. Clin. Invest. 71: 780-782, 1983.

27. Holt, M.; Hogan, P. F.; Nurse, G. T.: The ovalocytosis polymorphism
on the western border of Papua New Guinea. Hum. Biol. 53: 23-34,
1981.

28. Hsu, L.; Morrison, M.: A new variant of the anion transport protein
in human erythrocytes. Biochemistry 24: 3086-3090, 1985.

29. Ideguchi, H.; Okubo, K.; Ishikawa, A.; Futata, Y.; Hamasaki, N.
: Band 3-Memphis is associated with a lower transport rate of phosphoenolpyruvate. Brit.
J. Haemat. 82: 122-125, 1992.

30. Inaba, M.; Yawata, A.; Koshino, I.; Sato, K.; Takeuchi, M.; Takakuwa,
Y.; Manno, S.; Yawata, Y.; Kanzaki, A.; Sakai, J.; Ban, A.; Ono, K.;
Maede, Y.: Defective anion transport and marked spherocytosis with
membrane instability caused by hereditary total deficiency of red
cell band 3 in cattle due to a nonsense mutation. J. Clin. Invest. 97:
1804-1817, 1996.

31. Inoue, T.; Kanzaki, A.; Kaku, M.; Yawata, A.; Takezono, M.; Okamoto,
N.; Wada, H.; Sugihara, T.; Yamada, O.; Katayama, Y.; Nagata, N.;
Yawata, Y.: Homozygous missense mutation (band 3 Fukuoka: G130R):
a mild form of hereditary spherocytosis with near-normal band 3 content
and minimal changes of membrane ultrastructure despite moderate protein
4.2 deficiency. Brit. J. Haemat. 102: 932-939, 1998.

32. Iwase, S.; Ideguchi, H.; Takao, M.; Horiguchi-Yamada, J.; Iwasaki,
M.; Takahara, S.; Sekikawa, T.; Mochizuki, S.; Yamada, H.: Band 3
Tokyo: thr837-ala837 substitution in erythrocyte band 3 protein associated
with spherocytic hemolysis. Acta Haemat. 100: 200-203, 1998.

33. Jarolim, P.; Palek, J.; Rubin, H. L.; Prchal, J. T.; Korsgren,
C.; Cohen, C. M.: Band 3 Tuscaloosa: pro327-to-arg327 substitution
in the cytoplasmic domain of erythrocyte band 3 protein associated
with spherocytic hemolytic anemia and partial deficiency of protein
4.2. (Abstract) Blood 78 (suppl.): 252a, 1991.

34. Jarolim, P.; Rubin, H. L.; Brabec, V.; Chrobak, L.; Zolotarev,
A. S.; Alper, S. L.; Brugnara, C.; Wichterle, H.; Palek, J.: Mutations
of conserved arginines in the membrane domain of erythroid band 3
lead to a decrease in membrane-associated band 3 and to the phenotype
of hereditary spherocytosis. Blood 85: 634-640, 1995.

35. Jarolim, P.; Rubin, H. L.; Liu, S.-C.; Cho, M. R.; Brabec, V.;
Derick, L. H.; Yi, S. J.; Saad, S. T. O.; Alper, S.; Brugnara, C.;
Golan, D. E.; Palek, J.: Duplication of 10 nucleotides in the erythroid
band 3 (AE1) gene in a kindred with hereditary spherocytosis and band
3 protein deficiency (band 3-Prague). J. Clin. Invest. 93: 121-130,
1994.

36. Jarolim, P.; Rubin, H. L.; Zakova, D.; Storry, J.; Reid, M. E.
: Characterization of seven low incidence blood group antigens carried
by erythrocyte band 3 protein. Blood 92: 4836-4843, 1998.

37. Jarolim, P.; Rubin, H. L.; Zhai, S.; Sahr, K. E.; Liu, S.-C.;
Mueller, T. J.; Palek, J.: Band 3 Memphis: a widespread polymorphism
with abnormal electrophoretic mobility of erythrocyte band 3 protein
caused by substitution AAG-to-GAG (lys-to-glu) in codon 56. Blood 80:
1592-1598, 1992.

38. Jay, D. G.: Role of band 3 in homeostasis and cell shape. Cell 86:
853-854, 1996.

39. Jenkins, P. B.; Abou-Alfa, G. K.; Dhermy, D.; Bursaux, E.; Feo,
C.; Scarpa, A. L.; Lux, S. E.; Garbarz, M.; Forget, B. G.; Gallagher,
P. G.: A nonsense mutation in the erythrocyte band 3 gene associated
with decreased mRNA accumulation in a kindred with dominant hereditary
spherocytosis. J. Clin. Invest. 97: 373-380, 1996.

40. Jones, G. L.; Edmundson, H. M.; Wesche, D.; Saul, A.: Human erythrocyte
band-3 has an altered N terminus in malaria-resistant Melanesian ovalocytosis. Biochim.
Biophys. Acta 1096: 33-40, 1990.

41. Karet, F. E.; Gainza, F. J.; Gyory, A. Z.; Unwin, R. J.; Wrong,
O.; Tanner, M. J. A.; Nayir, A.; Alpay, H.; Santos, F.; Hulton, S.
A.; Bakkaloglu, A.; Ozen, S.; Cunningham, M. J.; di Pietro, A.; Walker,
W. G.; Lifton, R. P.: Mutations in the chloride-bicarbonate exchanger
gene AE1 cause autosomal dominant but not autosomal recessive distal
renal tubular acidosis. Proc. Nat. Acad. Sci. 95: 6337-6342, 1998.

42. Kay, M. M. B.: Band 3 in aging and neurological disease. Ann.
N.Y. Acad. Sci. 621: 179-204, 1991.

43. Kay, M. M. B.; Bosman, G. J. C. G. M.; Lawrence, C.: Functional
topography of band 3: specific structural alteration linked to functional
aberrations in human erythrocytes. Proc. Nat. Acad. Sci. 85: 492-496,
1988.

44. Kay, M. M. B.; Flowers, N.; Goodman, J.; Bosman, G.: Alteration
in membrane protein band 3 associated with accelerated erythrocyte
aging. Proc. Nat. Acad. Sci. 86: 5834-5838, 1989.

45. Kay, M. M. B.; Lawrence, C.; Bosman, G. J. C. G. M.: Molecular
anatomy of an anemia. (Abstract) Clin. Res. 35: 599A, 1987.

46. Kay, M. M. B.; Marchalonis, J. J.; Hughes, J.; Watanabe, K.; Schluter,
S. F.: Definition of a physiologic aging autoantigen by using synthetic
peptides of membrane protein band 3: localization of the active antigenic
sites. Proc. Nat. Acad. Sci. 87: 5734-5738, 1990.

47. Kidson, C.; Lamont, G.; Saul, A.; Nurse, G. T.: Ovalocytic erythrocytes
from Melanesians are resistant to invasion by malaria parasites in
culture. Proc. Nat. Acad. Sci. 78: 5829-5832, 1981.

48. Kittanakom, S.; Cordat, E.; Akkarapatumwong, V.; Yenchitsomanus,
P.; Reithmeier, R. A. F.: Trafficking defects of a novel autosomal
recessive distal renal tubular acidosis mutant (S773P) of the human
kidney anion exchanger (kAE1). J. Biol. Chem. 279: 40960-40971,
2004.

49. Langdon, R. G.; Holman, V. P.: Immunological evidence that band
3 is the major glucose transporter of the human erythrocyte membrane. Biochim.
Biophys. Acta 945: 23-32, 1988.

50. Lie-Injo, L. E.: Hereditary ovalocytosis and haemoglobin E-ovalocytosis
in Malayan aborigines. Nature 208: 1329, 1965.

51. Lie-Injo, L. E.; Fix, A.; Bolton, J. M.; Gilman, R. H.: Haemoglobin
E-hereditary elliptocytosis in Malayan aborigines. Acta Haemat. 47:
210-216, 1972.

52. Liu, S.-C.; Jarolim, P.; Rubin, H. L.; Palek, J.; Amato, D.; Hassan,
K.; Zaik, M.; Sapak, P.: The homozygous state for the band 3 protein
mutation in Southeast Asian ovalocytosis may be lethal. (Letter) Blood 84:
3590-3591, 1994.

53. Liu, S.-C.; Zhai, S.; Palek, J.; Golan, D. E.; Amato, D.; Hassan,
K.; Nurse, G. T.; Babona, D.; Coetzer, T.; Jarolim, P.; Zaik, M.;
Borwein, S.: Molecular defect of the band 3 protein in Southeast
Asian ovalocytosis. New Eng. J. Med. 323: 1530-1538, 1990.

54. Lux, S. E.; John, K. M.; Kopito, R. R.; Lodish, H. F.: Cloning
and characterization of band 3, the human erythrocyte anion-exchange
protein (AE1). Proc. Nat. Acad. Sci. 86: 9089-9093, 1989.

55. Maillet, P.; Vallier, A.; Reinhart, W. H.; Wyss, E. J.; Ott, P.;
Texier, P.; Baklouti, F.; Tanner, M. J. A.; Delaunay, J.; Alloisio,
N.: Band 3 Chur: a variant associated with band 3-deficient hereditary
spherocytosis and substitution in a highly conserved position of transmembrane
segment 11. Brit. J. Haemat. 91: 804-810, 1995.

56. McManus, K.; Lupe, K.; Coghlan, G.; Zelinski, T.: An amino acid
substitution in the putative second extracellular loop of RBC band
3 accounts for the Froese blood group polymorphism. Transfusion 40:
1246-1249, 2000.

57. Mohandas, N.; Winardi, R.; Knowles, D.; Leung, A.; Parra, M.;
George, E.; Conboy, J.; Chasis, J.: Molecular basis for membrane
rigidity of hereditary ovalocytosis: a novel mechanism involving the
cytoplasmic domain of band 3. J. Clin. Invest. 89: 686-692, 1992.

58. Mueller, T. J.; Morrison, M.: Heterogeneity of the major protein
in the human erythrocyte membrane. (Abstract) Fed. Proc. 36: 747,
1977.

59. Mueller, T. J.; Morrison, M.: Detection of a variant of protein
3, the major transmembrane protein of the human erythrocyte. J. Biol.
Chem. 252: 6573-6576, 1977.

60. Palatnik, M.; da Silva Simoes, M. L. M.; Alves, Z. M. S.; Laranjeira,
N. S. M.: The 60 and 63 kDa proteolytic peptides of the red cell
membrane band-3 protein: their prevalence in human and non-human primates. Hum.
Genet. 86: 126-130, 1990.

61. Palumbo, A. P.; Isobe, M.; Huebner, K.; Shane, S.; Rovera, G.;
Demuth, D.; Curtis, P. J.; Ballantine, M.; Croce, C. M.; Showe, L.
C.: Chromosomal localization of a human band 3-like gene to region
7q35-7q36. Am. J. Hum. Genet. 39: 307-316, 1986.

62. Paw, B. H.; Davidson, A. J.; Zhou, Y.; Li, R.; Pratt, S. J.; Lee,
C.; Trede, N. S.; Brownlie, A.; Donovan, A.; Liao, E. C.; Ziai, J.
M.; Drejer, A. H.; and 13 others: Cell-specific mitotic defect
and dyserythropoiesis associated with erythroid band 3 deficiency. Nature
Genet. 34: 59-64, 2003.

63. Pawloski, J. R.; Hess, D. T.; Stamler, J. S.: Export by red blood
cells of nitric oxide bioactivity. Nature 409: 622-626, 2001.

64. Peters, L. L.; Shivdasani, R. A.; Liu, S.-C.; Hanspal, M.; John,
K. M.; Gonzalez, J. M.; Brugnara, C.; Gwynn, B.; Mohandas, N.; Alper,
S. L.; Orkin, S. H.; Lux, S. E.: Anion exchanger 1 (band 3) is required
to prevent erythrocyte membrane surface loss but not to form the membrane
skeleton. Cell 86: 917-927, 1996.

65. Quilty, J. A.; Cordat, E.; Reithmeier, R. A. F.: Impaired trafficking
of human kidney anion exchanger (kAE1) caused by hetero-oligomer formation
with a truncated mutant associated with distal renal tubular acidosis. Biochem.
J. 368: 895-903, 2002.

66. Ranney, H. M.; Rosenberg, G. H.; Morrison, M.; Mueller, T. J.
: Frequencies of band 3 variants of human red cell membranes in some
different populations. Brit. J. Haemat. 76: 262-267, 1990.

67. Ravindranath, Y.; Goyette, G., Jr.; Johnson, R. M.: Southeast
Asian ovalocytosis in an African-American family. (Letter) Blood 84:
2823-2824, 1994.

68. Reinhart, W. H.; Wyss, E. J.; Arnold, D.; Ott, P.: Hereditary
spherocytosis associated with protein band 3 defect in a Swiss kindred. Brit.
J. Haemat. 86: 147-155, 1994.

69. Ribeiro, M. L.; Alloisio, N.; Almeida, H.; Gomes, C.; Texier,
P.; Lemos, C.; Mimoso, G.; Morle, L.; Bey-Cabet, F.; Rudigoz, R.-C.;
Delaunay, J.; Tamagnini, G.: Severe hereditary spherocytosis and
distal renal tubular acidosis associated with the total absence of
band 3. Blood 96: 1602-1604, 2000.

70. Richards, P.; Wrong, O. M.: Dominant inheritance in a family
with familial renal tubular acidosis. Lancet 300: 998-999, 1972.
Note: Originally Volume II.

71. Rybicki, A. C.; Qiu, J. J. H.; Musto, S.; Rosen, N. L.; Nagel,
R. L.; Schwartz, R. S.: Human erythrocyte protein 4.2 deficiency
associated with hemolytic anemia and a homozygous 40 glutamic acid-to-lysine
substitution in the cytoplasmic domain of band 3 (band 3 Montefiore). Blood 81:
2155-2165, 1993.

72. Sahr, K. E.; Taylor, W. M.; Daniels, B. P.; Rubin, H. L.; Jarolim,
P.: The structure and organization of the human erythroid anion exchanger
(AE1) gene. Genomics 24: 491-501, 1994.

73. Schofield, A. E.; Martin, P. G.; Spillett, D.; Tanner, M. J. A.
: The structure of the human red blood cell anion exchanger (EPB3,
AE1, Band 3) gene. Blood 84: 2000-2012, 1994.

74. Schulman, S.; Roth, E. F., Jr.; Cheng, B.; Rybicki, A. C.; Sussman,
I. I.; Wong, M.; Wang, W.; Ranney, H. M.; Nagel, R. L.; Schwartz,
R. S.: Growth of Plasmodium falciparum in human erythrocytes containing
abnormal membrane proteins. Proc. Nat. Acad. Sci. 87: 7339-7343,
1990.

75. Serjeantson, S.; Bryson, K.; Amato, D.; Babona, D.: Malaria and
hereditary ovalocytosis. Hum. Genet. 37: 161-167, 1977.

76. Showe, L. C.; Ballantine, M.; Huebner, K.: Localization of the
gene for the erythroid anion exchange protein, band 3 (EMPB3), to
human chromosome 17. Genomics 1: 71-76, 1987.

77. Southgate, C. D.; Chisti, A. H.; Mitchell, B.; Yi, S. J.; Palek,
J.: Targeted disruption of the murine erythroid band 3 gene results
in spherocytosis and severe haemolytic anaemia despite a normal membrane
skeleton. Nature Genet. 14: 227-230, 1996.

78. Sritippayawan, S.; Sumboonnanonda, A.; Vasuvattakul, S.; Keskanokwong,
T.; Sawasdee, N.; Paemanee, A.; Thuwajit, P.; Wilairat, P.; Nimmannit,
S.; Malasit, P.; Yenchitsomanus, P.: Novel compound heterozygous
SLC4A1 mutations in Thai patients with autosomal recessive distal
renal tubular acidosis. Am. J. Kidney Dis. 44: 64-70, 2004.

79. Stewart, E. A.; Kopito, R.; Bowcock, A. M.: A PstI polymorphism
for the human erythrocyte surface protein band 3 (EPB3) demonstrates
close linkage of EPB3 to the nerve growth factor receptor. Genomics 5:
633-635, 1989.

80. Tanner, M. J. A.: Molecular and cellular biology of the erythrocyte
anion exchanger (AE1). Seminars Hemat. 30: 34-57, 1993.

81. Tanner, M. J. A.; Bruce, L.; Martin, P. G.; Rearden, D. M.; Jones,
G. L.: Melanesian hereditary ovalocytes have a deletion in red cell
band 3. (Letter) Blood 78: 2785-2786, 1991.

82. Tanphaichitr, V. S.; Sumboonnanonda, A.; Ideguchi, H.; Shayakul,
C.; Brugnara, C.; Takao, M.; Veerakul, G.; Alper, S. L.: Novel AE1
mutations in recessive distal renal tubular acidosis: loss-of-function
is rescued by glycophorin A. J. Clin. Invest. 102: 2173-2179, 1998.

83. Toye, A. M.; Bruce, L. J.; Unwin, R. J.; Wrong, O.; Tanner, M.
J. A.: Band 3 Walton, a C-terminal deletion associated with distal
renal tubular acidosis, is expressed in the red cell membrane but
retained internally in kidney cells. Blood 99: 342-347, 2002.

84. Watts, J. D.; Brabb, T.; Bures, E. J.; Wange, R. L.; Samelson,
L. E.; Aebersold, R.: Identification and characterization of a substrate
specific for the T cell protein tyrosine kinase ZAP-70. FEBS Lett. 398:
217-222, 1996.

85. Wilder, J. A.; Stone, J. A.; Preston, E. G.; Finn, L. E.; Ratcliffe,
H. L.; Sudoyo, H.: Molecular population genetics of SLC4A1 and Southeast
Asian ovalocytosis. J. Hum. Genet. 54: 182-187, 2009.

86. Wrong, O. M.; Feest, T. G.; MacIver, A. G.: Immune-related potassium-losing
interstitial nephritis: a comparison with distal renal tubular acidosis. Quart.
J. Med. 86: 513-534, 1993.

87. Yannoukakos, D.; Vasseur, C.; Driancourt, C.; Blouquit, Y.; Delaunay,
J.; Wajcman, H.; Bursaux, E.: Human erythrocyte band 3 polymorphism
(band 3 Memphis): characterization of the structural modification
(lys56-to-glu) by protein chemistry methods. Blood 78: 1117-1120,
1991.

88. Yenchitsomanus, P.; Sawasdee, N.; Paemanee, A.; Keskanokwong,
T.; Vasuvattakul, S.; Bejrachandra, S.; Kunachiwa, W.; Fucharoen,
S.; Jittphakdee, P.; Yindee, W.; Promwong, C.: Anion exchanger 1
mutations associated with distal renal tubular acidosis in the Thai
population. J. Hum. Genet. 48: 451-456, 2003.

89. Yenchitsomanus, P.; Vasuvattakul, S.; Kirdpon, S.; Wasanawatana,
S.; Susaengrat, W.; Sreethiphayawan, S.; Chuawatana, D.; Mingkum,
S.; Sawasdee, N.; Thuwajit, P.; Wilairat, P.; Malasit, P.; Nimmannit,
S.: Autosomal recessive distal renal tubular acidosis caused by G701D
mutation of anion exchanger 1 gene. Am. J. Kidney Dis. 40: 21-29,
2002.

90. Yusoff, N. M.; Van Rostenberghe, H.; Shirakawa, T.; Nishiyama,
K.; Amin, N.; Darus, Z.; Zainal, N.; Isa, N.; Nozu, H.; Matsuo, M.
: High prevalence of Southeast Asian ovalocytosis in Malays with distal
renal tubular acidosis. J. Hum. Genet. 48: 650-653, 2003.

91. Zelinski, T.; Rusnak, A.; McManus, K.; Coghlan, G.: Distinctive
Swann blood group genotypes: molecular investigations. Vox Sang. 79:
215-218, 2000.

*FIELD* CS

Heme:
Hemolytic anemia (e.g. .0004 Band 3 Montefiore);
Spherocytosis (e.g. .0003 Band 3 Tuscaloosa);
Acanthocytosis;
Elliptocytosis;
Macrocytosis;
Stomatocytosis;
Reticulocytosis;
Increased red cell osmotic fragility

GI:
Splenomegaly

Skin:
Jaundice

Lab:
Band 3 erythrocyte membrane glycoprotein;
Senescent cell antigen (SCA), derived from degraded band 3 marks aging
and malaria-infected red cells for removal;
Chloride and bicarbonate exchange function;
Binding sites for hemoglobin and several glycolytic enzymes;
Transport for glucose, anions, and water;
Resistance to red cell invasion by malaria parasites;
Hyperbilirubinemia

Inheritance:
Autosomal dominant (17q21-q22)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/27/2009
Carol A. Bocchini - updated: 3/11/2009
Marla J. F. O'Neill - updated: 11/8/2007
Victor A. McKusick - updated: 11/1/2005
Marla J. F. O'Neill - updated: 2/9/2005
Victor A. McKusick - updated: 4/5/2004
Victor A. McKusick - updated: 12/23/2003
Victor A. McKusick - updated: 6/13/2003
Ada Hamosh - updated: 4/3/2003
Patricia A. Hartz - updated: 3/3/2003
Victor A. McKusick - updated: 1/27/2003
Victor A. McKusick - updated: 2/22/2002
Victor A. McKusick - updated: 9/20/2001
Victor A. McKusick - updated: 7/17/2001
Ada Hamosh - updated: 1/31/2001
Victor A. McKusick - updated: 1/9/2001
Victor A. McKusick - updated: 9/15/2000
Victor A. McKusick - updated: 11/4/1999
Victor A. McKusick - updated: 4/28/1999
Victor A. McKusick - updated: 3/15/1999
Victor A. McKusick - updated: 2/1/1999
Victor A. McKusick - updated: 1/5/1999
Victor A. McKusick - updated: 6/12/1998
Victor A. McKusick - updated: 6/10/1998
Jennifer P. Macke - updated: 5/26/1998
Victor A. McKusick - updated: 9/16/1997
Moyra Smith - updated: 4/6/1996

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

*FIELD* ED
carol: 08/30/2013
carol: 8/2/2013
terry: 3/15/2013
wwang: 6/3/2009
ckniffin: 5/27/2009
carol: 3/11/2009
carol: 3/10/2009
carol: 2/26/2009
terry: 1/8/2009
carol: 11/8/2007
mgross: 7/5/2007
terry: 6/23/2006
mgross: 6/23/2006
carol: 1/4/2006
terry: 12/22/2005
alopez: 11/4/2005
terry: 11/1/2005
carol: 7/26/2005
terry: 3/11/2005
terry: 2/9/2005
carol: 1/4/2005
alopez: 4/7/2004
terry: 4/5/2004
carol: 3/17/2004
carol: 3/2/2004
tkritzer: 12/26/2003
terry: 12/23/2003
cwells: 11/12/2003
cwells: 6/17/2003
terry: 6/13/2003
alopez: 4/30/2003
alopez: 4/10/2003
terry: 4/3/2003
mgross: 3/3/2003
alopez: 1/31/2003
mgross: 1/28/2003
terry: 1/27/2003
cwells: 3/13/2002
cwells: 3/11/2002
terry: 2/22/2002
mcapotos: 10/2/2001
mcapotos: 9/21/2001
terry: 9/20/2001
carol: 9/14/2001
mcapotos: 9/14/2001
mcapotos: 8/7/2001
mcapotos: 7/18/2001
terry: 7/17/2001
mcapotos: 3/13/2001
alopez: 1/31/2001
terry: 1/31/2001
mcapotos: 1/19/2001
mcapotos: 1/12/2001
terry: 1/9/2001
mcapotos: 10/9/2000
mcapotos: 9/28/2000
terry: 9/22/2000
terry: 9/15/2000
alopez: 11/12/1999
alopez: 11/9/1999
terry: 11/4/1999
terry: 6/9/1999
terry: 5/20/1999
alopez: 5/10/1999
terry: 4/28/1999
terry: 3/15/1999
carol: 2/4/1999
terry: 2/1/1999
carol: 1/13/1999
terry: 1/5/1999
dkim: 12/9/1998
dholmes: 7/9/1998
alopez: 7/7/1998
carol: 6/16/1998
terry: 6/12/1998
carol: 6/10/1998
carol: 5/26/1998
dholmes: 4/16/1998
mark: 9/22/1997
terry: 9/16/1997
alopez: 7/30/1997
alopez: 7/9/1997
jenny: 4/15/1997
mark: 12/26/1996
terry: 12/16/1996
jamie: 11/6/1996
terry: 11/6/1996
terry: 10/30/1996
terry: 10/28/1996
terry: 10/22/1996
mark: 10/7/1996
terry: 10/1/1996
mark: 5/31/1996
terry: 5/29/1996
mark: 5/17/1996
terry: 5/16/1996
mark: 4/6/1996
mark: 3/22/1996
terry: 3/18/1996
mark: 2/19/1996
terry: 2/15/1996
terry: 2/21/1995
carol: 1/27/1995
mimadm: 4/9/1994
carol: 10/20/1993
carol: 10/19/1993
carol: 6/3/1993

MIM 110500
*RECORD*
*FIELD* NO
110500
*FIELD* TI
#110500 BLOOD GROUP--DIEGO SYSTEM; DI
;;DIEGO BLOOD GROUP
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
read moreblood group antigens of the Diego system are caused by a single amino
acid variation in the SLC4A1 gene (109270), which encodes the
erythrocyte band-3 protein.

The Diego blood group system is controlled by 2 allelic genes: Di(a) and
Di(b). The Di(a) antigen was first described in Venezuela on the basis
of an antibody that had been the cause of hemolytic disease of the
newborn (Levine et al., 1956). A second example of anti-Di(a) was found
in Buffalo in the serum of a Polish mother, whose child also suffered
from hemolytic disease of the newborn (Tatarsky et al., 1959). The Diego
system shows polymorphism mainly in Mongolian peoples, e.g., Chinese and
American Indians. In a family of Polish origin, Kusnierz-Alejska and
Bochenek (1992) found anti-Di(a) antibody in the serum of a mother who
gave birth to a newborn with severe hemolytic anemia. They identified
the Di(a) antigen in 45 of 9,661 donor blood samples from different
regions of Poland (0.46%). All 45 were of Polish ancestry.

Zelinski et al. (1993) showed that the DI blood group is tightly linked
to the erythrocyte surface protein band-3 locus (SLC4A1); maximum lod =
5.42 at theta = 0.00. Looser linkage between DI and D17S41 (maximum lod
= 3.14 at theta = 0.09) for combined paternal and maternal meioses was
also established. The EPB3 gene is located at 17q21-q22.

Indeed, Bruce et al. (1994) demonstrated that the Di(a)/Di(b)
polymorphism is a single amino acid substitution at position 854 of the
band-3 protein, with proline of the wildtype band-3 protein
corresponding to the Di(b) antigen and leucine to the Di(a) antigen
(109270.0017).

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* SA
Lewis et al. (1976)
*FIELD* RF
1. Bruce, L. J.; Antsee, D. J.; Spring, F. A.; Tanner, M. J. A.:
Band 3 Memphis variant. II. Altered stilbene disulfonate binding and
the Diego (Di(a)) blood group antigen are associated with the human
erythrocyte band-3 mutation pro854-to-leu. J. Biol. Chem. 269: 16155-16158,
1994.

2. Kusnierz-Alejska, G.; Bochenek, S.: Haemolytic disease of the
newborn due to anti-Di(a) and incidence of the Di(a) antigen in Poland. Vox
Sang. 62: 124-126, 1992.

3. Levine, P.; Layrisse, M.; Robinson, E. A.; Arends, T.; Domingues
Sisco, R.: The Diego blood factor. Nature 177: 40-41, 1956.

4. Lewis, M.; Kaita, H.; Chown, B.; Giblett, E. R.; Anderson, J.;
Steinberg, A. G.: The Diego blood groups: a genetic linkage analysis. Am.
J. Hum. Genet. 28: 18-21, 1976.

5. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World Distribution.
New York: Oxford Univ. Press (pub.) 1988.

6. Tatarsky, J.; Stroup, M.; Levine, P.; Ernoehazy, W. S.: Another
example of anti-Diego (Di-a). Vox Sang. 4: 152-154, 1959.

7. Zelinski, T.; Coghlan, G.; White, L.; Philipps, S.: The Diego
blood group locus is located on chromosome 17q. Genomics 17: 665-666,
1993.

*FIELD* CN
Victor A. McKusick - updated: 2/1/1999

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

*FIELD* ED
carol: 01/04/2006
terry: 3/15/2000
terry: 6/9/1999
carol: 2/4/1999
terry: 2/1/1999
mimadm: 2/11/1994
carol: 9/21/1993
carol: 8/11/1992
carol: 6/19/1992
carol: 6/15/1992
supermim: 3/16/1992

MIM 112010
*RECORD*
*FIELD* NO
112010
*FIELD* TI
#112010 BLOOD GROUP--WALDNER TYPE; WD
;;WALDNER BLOOD GROUP ANTIGEN
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreWaldner blood group expression is caused by a point mutation in the
SLC4A1 gene (109270).

Lewis and Kaita (1981) found a 'new' red cell antigen in Hutterites of
the surname Waldner. Zelinski et al. (1995) stated that the WD blood
group antigen had been identified in Khoisans in South Africa and in a
family in Holland. By genetic linkage analysis, they showed that WD is
loosely linked to the reference marker D17S41 at 17q12-q24 and closely
linked to the SLC4A1 locus at 17q12-q21.

Bruce et al. (1995) demonstrated that the Wd(a) results from a
substitution of methionine for valine-557 in erythrocyte band-3
(109270.0011).

*FIELD* RF
1. Bruce, L. J.; Tanner, M. J. A.; Zelinski, T.: The low incidence
blood group antigen, Wd(a), is associated with the substitution val557-to-met
in human erythrocyte band 3. (Abstract) Transfusion 35 (suppl.):
52S only, 1995.

2. Lewis, M.; Kaita, H.: A 'new' low incidence 'Hutterite' blood
group antigen Waldner (Wd-a). Am. J. Hum. Genet. 33: 418-420, 1981.

3. Zelinski, T.; Coghlan, G.; White, L.; Phillips, S.: Assignment
of the Waldner blood group locus (WD) to 17q12-q21. Genomics 25:
320-322, 1995.

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

*FIELD* ED
carol: 12/28/2005
alopez: 6/26/1997
mark: 12/26/1996
terry: 12/16/1996
carol: 2/10/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
root: 1/28/1988

MIM 112050
*RECORD*
*FIELD* NO
112050
*FIELD* TI
#112050 BLOOD GROUP--WRIGHT ANTIGEN; WR
;;WRIGHT BLOOD GROUP ANTIGEN
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
read moreblood group Wright antigens are associated with a polymorphism in human
erythrocyte band-3 (SLC4A1; 109270).

The Wright antigen, a 'private' blood group (see 111500), was found by
Holman (1953). Although it is very rare, the early date of its discovery
and the ready availability of testing sera led to a large number of
persons and variety of populations being tested. The frequency of the
gene for the Wr(a) antigen was found to be about 3 in 10,000 among
Europeans (Mourant et al., 1978).

Because the Wr(b) antigen appeared to involve both red blood cell band-3
and glycophorin A (GPA; 111300), Bruce et al. (1995) examined the cDNA
sequences of band-3 and GPA of 1 of the 2 known Wr(a+b-) individuals.
They showed that this person was homozygous for a glu658-to-lys mutation
in the BND3 gene, but had normal GPA. Putative heterozygotes with
Wr(a+b+) RBCs had both glu and lys at residue 658 of band-3, whereas the
common Wr(a-b+) RBC phenotype had only band-3 with glu658. Thus, the
Wr(a) and Wr(b) antigens are determined by the amino acid at residue 658
of band-3 (109270.0006) and are antithetical. Bruce et al. (1995)
proposed that arg61 of GPA interacts with glu658 of band-3 to form the
Wr(b) antigen.

*FIELD* RF
1. Bruce, L. J.; Ring, S. M.; Anstee, D. J.; Reid, M. E.; Wilkinson,
S.; Tanner, M. J. A.: Changes in the blood group Wright antigens
are associated with a mutation at amino acid 658 in human erythrocyte
band 3: a site of interaction between band 3 and glycophorin A under
certain conditions. Blood 85: 541-547, 1995.

2. Holman, C. A.: A new rare human blood group antigen, Wr(a). Lancet 262:
119-120, 1953. Note: Originally Volume II.

3. Mourant, A. E.; Kopec, A. C.; Domaniewska-Sobczak, K.: The Genetics
of Jews. Oxford: Clarendon Press (pub.) 1978. P. 7 only.

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

*FIELD* ED
terry: 01/08/2009
carol: 12/28/2005
terry: 4/14/2003
terry: 3/15/2000
carol: 2/20/1995
supermim: 3/16/1992
carol: 2/6/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

MIM 130600
*RECORD*
*FIELD* NO
130600
*FIELD* TI
#130600 ELLIPTOCYTOSIS 2; EL2
;;ELLIPTOCYTOSIS, RHESUS-UNLINKED TYPE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreelliptocytosis-2 is caused by heterozygous mutation in the
alpha-spectrin gene (SPTA1; 182860) on chromosome 1q23.

For a general description and a discussion of genetic heterogeneity of
elliptocytosis (HE), see EL1 (611804).

CLINICAL FEATURES

In some families with HE, spectrin is abnormally heat-sensitive (Lux and
Wolfe, 1980). Coetzer and Zail (1981) studied spectrin in 4 cases of
hereditary elliptocytosis and found an abnormality of tryptic digestion
in 1. This patient was previously reported by Gomperts et al. (1973) as
an instance of hemolytic anemia due to HE.

Liu et al. (1982) examined erythrocytes from 18 patients with hereditary
elliptocytosis. In 8 patients (referred to as type 1), spectrin was
defective in dimer-dimer association as demonstrated in 2 ways. First,
spectrin dimer was increased and tetramer decreased; spectrin dimer
represented 15 to 33% of total spectrin compared with a normal range of
3 to 7%. Second, the equilibrium constants of spectrin dimer-dimer
association was decreased in both solution and in situ in red cell
membranes. In the other 10 patients (referred to as type 2), dimer-dimer
association was normal. Membrane skeletons, produced from both types of
elliptocytosis by Triton X-100 extraction of the red cell ghosts, were
unstable when mechanically shaken. Spectrin tetramers but not dimers can
crosslink actin.

Evans et al. (1983) studied a family in which 3 sibs had severe
transfusion-dependent, presumably homozygous elliptocytosis and both
parents had asymptomatic elliptocytosis. Red cell membranes of all 3
sibs showed an excess of spectrin dimers over tetramers in spectrin
extracts. Both parents showed an intermediate increase in spectrin
dimers.

In 7 black patients (from 5 unrelated families) with mild HE, Lecomte et
al. (1985) found an abnormal thermal sensitivity and an important defect
of spectrin dimer self-association. An excess of spectrin dimer and
deficient dimer-to-tetramer conversion were demonstrated. Peptide
patterns of crude spectrin showed a marked decrease in the 80-kD peptide
(previously identified as the dimer-dimer interaction domain of the
alpha chain) and a concomitant appearance of a novel 65-kD peptide.
Anti-alpha-spectrin antibodies showed that the latter peptide was
derived from the alpha chain. The patients were 3 unrelated adults, 2
children with hemolytic anemia, and the father of each child.

Lawler et al. (1984, 1985) described a molecular defect in the alpha
subunit of spectrin in a subset of patients with hereditary
elliptocytosis; the self-association of alpha-beta heterodimers to form
tetramers was defective.

Abnormality of alpha spectrin was reported by Ravindranath and Johnson
(1985) in a case of congenital hemolytic anemia.

Lambert and Zail (1987) also found a variant of the alpha subunit. Two
brothers with the poikilocytic variant of hereditary elliptocytosis were
found to have a defect in spectrin dimer association and a decreased
spectrin/band 3 ratio. The major abnormal tryptic peptides derived from
the alpha-I domain had lower molecular weights and more basic
isoelectric points than hitherto described. The propositus of Lambert
and Zail (1987) was a black South African miner.

In a 6-week-old black infant, Garbarz et al. (1986) found hemolytic
anemia with red cell fragmentation, poikilocytosis, and elliptocytosis.
Both parents and a brother of the propositus had compensated mild
hereditary elliptocytosis. Studies indicated that the proband was
homozygous for an alpha-I/65 spectrin variant whereas both parents were
heterozygous.

In a family with hereditary elliptocytosis, Lane et al. (1987) found
that alpha-spectrin subunits migrated anomalously in SDS-PAGE. The
quantity of the alpha-spectrin mutant, expressed as a percentage of the
total alpha spectrin, varied from 9.9 to 45.2% among 6 affected persons.
Other findings suggested that this new alpha-spectrin mutant is
responsible for decreased spectrin dimer-dimer association and for red
cell instability. The propositus, a 23-month-old boy, exhibited anemia,
hyperbilirubinemia requiring phototherapy, and striking red cell
poikilocytosis at birth. His only sib, a 4-year-old who had
hyperbilirubinemia at birth, exhibited elliptocytosis without
poikilocytosis at the time of study. The mother, 2 of her sibs, and the
maternal grandfather had elliptocytosis.

MAPPING

Morton (1956) defined the existence of Rh-linked (611804) and
Rh-unlinked forms of elliptocytosis and emphasized the usefulness of
linkage studies in demonstration of genetic heterogeneity.

Keats (1979) suggested that a second elliptocytosis locus unlinked to Rh
is on chromosome 1. She found a lod score of 1.97 for theta of 0.0 for
linkage with Duffy. From analysis of the data by a maximum likelihood
method, Rao et al. (1979) concluded that there is 'nonsignificant
evidence of linkage' of an Rh-unlinked form of elliptocytosis to
chromosome 1 (lod score, 2.08).

MOLECULAR GENETICS

By in situ hybridization, the SPTA1 gene was mapped to 1q22-1q25
(Huebner et al., 1985) in the region proposed by Keats (1979) for a
non-Rh-linked form of elliptocytosis. In patients with elliptocytosis,
Marchesi et al. (1987) identified heterozygous mutations in the SPTA1
gene (182860.0001-182860.0002). This is one of the first examples of
positive results from the 'candidate gene' approach to elucidating
etiopathogenesis.

*FIELD* SA
Lux et al. (1981)
*FIELD* RF
1. Coetzer, T.; Zail, S. S.: Tryptic digestion of spectrin in variants
of hereditary elliptocytosis. J. Clin. Invest. 67: 1241-1248, 1981.

2. Evans, J. P. M.; Baines, A. J.; Hann, I. M.; Al-Hakim, I.; Knowles,
S. M.; Hoffbrand, A. V.: Defective spectrin dimer-dimer association
in a family with transfusion dependent homozygous hereditary elliptocytosis. Brit.
J. Haemat. 54: 163-172, 1983.

3. Garbarz, M.; Lecomte, M. C.; Dhermy, D.; Feo, C.; Chaveroche, I.;
Gautero, H.; Bournier, O.; Picat, C.; Goepp, A.; Boivin, P.: Double
inheritance of an alpha I/65 spectrin variant in a child with homozygous
elliptocytosis. Blood 67: 1661-1667, 1986.

4. Gomperts, E. D.; Cayannis, F.; Metz, J.; Zail, S. S.: A red cell
membrane protein abnormality in hereditary elliptocytosis. Brit.
J. Haemat. 25: 415-420, 1973.

5. Huebner, K.; Palumbo, A. P.; Isobe, M.; Kozak, C. A.; Monaco, S.;
Rovera, G.; Croce, C. M.; Curtis, P. J.: The alpha-spectrin gene
is on chromosome 1 in mouse and man. Proc. Nat. Acad. Sci. 82: 3790-3793,
1985.

6. Keats, B. J. B.: Another elliptocytosis locus on chromosome 1? Hum.
Genet. 50: 227-230, 1979.

7. Lambert, S.; Zail, S.: A new variant of the alpha-subunit of spectrin
in hereditary elliptocytosis. Blood 69: 473-478, 1987.

8. Lane, P. A.; Shew, R. L.; Iarocci, T. A.; Mohandas, N.; Hays, T.;
Mentzer, W. C.: Unique alpha-spectrin mutant in a kindred with common
hereditary elliptocytosis. J. Clin. Invest. 79: 989-996, 1987.

9. Lawler, J.; Coetzer, T. L.; Palek, J.; Jacob, H. S.; Luban, N.
: Sp alpha(I/65): a new variant of the alpha subunit of spectrin in
hereditary elliptocytosis. Blood 66: 706-709, 1985.

10. Lawler, J.; Liu, S.-C.; Palek, J.; Prchal, J.: A molecular defect
in spectrin with a subset of patients with hereditary elliptocytosis:
alterations in the alpha-subunit domain involved in spectrin self-association. J.
Clin. Invest. 73: 1688-1695, 1984.

11. Lecomte, M.-C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
Bournier, O.; Picat, C.; Chaveroche, I.; Ester, A.; Galand, C.; Boivin,
P.: Pathologic and nonpathologic variants of the spectrin molecule
in two black families with hereditary elliptocytosis. Hum. Genet. 71:
351-357, 1985.

12. Liu, S.-C.; Palek, J.; Prchal, J. T.: Defective spectrin dimer-dimer
association in hereditary elliptocytosis. Proc. Nat. Acad. Sci. 79:
2072-2076, 1982.

13. Lux, S. E.; Wolfe, L. C.: Inherited disorders of the red cell
membrane skeleton. Pediat. Clin. N. Am. 27: 463-486, 1980.

14. Lux, S. E.; Wolfe, L. C.; Pease, B.; Tomaselli, M. B.; John, K.
M.; Bernstein, S. E.: Hemolytic anemias due to abnormalities of red
cell spectrin: a brief review. Prog. Clin. Biol. Res. 45: 159-168,
1981.

15. Marchesi, S. L.; Letsinger, J. T.; Speicher, D. W.; Marchesi,
V. T.; Agre, P.; Hyun, B.; Gulati, G.: Mutant forms of spectrin alpha-subunits
in hereditary elliptocytosis. J. Clin. Invest. 80: 191-198, 1987.

16. Morton, N. E.: The detection and estimation of linkage between
the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8:
80-96, 1956.

17. Rao, D. C.; Keats, B. J.; Lalouel, J. M.; Morton, N. E.; Yee,
S.: A maximum likelihood map of chromosome 1. Am. J. Hum. Genet. 31:
680-696, 1979.

18. Ravindranath, Y.; Johnson, R. M.: Altered spectrin association
and membrane fragility without abnormal spectrin heat sensitivity
in a case of congenital hemolytic anemia. Am. J. Hemat. 20: 53-65,
1985.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Elliptocytosis

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the spectrin, alpha, erythrocytic-1 gene (SPTA1,
182860.0001)

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

*FIELD* ED
joanna: 05/18/2011

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

*FIELD* ED
carol: 04/30/2012
terry: 3/27/2012
terry: 3/18/2009
carol: 3/18/2009
mgross: 2/21/2008
terry: 4/30/1999
dkim: 7/21/1998
mimadm: 9/24/1994
carol: 5/13/1994
carol: 5/6/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/17/1992

MIM 179800
*RECORD*
*FIELD* NO
179800
*FIELD* TI
#179800 RENAL TUBULAR ACIDOSIS, DISTAL, AUTOSOMAL DOMINANT
;;RTA, DISTAL TYPE, AUTOSOMAL DOMINANT;;
read moreRENAL TUBULAR ACIDOSIS I;;
RTA, CLASSIC TYPE;;
RTA, GRADIENT TYPE
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
distal renal tubular acidosis has been found to be caused by mutation in
the SLC4A1 gene (109270).

CLINICAL FEATURES

Randall and Targgart (1961) observed renal tubular acidosis in members
of several successive generations. All affected members showed both
acidosis and nephrocalcinosis. Randall (1967) provided follow-up of this
family. The pedigree included 4 instances of male-to-male transmission.
The features were nephrocalcinosis, fixed urinary specific gravity,
fixed urinary pH of about 5.0, high serum chloride, low serum
bicarbonate, osteomalacia, and hypocalcemia. Alkalinization was
effective therapy.

Seedat (1968) observed 18 affected persons in 3 generations. In the
well-studied family reported by Gyory and Edwards (1968), 10 persons
were affected by test, 3 others were (by genealogic connections)
presumably affected and 2 others were reportedly affected. Male-to-male
transmission occurred. Richards and Wrong (1972) described familial
renal tubular acidosis in a mother and her 3 children.

Morris (1970) suggested that at least 3 types of renal tubular acidosis
could be recognized: a classic type (RTA I), in which the bicarbonate
threshold is normal and the defect is primarily in the distal tubule; a
proximal type (RTA II, see 604278), in which the bicarbonate threshold
is normal and the defect is primarily in the proximal tubule; and a
'dislocation,' or bicarbonate-wasting, type (RTA III, see 267200).

A phenocopy of the genetic disorder is produced by amphotericin B
(McCurdy et al., 1968).

Buckalew et al. (1974) suggested that there are 2 autosomal dominant
forms of RTA, one with hypercalciuria and one without. Hamed et al.
(1979) presented studies of a large kindred that appeared to indicate
that absorptive hypercalciuria is an autosomal dominant trait with
complete penetrance and variable expressivity, that can lead to renal
tubular acidosis and nephrocalcinosis. Buckalew et al. (1974) had also
shown in 1 family that hypercalciuria preceded RTA.

Chaabani et al. (1994) reported a family in which 28 members had primary
RTA I. In this large family, as well as in 2 other families with a small
number of affected individuals, some of the affected members were
asymptomatic. Clinical abnormalities commonly associated with RTA I,
such as nephrocalcinosis and growth retardation, appeared only in 3
cases among offspring when both parents were affected. Linkage studies
excluded close linkage to ABO, MNS, GM, and RH. Chaabani et al. (1994)
suggested that theirs was the first reported large family with primary
RTA I. Other families, such as those reported by Buckalew et al. (1974)
and Hamed et al. (1979), had RTA I secondary to hereditary
hypercalciuria.

In 2 unrelated males with primary renal tubular acidosis, Kondo et al.
(1978) found an inactive form of carbonic anhydrase B (CA2; 611492) in
red cells. Although antigenically and electrophoretically normal, it
showed decreased zinc binding. The zinc contained in isolated enzyme was
reduced and enzyme activity in hemolysates was restored by addition of
zinc chloride. One mother had depressed CA-B, but no increase in
specific activity was observed after addition of zinc. The authors
estimated that 41 and 62% of CA-B was of mutant type in their 2 cases
and apparently favored dominant inheritance. RTA of prominently distal
type associated with osteopetrosis (259730) has been found to have a
defect in CA2.

Bruce et al. (1997) studied 4 families with distal RTA. Most of the
patients presented clinically with renal stones, and the majority had
nephrocalcinosis. One patient had rickets when initially seen at age 10
years and developed osteomalacia at the age of 32 after she stopped
taking alkali therapy, but no other patient had bone disease. Eight
patients were not acidotic when first seen, and were diagnosed as
'incomplete' dominant RTA because they were unable to excrete a urine
more acid than pH 5.3 after oral acute ammonium chloride challenge.
Compared with acidotic cases, these patients tended to be younger, with
lower plasma creatinines, better preservation of urinary concentrating
ability, and less (or no) nephrocalcinosis; over a 10-year period, 2 of
the patients spontaneously developed acidosis. Acidotic patients were
treated with oral alkalis, usually 6 gm of sodium bicarbonate daily, and
had normal acid-base status at the time of the study; nonacidotic
patients were not treated.

MOLECULAR GENETICS

Bruce et al. (1997) and Karet et al. (1998) found that autosomal
dominant distal renal tubular acidosis is associated with mutations in
the SLC4A1 gene (see 109270.0012-109270.0015), which encodes the band 3
protein of the red cell membrane. Three of the mutations involved
arginine-589.

Fry and Karet (2007) reviewed the clinical features and molecular
genetics of the inherited renal acidoses.

HISTORY

Lewis (1992) proposed that Tiny Tim, the crippled son of Ebenezer
Scrooge's clerk, Bob Cratchit, in 'A Christmas Carol' by Charles Dickens
(1843), had distal renal tubular acidosis (type I). The description of
his affliction suggests the growth failure, osteomalacia with pathologic
fractures, hypokalemic muscle weakness, and periodic paralysis that are
characteristic of that disorder.

*FIELD* SA
Buckalew (1968); Coe and Parks (1980); Musgrave et al. (1972); Seldin
and Wilson (1972)
*FIELD* RF
1. Bruce, L. J.; Cope, D. L.; Jones, G. K.; Schofield, A. E.; Burley,
M.; Povey, S.; Unwin, R. J.; Wrong, O.; Tanner, M. J. A.: Familial
distal renal tubular acidosis is associated with mutations in the
red cell anion exchanger (band 3, AE1) gene. J. Clin. Invest. 100:
1693-1707, 1997.

2. Buckalew, V. M.; Purvis, M. L.; Shulman, M. G.; Herndon, C. N.;
Rudman, D.: Hereditary renal tubular acidosis: report of a 64 member
kindred with variable clinical expression including idiopathic hypercalcinuria. Medicine 53:
229-254, 1974.

3. Buckalew, V. M., Jr.: Familial renal tubular acidosis. Ann. Intern.
Med. 68: 1367-1368, 1968.

4. Chaabani, H.; Hadj-Khlil, A.; Ben-Dhia, N.; Braham, H.: The primary
hereditary form of distal renal tubular acidosis: clinical and genetic
studies in 60-member kindred. Clin. Genet. 45: 194-199, 1994.

5. Coe, F. L.; Parks, J. H.: Stone disease in hereditary distal renal
tubular acidosis. Ann. Intern. Med. 93: 60-61, 1980.

6. Fry, A. C.; Karet, F. E.: Inherited renal acidoses. Physiology 22:
202-211, 2007.

7. Gyory, A. Z.; Edwards, K. D. G.: Renal tubular acidosis: a family
with an autosomal dominant genetic defect in renal hydrogen ion transport
with proximal tubular and collecting duct dysfunction and increased
metabolism of citrate and ammonia. Am. J. Med. 45: 43-62, 1968.

8. Hamed, I. A.; Crerwinski, A. W.; Coats, B.; Kaufman, C.; Altmiller,
D. H.: Familial absorptive hypercalcinuria and renal tubular acidosis. Am.
J. Med. 67: 385-391, 1979.

9. Karet, F. E.; Gainza, F. J.; Gyory, A. Z.; Unwin, R. J.; Wrong,
O.; Tanner, M. J. A.; Nayir, A.; Alpay, H.; Santos, F.; Hulton, S.
A.; Bakkaloglu, A.; Ozen, S.; Cunningham, M. J.; di Pietro, A.; Walker,
W. G.; Lifton, R. P.: Mutations in the chloride-bicarbonate exchanger
gene AE1 cause autosomal dominant but not autosomal recessive distal
renal tubular acidosis. Proc. Nat. Acad. Sci. 95: 6337-6342, 1998.

10. Kondo, T.; Taniguchi, N.; Taniguchi, K.; Matsuda, I.; Murao, M.
: Inactive form of erythrocyte carbonic anhydrase B in patients with
primary renal tubular acidosis. J. Clin. Invest. 62: 610-617, 1978.

11. Lewis, D. W.: What was wrong with Tiny Tim? Am. J. Dis. Child. 146:
1403-1407, 1992.

12. McCurdy, D. K.; Frederic, M.; Elkinton, J. R.: Renal tubular
acidosis due to amphotericin B. New Eng. J. Med. 278: 124-131, 1968.

13. Morris, R. C., Jr.: Renal tubular acidosis: mechanisms, classification
and implications. New Eng. J. Med. 281: 1405-1413, 1970.

14. Musgrave, J. E.; Bennett, W. M.; Campbell, R. A.; Eisenberg, C.
S.: Renal tubular acidosis. (Letter) Lancet 300: 1364 only, 1972.
Note: Originally Volume 2.

15. Randall, R. E., Jr.: Familial renal tubular acidosis revisited.
(Letter) Ann. Intern. Med. 66: 1024-1025, 1967.

16. Randall, R. E., Jr.; Targgart, W. H.: Familial renal tubular
acidosis. Ann. Intern. Med. 54: 1108-1116, 1961.

17. Richards, P.; Wrong, O. M.: Dominant inheritance in a family
with familial renal tubular acidosis. Lancet 300: 998-999, 1972.
Note: Originally Volume 2.

18. Seedat, Y. K.: Familial renal tubular acidosis. (Letter) Ann.
Intern. Med. 69: 1329 only, 1968.

19. Seldin, D. W.; Wilson, J. D.: Renal tubular acidosis.In: Stanbury,
J. B.; Wyngaarden, J. B.; Fredrickson, D. S.: The Metabolic Basis
of Inherited Disease. New York: McGraw-Hill (pub.) (3rd ed.)
: 1972. Pp. 1548-1566.

*FIELD* CS

Metabolic:
Renal tubular acidosis

GU:
Nephrocalcinosis

Skel:
Osteomalacia;
Pathologic fractures

Growth:
Growth failure

Muscle:
Hypokalemic muscle weakness;
Periodic paralysis

Lab:
Fixed urinary specific gravity;
Fixed urinary pH of about 5.0;
High serum chloride;
Low serum bicarbonate;
Hypocalcemia

Inheritance:
Autosomal dominant form;
multiple dominant and a recessive form(s)

*FIELD* CN
Marla J. F. O'Neill - updated: 11/13/2007
Marla J. F. O'Neill - updated: 11/8/2007
Victor A. McKusick - updated: 6/12/1998

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

*FIELD* ED
terry: 04/08/2009
wwang: 11/28/2007
terry: 11/13/2007
carol: 11/8/2007
carol: 10/11/2007
carol: 1/4/2005
terry: 6/2/2004
alopez: 11/2/1999
terry: 6/11/1999
carol: 6/16/1998
terry: 6/12/1998
carol: 6/10/1998
mimadm: 3/25/1995
davew: 8/1/1994
jason: 6/7/1994
warfield: 4/21/1994
carol: 3/15/1994
carol: 11/16/1993

MIM 601550
*RECORD*
*FIELD* NO
601550
*FIELD* TI
#601550 BLOOD GROUP--SWANN SYSTEM; SW
;;SWANN BLOOD GROUP
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
read moreSwann blood group antigens result from variation in the SLC4A1 gene
(109270), which encodes the erythrocyte band-3 protein, on chromosome
17q21.

DESCRIPTION

The low-incidence red cell antigen Sw(a) of the Swann blood group system
was described by Cleghorn (1959). It was shown to be inherited as an
autosomal dominant trait and, although it was not very polymorphic in
the general population, sizable kindreds segregating for the SW locus
were identified (Lewis et al., 1988).

MAPPING

Genetic linkage studies excluded SW from 17 of the 23 established blood
group systems (Daniels et al., 1995). Zelinski et al. (1996) found a
peak lod score of 3.01 for the linkage of SW and D17S41, a RFLP
polymorphism on chromosome 17. No evidence of recombination was found.
Families studied were 3 nuclear families from a previously described
French Canadian kindred (Lewis et al., 1988). The SW locus is in the
same region of 17q as the Waldner group locus (WD; 112010) and the
Froese blood group locus (FR; 601551); although each resides within the
17q12-q24 region, each is clearly unique. Zelinski et al. (1996) showed
that the FR locus is tightly linked to the SLC4A1 gene, where mutations
causing the Waldner polymorphism are known to be located. They suggested
that Fr(a) and Sw(a) may be due to mutations in the SLC4A1 gene.

MOLECULAR GENETICS

Molecular analysis demonstrating that Fr(a) and Sw(a) are caused by
mutation in the SLC4A1 gene was provided by McManus et al. (2000) and by
Zelinski et al. (2000), respectively; see 109270.0029 and 109270.0030.

*FIELD* RF
1. Cleghorn, T. E.: A 'new' human blood group antigen, Sw(a). Nature 184:
1324-1325, 1959.

2. Daniels, G. L.; Anstee, D. J.; Cartron, J. P.; Dahr, W.; Issitt,
P. D.; Jorgensen, J.; Kornstad, L.; Levene, C.; Lomas-Francis, C.;
Lubenko, A.; Mallory, D.; Moulds, J. J.; and 9 others: Blood group
terminology 1995: ISBT Working Party on terminology for red cell surface
antigens. Vox Sang. 69: 265-279, 1995.

3. Lewis, M.; Kaita, H.; Philipps, S.; Coghlan, G.; Belcher, E.; Zelinski,
T.; McAlpine, P. J.; Coopland, G.: The Swann phenotype 700:4,-41:
genetic studies. Vox Sang. 54: 184-187, 1988.

4. McManus, K.; Lupe, K.; Coghlan, G.; Zelinski, T.: An amino acid
substitution in the putative second extracellular loop of RBC band
3 accounts for the Froese blood group polymorphism. Transfusion 40:
1246-1249, 2000.

5. Zelinski, T.; McKeown, I.; McAlpine, P. J.; Philipps, S.; Coghlan,
G.: Assignment of the gene(s) governing Froese and Swann blood group
polymorphism to chromosome 17q. Transfusion 36: 419-420, 1996.

6. Zelinski, T.; Rusnak, A.; McManus, K.; Coghlan, G.: Distinctive
Swann blood group genotypes: molecular investigations. Vox Sang. 79:
215-218, 2000.

*FIELD* CN
Victor A. McKusick - updated: 12/22/2005

*FIELD* CD
Victor A. McKusick: 12/4/1996

*FIELD* ED
carol: 04/09/2012
carol: 12/28/2005
terry: 12/22/2005
joanna: 3/18/2004
mark: 7/16/1997
alopez: 7/3/1997
alopez: 6/27/1997
mark: 12/9/1996
mark: 12/5/1996

MIM 601551
*RECORD*
*FIELD* NO
601551
*FIELD* TI
#601551 BLOOD GROUP--FROESE
;;FR;;
FROESE BLOOD GROUP ANTIGEN
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
read morelow-incidence Froese blood group antigen polymorphism is based on a
change in the SLC4A1 (109270) gene, which encodes erythrocyte protein
band-3, on chromosome 17q21.

DESCRIPTION

The low-incidence red cell antigen Fr(a) was described by Lewis et al.
(1978) in Mennonite kindreds in Manitoba. It was shown to be inherited
as an autosomal dominant trait, and although it was not very polymorphic
in the general population, it was studied in sizable kindreds.

MAPPING

Genetic linkage excluded the FR locus from 17 of the 23 established
blood group systems (Daniels et al., 1995). Another private blood group
antigen, Wd(a), which defines the Waldner blood group locus (WD; 112010)
was shown to map to 17q and to a point mutation in the SLC4A1 gene
(109270). Zelinski et al. (1996) showed that the FR locus is tightly
linked to SLC4A1 with a peak lod score of 5.72 in 5 nuclear families
from 3 previously unpublished Mennonite kindreds. The Swann blood group
locus (SW; 601550) and the WD and FR loci all mapped to the 17q12-q24
region, suggesting that they may represent separate alleles of the
SLC4A1 gene.

MOLECULAR GENETICS

In 2 unrelated Mennonite kindreds segregating for Fr(a), McManus et al.
(2000) demonstrated an SLC4A1 exon 13 mobility shift in the SSCP
analysis in the DNA from all Fr(a+) persons that was not seen in the DNA
from Fr(a-) family members or control subjects. Linkage between the exon
13 SSCP and Fr(a) was established, with peak lods of 3.62 at theta =
0.00 for combined paternal and maternal meioses. DNA sequencing revealed
a GAG-to-AAG mutation that underlies a glu480-to-lys substitution in
erythrocyte protein band 3. McManus et al. (2000) defined Fr(a) as a
Diego system (110500) member. On the basis of erythrocyte band-3
structural predictions, they concluded that the glu480-to-lys
substitution is located in the second extracellular loop of the protein;
thus, Fr(a) was the first antigen to be localized to this region of the
molecule.

*FIELD* RF
1. Daniels, G. L.; Anstee, D. J.; Cartron, J. P.; Dahr, W.; Issitt,
P. D.; Jorgensen, J.; Kornstad, L.; Levene, C.; Lomas-Francis, C.;
Lubenko, A.; Mallory, D.; Moulds, J. J.; and 9 others: Blood group
terminology 1995: ISBT Working Party on terminology for red cell surface
antigens. Vox Sang. 69: 265-279, 1995.

2. Lewis, M.; Kaita, H.; McAlpine, P. J.; Fletcher, J.; Moulds, J.
J.: A 'new' blood group antigen Fr(a): incidence, inheritance and
genetic linkage analysis. Vox Sang. 35: 251-254, 1978.

3. McManus, K.; Lupe, K.; Coghlan, G.; Zelinski, T.: An amino acid
substitution in the putative second extracellular loop of RBC band
3 accounts for the Froese blood group polymorphism. Transfusion 40:
1246-1249, 2000.

4. Zelinski, T.; McKeown, I.; McAlpine, P. J.; Philipps, S.; Coghlan,
G.: Assignment of the gene(s) governing Froese and Swann blood group
polymorphism to chromosome 17q. Transfusion 36: 419-420, 1996.

*FIELD* CN
Victor A. McKusick - updated: 12/22/2005

*FIELD* CD
Victor A. McKusick: 12/4/1996

*FIELD* ED
carol: 04/09/2012
carol: 4/28/2011
carol: 12/28/2005
terry: 12/22/2005
joanna: 3/18/2004
joanna: 7/7/1997
alopez: 6/27/1997
mark: 12/9/1996
mark: 12/5/1996

MIM 611162
*RECORD*
*FIELD* NO
611162
*FIELD* TI
#611162 MALARIA, SUSCEPTIBILITY TO
MALARIA, RESISTANCE TO, INCLUDED;;
MALARIA, SEVERE, SUSCEPTIBILITY TO, INCLUDED;;
read moreMALARIA, SEVERE, RESISTANCE TO, INCLUDED;;
MALARIA, CEREBRAL, SUSCEPTIBILITY TO, INCLUDED;;
MALARIA, CEREBRAL, RESISTANCE TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because variation in several
different genes influences susceptibility and resistance to malaria, as
well as disease progression and severity. These genes include HBB
(141900), ICAM1 (147840), CD36 (173510), CR1 (120620), GYPA (111300),
GYPB (111740), GYPC (110750), TNF (191160), NOS2A (163730), TIRAP
(606252), FCGR2B (604590), and CISH (602441). In addition, a locus
associated with Plasmodium falciparum blood infection level has been
mapped to chromosome 5q31-q33 (PFBI; 248310), a locus for susceptibility
to mild malaria has been mapped to chromosome 6p21.3 (MALS; 609148), a
locus associated with malaria fever episodes has been mapped to
chromosome 10p15 (PFFE1; 611384), and a locus for susceptibility to
placental malarial infection has been mapped to chromosome 6 (FUT9;
606865). Complete protection from Plasmodium vivax infection is
associated with the Duffy blood group-negative phenotype (see 110700).
Alpha(+)-thalassemia (141800), the X-linked disorder G6PD deficiency
(300908), and Southeast Asian ovalocytosis (109270) are associated with
resistance to malaria.

DESCRIPTION

Malaria, a major cause of child mortality worldwide, is caused by
mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the
4 species that infect humans, P. falciparum causes the most severe forms
of malaria and is the major cause of death and disease. Although less
fatal, P. malariae, P. ovale, and, in particular, P. vivax infections
are major causes of morbidity. The parasite cycle involves a first stage
in liver cells and a subsequent stage at erythrocytes, when malaria
symptoms occur. A wide spectrum of phenotypes are observed, from
asymptomatic infection to mild disease, including fever and mild anemia,
to severe disease, including cerebral malaria, profound anemia, and
respiratory distress. Genetic factors influence the response to
infection, as well as disease progression and severity. Malaria is the
strongest known selective pressure in the recent history of the human
genome, and it is the evolutionary driving force behind sickle-cell
disease (603903), thalassemia (see 141800), glucose-6-phosphatase
deficiency (300908), and other erythrocyte defects that together
constitute the most common mendelian diseases of humans (Kwiatkowski,
2005; Campino et al., 2006).

PATHOGENESIS

Compared with other microorganisms, P. falciparum malaria parasites
reach very high densities in blood. P. falciparum-infected erythrocytes
(PfIRBCs) induce ICAM1 (147840) expression on human brain microvascular
endothelial cells (HBMECs), but not on human umbilical vein endothelial
cells. PfIRBCs compromise the electrical function of brain endothelium
independently of PfIRBC binding phenotype, suggesting a role for soluble
parasite factors. By performing genomewide transcriptional profiling of
HBMECs after exposure to isogenic PfIRBCs, followed by ELISA for protein
identification, Tripathi et al. (2009) identified upregulated molecules
involved in immune response, apoptosis and antiapoptosis, inflammatory
response, cell-cell signaling, and signal transduction and activation of
the NF-kappa-B (see 164011) cascade. Proinflammatory molecules,
including CCL20 (601960), CXCL1 (155730), CXCL2 (139110), IL6 (147620),
and IL8 (146930), were upregulated more than 100-fold. Tripathi et al.
(2009) concluded that PfIRBC exposure to HBMECs results in a
predominantly proinflammatory response mediated by NF-kappa-B
activation.

By incubating erythrocytes with increasing amounts of anti-CR1
antibodies or soluble CR1 (120620), followed by immunoprecipitation
analysis, Tham et al. (2010) showed that the P. falciparum merozoite
ligand PfRh4 bound to CR1. Levels of PfRh4 binding correlated with CR1
expression on the erythrocyte surface, which is controlled by the CR1
exon 22 SNP (120620.0001). Binding was reduced in individuals homozygous
for low CR1 expression. Parasite invasion of neuraminidase-treated
erythrocytes was also reduced. Tham et al. (2010) concluded that CR1 is
an erythrocyte receptor used by P. falciparum PfRh4 for sialic
acid-independent invasion.

By systematic screening of a library of erythrocyte proteins, Crosnier
et al. (2011) identified basigin (BSG; 109480) as a receptor for PfRh5,
a P. falciparum ligand essential for blood stage growth of the parasite.
Soluble basigin or basigin knockdown inhibited erythrocyte invasion by
all P. falciparum strains, and complete blocking was achieved by
anti-basigin antibodies. OK(a-) red blood cells, which express the
glu92-to-lys (E92K; 109480.0001) variant of basigin, had reduced binding
to PfRh5 due to slower association and faster dissociation rates.
Another basigin variant, leu90 to pro (L90P), did not interact with
PfRh5 at all. Crosnier et al. (2011) concluded that the dependence on a
single receptor-ligand pair across many P. falciparum strains may
provide novel possibilities for therapeutic intervention.

By screening an array of full-length plasma membrane proteins expressed
on human embryonic kidney cells, Turner et al. (2013) identified the
endothelial protein C receptor (EPCR; 600646) as a binding partner of
domain cassette-8 of the Plasmodium falciparum erythrocyte membrane
protein-1 (DC8-PfEMP1). They mapped the PfEMP1 EPCR-binding domain by
ELISA with DC8-PfEMP1C8 variants. Further analysis confirmed that PfEmp1
proteins have diverged into CD36 (173510)- and EPCR-binding subtypes.
DC8-PfEMP1-expressing and parasitized erythrocytes bound to brain
endothelial cells and were inhibited by recombinant EPCR or anti-EPCR
antibodies. Turner et al. (2013) proposed that PfEMP1-EPCR-mediated
cytoadhesion is the major virulence phenotype for severe malaria.

Cserti-Gazdewich et al. (2012) conducted a prospective analysis of ABO
blood groups (see 110300) and cytoadhesion receptors CD36 and ICAM1 in
approximately 2,000 Ugandan children with either uncomplicated or severe
malaria, including cerebral malaria (CM), severe anemia (SA), and lactic
acidosis (LA). Survival was enhanced in individuals with blood group O
and increased monocyte expression of CD36 and ICAM1. Blood group O was
nearly 50% in 180,000 adult blood donors and in children with
uncomplicated malaria, whereas it was approximately 40% in children with
severe malaria. High case fatality rates in cerebral malaria and lactic
acidosis were associated with high platelet CD36 expression and
thrombocytopenia, whereas severe anemia was characterized by low ICAM1
expression. Logistic regression analysis showed that the odds ratios for
the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were
greater than that of sickle cell hemoglobin. Cserti-Gazdewich et al.
(2012) concluded that selection pressure by P. falciparum continues to
shape the human genome.

MAPPING

Rihet et al. (1998) provided evidence for linkage of the level of blood
infection with Plasmodium falciparum and chromosome region 5q31-q33 (see
248310).

Flori et al. (2003) demonstrated linkage of mild malaria to the MHC
region in an urban population living in an endemic area in Burkina Faso
(see 609148).

Timmann et al. (2007) reported significant association between malaria
fever episodes and a locus on chromosome 10p15 (PFFE1; 611384) in a
rural Ghanaian population.

Fortin et al. (2002) reviewed the mapping of gene effects in malaria,
both in humans and in mice, using population studies and experimental
models of malaria susceptibility.

- Associations Pending Confirmation

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) identified novel
resistance loci for severe malaria within the ATP2B4 gene (108732) on
chromosome 1q32.1 and near the MARVELD3 gene (614094) on chromosome
16q22.2. Several SNPs within the ATP2B4 gene showed significant
association, with dbSNP rs10900585 within intron 2 showing strongest
association (odds ratio = 0.65; P = 6.1 x 10(-9)). ATP2B4 encodes the
major Ca(2+) pump in erythrocytes, the host cells of the pathogenic
stage of malaria, and Timmann et al. (2012) hypothesized that variants
in ATP2B4 may disturb homeostasis of intraerythrocytic Ca(2+)
concentrations and impact parasite reproduction and maturation. The
associated SNP on chromosome 16q22.2, dbSNP 2334880 (odds ratio = 1.24;
P = 3.9 x 10(-8)), is located 6.4 kb upstream of the MARVELD3 gene. The
MARVELD3 product is part of tight junction structures of epithelial and
vascular endothelial cells, and Timmann et al. (2012) noted that
endothelial adherence is important in the pathology of severe malaria.

MOLECULAR GENETICS

- Variation in HBB and Resistance to Malaria

In a review, Kwiatkowski (2005) noted that 3 coding SNPs in the HBB gene
confer resistance to malaria and have risen to high frequency in
different populations: HbS (141900.0243), HbC (141900.0038), and HbE
(141900.0071). The HbS allele is maintained at a frequency of 10% in
malaria-endemic regions, including sub-Saharan Africa and parts of the
Middle East. HbS homozygotes have sickle-cell disease (603903), a
debilitating and often fatal disorder. The heterozygous state, denoted
HbAS, is not associated with any clinical abnormality and confers a
10-fold increase in protection from life-threatening malaria and lesser
protection against mild malaria. The HbC allele is found in several
parts of West Africa, but is less common than HbS. Homozygotes have
relatively mild hemolytic anemia, and both homozygotes and heterozygotes
are protected against severe malaria, though homozygotes show
substantially greater protection. HbE is common in Southeast Asia.
Homozygotes generally have symptomless anemia, and erythrocytes from HbE
heterozygotes are resistant to invasion by P. falciparum.

Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs)
from 53 families in Burkina Faso over 2 years and found that hemoglobin
C carriers were found to have less frequent malaria attacks than AA
individuals within the same age group (P = 0.01). Analysis of individual
hemoglobin alleles yielded a negative association between Hb C and
malaria attack (P = 0.00013). Analyses that took into account
confounding factors confirmed the negative association of Hb C with
malaria attack (P = 0.0074) and evidenced a negative correlation between
Hb C and parasitemia (P = 0.0009).

Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the
cell-surface properties of P. falciparum-infected erythrocytes involved
in pathogenesis. Relative to parasite-infected normal erythrocytes (Hb
AA), parasitized AC and CC erythrocytes showed reduced adhesion to
endothelial monolayers expressing CD36 (173510) and intercellular
adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting
interactions with nonparasitized erythrocytes, and reduced agglutination
in the presence of pooled sera from malaria-immune adults. Abnormal
cell-surface display of the main variable cytoadherence ligand, PfEMP-1
(P. falciparum erythrocyte membrane protein-1), correlated with these
findings. The abnormalities in PfEMP-1 display were associated with
markers of erythrocyte senescence, and were greater in CC than in AC
erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might
protect against malaria by reducing PfEMP1-mediated adherence of
parasitized erythrocytes, thereby mitigating the effects of their
sequestration in the microvasculature.

Ayodo et al. (2007) performed an association study combined with
evidence of natural selection. The association study tested 10 putative
resistance variants in 471 severe malaria cases (mean age 2.6 years) and
474 controls (mean age 16.9 years) from the Luo tribe, who live in a
malaria-endemic region of Kenya. The authors replicated associations
with HBB and CD36. In the selection study, Ayodo et al. (2007) assembled
population control samples from the Masai, Kikuyu, and Yoruba ethnic
groups. They found that the same variants are unusually differentiated
between the Luo and Yoruba (also historically exposed to malaria in
Nigeria) and the Masai and Kikuyu tribes (both living in nonendemic
regions of Kenya). Although evidence of association for HBB and CD36 was
only moderate by the association analysis alone, formal combination of
evidence of association with evidence from the selection test yielded
greatly increased significance, up to P = 0.000018 for HBB and P =
0.00043 for CD36. Ayodo et al. (2007) concluded that they empirically
demonstrated the theoretical concept of increasing statistical power by
orders of magnitude to detect disease variants by combining association
analysis with evidence of natural selection.

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) confirmed the
protective effect of sickle cell trait.

- Thalassemia and Resistance to Malaria

The suggestion that alpha(+)-thalassemia (141800) has achieved a high
frequency in some populations as a result of selection by malaria is
based on a number of epidemiologic studies. In the southwest Pacific
region, there is a striking geographic correlation between the frequency
of alpha(+)-thalassemia and the endemicity of Plasmodium falciparum.
Allen et al. (1997) undertook a prospective case-control study of
children with severe malaria on the north coast of Papua New Guinea,
where malaria transmission is intense and alpha(+)-thalassemia affects
more than 90% of the population (homozygotes comprise approximately 55%
and heterozygotes 37% of the population). Compared with normal children,
the risk of having severe malaria was 0.40 in alpha(+)-thalassemia
homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of
hospital admission with infections other than malaria also was reduced
to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This
clinical study demonstrated that a malaria resistance gene protects
against disease caused by infections other than malaria. A reduction in
mortality greater than that attributable directly to malaria had been
observed after the prevention of malaria by insecticides,
chemoprophylaxis, and insecticide-impregnated bed nets. Previous
observations that direct malaria mortality cannot account for observed
hemoglobin S gene frequencies suggest that the findings of this study
may apply equally to other malaria resistance genes.

In a study of the epidemiology of childhood malaria on the southwestern
Pacific island of Espiritu Santo in Vanuatu, Williams et al. (1996)
found that, paradoxically, both the incidence of uncomplicated malaria
and the prevalence of splenomegaly, an index of malarial infection, were
significantly higher in young children with alpha(+)-thalassemia than in
normal children. Furthermore, this effect was most marked in the
youngest children and for the nonlethal parasite Plasmodium vivax. The
authors speculated that the alpha(+)-thalassemias may have been selected
for the ability to increase susceptibility to P. vivax, which, by acting
as a natural vaccine in this community, induced limited cross-species
protection against subsequent severe P. falciparum malaria.

- Variation in FY and Resistance to P. Vivax Infection

The Duffy-null phenotype (see 110700), which results from a promoter SNP
in the DARC gene (613665.0002), provides complete protection against P.
vivax infection (Kwiatkowski, 2005).

- G6PD Deficiency and Resistance to Malaria

Among Nigerian children with convulsions and heavy parasitemia from
falciparum malaria, Martin et al. (1979) noted a reduced frequency of
G6PD deficiency (305900), an X-linked disorder. They pointed out that
the only support for a role of malaria in selecting for deficiency genes
had been geographic association. The mechanism of protection of
G6PD-deficient cells against falciparum malaria was worked out by
Friedman and Trager (1981). G6PD is critical to the regeneration of
NADPH, a coenzyme that is essential for protection against and repair of
oxidative damage. Red cells deficient in G6PD are more sensitive to
hydrogen peroxide generated by the malaria parasite. The loss of
potassium from the cell and from the parasite is largely responsible for
the death of the parasite. The fava bean contains a variety of
substances that increase the red cells' sensitivity to oxidants. Eating
fava beans and perhaps other foods as yet not identified would be
expected to increase the level of protection against malaria in people
who are heterozygous for G6PD deficiency and for thalassemia. Fetal red
cells likewise have an increased sensitivity to oxidants and a resulting
resistance to malaria. This is true of adult cells that have unusually
high concentration of fetal hemoglobin. Roth et al. (1983) found that
G6PD-deficient red cells of Sardinian hemizygotes and heterozygotes
supported growth of the Plasmodium falciparum parasite in vitro only
about one-third as well as normal red cells. No abnormality of growth
could be demonstrated in red cells from Sardinians with the
beta-zero-thalassemia trait. The authors suggested that the data support
a selective advantage of G6PD deficiency in malarious areas; the
advantage of the female heterozygote may be particularly strong if
resistance to malaria equals that in the hemizygous male, without the
risk of fatal hemolysis.

That resistance to severe malaria is the basis of the high frequency of
G6PD deficiency and that both hemizygotes and heterozygotes enjoy an
advantage was established by Ruwando et al. (1995) in 2 large
case-control studies of more than 2,000 African children. They found
that the common African form of G6PD deficiency (G6PD A-; 305900.0002)
was associated with a 46 to 58% reduction in risk of severe malaria for
both female heterozygotes and male hemizygotes. A mathematical model
incorporating the measured selective advantage against malaria suggested
that a counterbalancing selective disadvantage, associated with this
enzyme deficiency, has retarded its rise in frequency in malaria-endemic
regions.

Cappadoro et al. (1998) found that with 5 different strains of
Plasmodium falciparum, there was no significant difference in either
invasion or maturation when the parasites were grown in either normal or
G6PD-deficient (Mediterranean variant; 305900.0006) erythrocytes. With
all of these strains and at different maturation stages, they were
unable to detect any difference in the amount of P. falciparum-specific
G6PD mRNA in normal versus deficient parasitized erythrocytes. By
contrast, in studies of phagocytosis of parasitized erythrocytes by
human adherent monocytes, they found that when the parasites were at the
ring stage, deficient ring-stage parasitized erythrocytes (RPE) were
phagocytized 2.3 times more intensely than normal RPEs, whereas there
was no difference when the parasites were at the more mature trophozoite
stage, i.e., trophozoite-stage parasitized erythrocytes (TPEs). The
level of reduced glutathione was remarkably lower in deficient RPEs
compared with normal RPEs. Cappadoro et al. (1998) concluded that
impaired antioxidant defense in deficient RPEs may be responsible for
membrane damage followed by phagocytosis. Because RPEs, unlike TPEs, are
nontoxic to phagocytes, the increased removal by phagocytosis of RPEs
would reduce maturation to TPEs and to schizonts and may be a highly
efficient mechanism of malaria resistance in deficient subjects.

Louicharoen et al. (2009) investigated the effect of the G6PD-Mahidol
487A variant (305900.0005) on human survival related to P. vivax and P.
falciparum malaria in Southeast Asia. They showed that strong and recent
positive selection has targeted the Mahidol variant over the past 1,500
years. The authors found that the G6PD-Mahidol variant reduces vivax,
but not falciparum, parasite density in humans, which indicates that P.
vivax has been a driving force behind the strong selective advantage
conferred by this mutation.

- Variation in GYPA and Resistance to Malaria

Red cells with the rare En(a-) variant of GYPA (111300) are resistant to
falciparum malaria (Pasvol et al., 1982).

- Variation in GYPB and Resistance to Malaria

Red cells with the rare U(-) variant of GYPB (111740) are relatively
resistant to invasion by P. falciparum (Pasvol and Wilson, 1982).

- Variation in GYPC and Resistance to Malaria

Deletion of exon 3 in the GYPC gene (110750.0002) has been found in
Melanesians; this alteration changes the serologic phenotype of the
Gerbich (Ge) blood group system (110750), resulting in Ge negativity
(Booth and McLoughlin, 1972; Serjeantson et al., 1994). The GYPC exon 3
deletion allele reaches a high frequency (46.5%) in coastal areas of
Papua New Guinea where malaria is hyperendemic (Patel et al., 2001).
Plasmodium falciparum erythrocyte-binding antigen-140 (EBA140, also
known as BAEBL) binds with high affinity to the surface of human
erythrocytes. Maier et al. (2003) showed that the receptor for EBA140 is
glycophorin C and that this interaction mediates a principal P.
falciparum invasion pathway into human erythrocytes. EBA140 does not
bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade
such cells using this invasion pathway. This provides compelling
evidence that Ge negativity has arisen in Melanesian populations through
natural selection by severe malaria.

- Southeast Asian Ovalocytosis and Resistance to Cerebral
Malaria

Kidson et al. (1981) found that ovalocytic erythrocytes from Melanesians
were resistant to invasion by malaria parasites. Baer (1988) suggested
that Malaysian elliptocytosis (109270) may be a balanced polymorphism,
i.e., that individuals homozygous for the elliptocytosis allele may be
differentially susceptible to mortality, whereas the heterozygote is at
an advantage. Hadley et al. (1983) showed that Melanesian elliptocytes
were highly resistant to invasion by Plasmodium knowlesi and P.
falciparum in vitro.

The band 3 variant in southeast Asian ovalocytosis (109270.0002) may
prevent cerebral malaria, but it exacerbates malarial anemia and may
also increase acidosis, a major determinant of mortality in malaria.
Allen et al. (1999) undertook a case-control study of children admitted
to hospital in a malarious area of Papua New Guinea. The 24-bp deletion,
detected by PCR, was present in 0 of 68 children with cerebral malaria,
compared with 6 (8.8%) of 68 matched community controls. Median
hemoglobin levels were 1.2 g/dl lower in malaria cases with southeast
Asian ovalocytosis than in controls (P = 0.035), but acidosis was not
affected. The band 3 protein mediates the cytoadherence of parasitized
erythrocytes in vitro. The remarkable protection that the variant
affords against cerebral malaria may offer a valuable approach to a
better understanding of the mechanisms of adherence of parasitized
erythrocytes to vascular endothelium and the pathogenesis of cerebral
malaria.

- Variation in CD36 and Susceptibility or Resistance to Cerebral
Malaria

CD36 is a major receptor for Plasmodium falciparum-infected
erythrocytes. Aitman et al. (2000) found that African populations
contain an exceptionally high frequency of mutations in CD36 (173510).
Unexpectedly, these mutations (173510.0002 and 173510.0003) that cause
CD36 deficiency (608404) were associated with susceptibility to severe
cerebral malaria, suggesting that the presence of distinct CD36
mutations in Africans and Asians is due to some selection pressure other
than malaria.

In 475 adult Thai patients with P. falciparum malaria, Omi et al. (2003)
screened for variation in the CD36 gene and examined possible
association between CD36 polymorphisms and the severity of malaria. They
identified 9 CD36 polymorphisms with a frequency of more than 15% for
the minor allele. Of these, the -14T-C allele in the upstream promoter
region and the -53G-T allele in the downstream promoter region were
significantly decreased in patients with cerebral malaria compared with
those with mild malaria. Linkage disequilibrium (LD) analysis between
the 9 common polymorphisms revealed 2 blocks with strong LD in the CD36
gene; the -14T-C and -53G-T polymorphisms were within the upstream block
of 35 kb from the upstream promoter to exon 8. Another polymorphism,
consisting of 12 TG repeats in intron 3 (173510.0004), was strongly
associated with reduction in the risk of cerebral malaria. Omi et al.
(2003) demonstrated by RT-PCR amplification that this IVS3(TG)12
polymorphism is involved in the nonproduction of the variant CD36
transcript that lacks exons 4 and 5. Because exon 5 of the gene is known
to encode the ligand-binding domain for P. falciparum-infected
erythrocytes, IVS3(TG)12 itself or a primary variant on the haplotype
with IVS3(TG)12 may be responsible for protection from cerebral malaria
in Thailand.

Ayodo et al. (2007) sought to demonstrate that statistical power to
detect disease variants can be increased by weighting candidates by
their evidence of natural selection. Although evidence of association
for HBB and CD36 was only moderate by an association analysis alone,
formal combination of evidence of association with evidence from a
selection test yielded greatly increased significance, up to P =
0.000018 for HBB and P = 0.00043 for CD36.

- Variation in CR1 and Resistance to Malaria

The Knops blood group system (607486) is a system of antigens located on
CR1. Rowe et al. (1997) demonstrated that CR1 is involved in malarial
rosetting, a process associated with cerebral malaria, which is the
major cause of mortality in Plasmodium falciparum malaria. They showed
that rosette formation was considerably reduced with Sl(a-) Knops
phenotype RBCs, indicating that this antigen on CR1 is involved in
rosetting. Because Sl(a-) is more common in persons of African ancestry,
a protective role was suggested (Moulds and Moulds, 2000).

CR1-deficient RBCs show greatly reduced rosetting, leading Cockburn et
al. (2004) to hypothesize that if rosetting is a direct cause of malaria
pathology, CR1-deficient individuals should be protected against severe
disease. They showed that RBC CR1 deficiency occurs in up to 80% of
healthy individuals from the malaria-endemic regions of Papua New
Guinea. This RBC CR1 deficiency is associated with polymorphisms in the
CR1 gene (e.g., 120620.0001) and, unexpectedly, with alpha-thalassemia,
a common genetic disorder in Melanesian populations. Analysis of a
case-control study demonstrated that the CR1 polymorphisms and
alpha-thalassemia independently confer protection against severe
malaria. Thus, Cockburn et al. (2004) identified CR1 as a new malaria
resistance gene and provided compelling evidence that rosetting is an
important parasite virulence phenotype that should be a target for drug
and vaccine development.

- Variation in ICAM1 and Susceptibility to Cerebral Malaria

The malarial parasite Plasmodium falciparum has acted as a potent
selective force on the human genome. The particular virulence of this
organism was thought to be due to the adherence of parasitized red blood
cells to small vessel endothelium through several receptors, including
CD36, thrombospondin (THBS1; 188060), and ICAM1, and parasite isolates
differ in their ability to bind to each. Immunohistochemical studies
implicated ICAM1 as having potential importance in the pathogenesis of
cerebral malaria, leading Fernandez-Reyes et al. (1997) to reason that
if any single receptor were involved in the development of cerebral
malaria, then in view of the high mortality of that complication,
natural selection should have produced variants with reduced binding
capacity. Fernandez-Reyes et al. (1997) amplified and sequenced the
N-terminal immunoglobulin-like domain of the ICAM1 gene from the genomic
DNA of 24 asymptomatic children in Kilifi, Kenya. The only mutation
found was an A-to-T transversion at nucleotide 179, causing a
lys29-to-met substitution (K29M; 147840.0001), which the authors called
'ICAM1 Kilifi.' In studies of the association of the K29M polymorphism
with cerebral malaria, they found, to their surprise, that the
homozygous ICAM1 Kilifi genotype was associated with susceptibility to
cerebral malaria with a relative risk of 2.23, and heterozygotes with a
relative risk of 1.39. The frequency of the K29 allele was 0.668 and the
frequency of the M29 Kilifi allele was 0.332. Fernandez-Reyes et al.
(1997) noted that, while this association strengthened the link between
ICAM1 and cerebral malaria, a mutation that confers susceptibility is
unlikely to have arisen at such high frequency in the absence of some
counteractive selective advantage. These counterintuitive results had
implications for the mechanism of malaria pathogenesis, resistance to
other infectious agents, and transplant immunology. The Kilifi allele
was not identified in 99 unrelated Caucasians or in 40 multigeneration
families from the CEPH collection. Screening of 20 Gambian samples
produced a similar frequency of the Kilifi allele to that seen in Kenya.

Bellamy et al. (1998) found no association between the ICAM1 Kilifi
variant and cerebral malaria in a case-control study of West Africans.

- Variation in Major Histocompatibility Complex Genes and
Resistance to Severe Malaria

By means of a large case-controlled study of malaria in West African
children, Hill et al. (1991) showed that HLA-Bw53 (see HLA-B; 142830)
and the HLA class II haplotype, DRB1*1302/DQB1*0501 (see HLA-DRB1;
142857), were independently associated with protection from severe
malaria. The antigens listed are common in West Africans but rare in
other racial groups. In this population, they account for as great a
reduction in disease incidence as the sickle-cell hemoglobin variant.
Although the relative strength of the protection is less than that of
the sickle-cell variant, the greater frequency of the DQB1 (see
HLA-DQB1; 604305) polymorphism makes the net effect on resistance to
malaria comparable. The findings support the hypothesis that the
extraordinary polymorphism of major histocompatibility complex genes has
evolved primarily through natural selection by infectious pathogens.

Hill et al. (1992) further investigated the protective association
between HLA-B53 and severe malaria by sequencing peptides eluted from
this molecule followed by screening of candidate epitopes from
pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical
and cellular assays. Among malaria-immune Africans, they found that
HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved
nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no
HLA-B53-restricted epitopes were identified in other malaria antigens.
The findings of this 'reverse immunogenetic' approach indicated a
possible molecular basis for this HLA-disease association and supported
the candidacy of LSA-1 as a component for a malaria vaccine.

Sjoberg et al. (1992) found that levels of antibody to a major malarial
antigen developing in individuals living in northern Liberia, where
malaria is holoendemic and perennial, were more concordant within
monozygotic twin pairs than in dizygotic pairs or in age- and
sex-matched sibs living under similar environmental conditions. The
results supported the conclusion that the antibody responses were
genetically regulated. No association was found with different HLA class
II alleles and haplotypes, suggesting that the variation in the antibody
response found in this study reflected the impact of factors encoded by
genes outside the HLA class II region.

- Variation in TNF and Susceptibility to Cerebral Malaria

Because fatal cerebral malaria is associated with high circulating
levels of TNFA (TNF; 191160), McGuire et al. (1994) undertook a large
case-control study in Gambian children. The study showed that
homozygotes for the TNF2 allele (-308G-A; 191160.0004), a variant of the
TNFA gene promoter region, had a relative risk of 7 for death or severe
neurologic sequelae due to cerebral malaria. Although the TNF2 allele is
in linkage disequilibrium with several neighboring HLA alleles, McGuire
et al. (1994) showed that this disease association was independent of
HLA class I and class II variation. The data suggested that regulatory
polymorphisms of cytokine genes can affect the outcome of severe
infection. The maintenance of the TNF2 allele at a gene frequency of
0.16 in The Gambia implies that the increased risk of cerebral malaria
in homozygotes is counterbalanced by some biologic advantage.

Through systematic DNA fingerprinting of the TNF promoter region, Knight
et al. (1999) identified a SNP (-376G-A; 191160.0003) that caused the
helix-turn-helix transcription factor OCT1 (POU2F1; 164175) to bind to a
novel region of complex protein-DNA interactions and alter gene
expression in human monocytes. The OCT1-binding genotype, found in
approximately 5% of Africans, was associated with 4-fold increased
susceptibility to cerebral malaria in large studies comparing cases and
controls in West African and East African populations, after correction
for other known TNF polymorphisms and linked HLA alleles.

- Variation in NOS2A and Resistance to Malaria

Kun et al. (1998) examined whether high plasma concentrations of nitric
oxide found in severe malaria were due to variation in the promoter
region of NOS2 (163730). Heterozygosity for a -969G-C SNP (163730.0002)
was present in 30 of 100 Gambian children with mild malaria, but in only
17 of 100 Gambian children with severe malaria. The SNP was not found in
any of 100 Germans. Heterozygous individuals were also at a
significantly lower risk of reinfection.

From studies in Tanzania and Kenya, Hobbs et al. (2002) identified a
novel SNP, -1173C-T (163730.0001), in the NOS2A promoter that was
significantly associated with protection from symptomatic malaria and
severe malarial anemia.

- Variation in TIRAP and Resistance to Malaria

Khor et al. (2007) reported a case-control study of 6,106 individuals
from the U.K., Vietnam, and several African countries with invasive
pneumococcal disease (see 610799), bacteremia, malaria, and tuberculosis
(607948). Genotyping 33 SNPs, they found that heterozygous carriage of a
leucine substitution of ser180 (606252.0001) in TIRAP (606252) was
associated independently with all 4 infectious diseases in the different
study populations. Combining the study groups, they found substantial
support for protective effect of S180L heterozygosity against these
infectious diseases.

- Variation in FCGR2B and Resistance to Malaria

Clatworthy et al. (2007) found an increased frequency of the I232T
polymorphism (604590.0001) of the FCGR2B gene (604590) in Asian and
African populations, broadly corresponding to regions where malaria is
endemic. The systemic lupus erythematosus (SLE; 152700)-associated I232T
polymorphism was associated with enhanced phagocytosis of Plasmodium
falciparum-infected human erythrocytes. Clatworthy et al. (2007)
concluded that FCGR2B is important in controlling the immune response to
malaria parasites and suggested that polymorphisms predisposing to SLE
in Asians and Africans may be maintained because the variants reduce
susceptibility to malaria.

By comparing genotypes of patients with SLE from Hong Kong and the UK
with those of ethnically matched controls, followed by metaanalysis
using with other studies on southeast Asian and Caucasian SLE patients,
Willcocks et al. (2010) found that homozygosity for T232 of the I232T
polymorphism was strongly associated with SLE in both ethnic groups.
When studies in Caucasians and southeast Asians were combined, T232
homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0
x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP
is more common in southeast Asians and Africans, populations where
malaria is endemic, than in Caucasians. Homozygosity for T232 was
significantly associated with protection from severe malaria in Kenyan
children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was
found with susceptibility to bacterial infection. Willcocks et al.
(2010) proposed that malaria may have driven retention of a polymorphism
predisposing to a polygenic autoimmune disease and thus may begin to
explain the ethnic differences seen in the frequency of SLE.

- Blood Group O and Resistance to Severe Malaria

Rowe et al. (2007) noted that Plasmodium falciparum-induced rosetting
(i.e., the spontaneous binding of infected erythrocytes to uninfected
erythrocytes) is thought to contribute to the pathogenesis of severe
malaria by obstructing microvascular blood flow. Rosetting is reduced in
blood group O (see 110300) erythrocytes compared with non-O blood
groups, presumably due to group O individuals having disaccharide H
antigens resulting from a lack of the terminal glycosyltransferases
necessary to produce the trisaccharides found with A and B antigens.
Rosettes that do form in group O red cells are smaller and more easily
disrupted than those in group A, B, or AB red cells. Rowe et al. (2007)
confirmed that rosetting was reduced in individuals with blood group O,
intermediate in blood groups A and B, and highest in group AB. A matched
case control study of 567 Malian children found that group O was present
in only 21% of severe malaria cases compared with approximately 44% of
uncomplicated malaria control cases and healthy controls. Rowe et al.
(2007) concluded that group O is associated with a 66% reduction in the
odds of developing severe malaria compared with non-O blood groups, and
they reported preliminary evidence that similar protection is found in
Kenyan children. The authors also proposed that group O does not occur
at higher frequency in some malaria endemic regions due to increased
susceptibility to cholera and other diarrheal diseases, resulting in
balanced polymorphism.

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) confirmed the
protective effect of blood group O.

- Variation in GNAS and Susceptibility to Severe Malaria

Using metaanalysis combining data from case control and family studies
in Gambia, Kenya, and Malawi and a case control study from Ghana, Auburn
et al. (2008) detected associations between intronic or conservative
SNPs of GNAS (139320) and severe malaria. SNPs with significant
associations clustered in the 5-prime end of GNAS. Auburn et al. (2008)
proposed that the impact of GNAS on malaria parasite invasion efficacy
may alter susceptibility to disease.

- Variation in TIM1 and Resistance to Cerebral Malaria

By screening for polymorphisms of TIM1 (HAVCR1; 606518), TIM3 (HAVCR2;
606652), and TIM4 (TIM4D; 610096) in 478 Thai patients infected with
Plasmodium falciparum, Nuchnoi et al. (2008) identified a statistically
significant association between protection against cerebral malaria and
a TIM1 promoter haplotype consisting of 3 derived alleles, -1637G-A
(dbSNP rs7702919), -1549G-C (dbSNP rs41297577), and -1454G-A (dbSNP
rs41297579). Allele-specific transcription quantification analysis
revealed that TIM1 mRNA levels were higher for the protective promoter
haplotype than for the other promoter haplotype. Nuchnoi et al. (2008)
proposed that engagement of TIM1 and T-cell receptor stimulation may
induce antiinflammatory Th2 cytokine production and protect from
development of cerebral malaria by downregulating inflammatory cytokines
such as TNF (191160) and IFNG (147570).

- Variation in IL12B and Susceptibility to Cerebral Malaria

Using a family-based association study with 240 Malian families, Marquet
et al. (2008) investigated 21 markers in IL12-related genes for
involvement in susceptibility to cerebral malaria (CM). They found that
the IL12B (161561) promoter polymorphism dbSNP rs17860508, in which GC
is replaced with CTCTAA, was associated with susceptibility to CM. The
CTCTAA allele and the GC/CTCTAA heterozygous genotype were associated
with increased risk of CM (P of 0.0002 and 0.00002, respectively).
Children with the GC/CTCTAA genotype had a higher risk of CM than
children homozygous for either allele (odds ratio of 2.11; P less than
0.0001). Among 134 CM children with a heterozygous parent, a significant
number received the CTCTAA allele. Marquet et al. (2008) noted that
heterozygosity for dbSNP rs17860508 is associated with reduced IL12B
expression and reduced IL12 secretion, and that low IL12 and IFNG
(147570) levels are associated with CM. They proposed that Th1 responses
may reduce the parasite load and severe malaria risk.

- Variation in FUT9 and Susceptibility to Placental Malaria
Infection

Sikora et al. (2009) carried out a nested case-control study on 180
Mozambican pregnant women with placental malaria infection and 180
controls within an intervention trial of malaria prevention. Subjects
were genotyped at 880 SNPs in a set of 64 functionally related genes
involved in glycosylation and innate immunity. A T-C SNP (dbSNP
rs3811070) located in the 5-prime untranslated region (UTR) of the FUT9
gene (606865) on chromosome 6q16 was significantly associated with
placental malaria infection (odds ratio, 2.31; corrected p = 0.038).
Haplotype analysis revealed a similarly strong association for a common
4-SNP TTCA haplotype including dbSNP rs3811070. The TTCA haplotype spans
40 kb in the 5-prime UTR and contains the second exon of FUT9. The FUT9
gene encodes a fucosyltransferase that catalyzes the last step in the
biosynthesis of the Lewis-x antigen, which forms part of the Lewis blood
group-related antigens. Sikora et al. (2009) suggested an involvement of
this antigen in the pathogenesis of placental malaria infection.

- Variation in FCGR2A and Susceptibility to Severe Malaria

The his131-to-arg (H131R; 146790.0001) polymorphism in the extracellular
domain of FCGR2A reduces the receptor's affinity for IgG2 and IgG3
isotypes (see 147100) but increases its binding of C-reactive protein
(CRP; 123260). By studying 2,504 Ghanaian children with severe malaria
and 2,027 healthy matched controls, Schuldt et al. (2010) found that
homozygosity for 131R was positively associated with severe malaria
(odds ratio = 1.20; p = 0.007; p corrected for multiple testing =
0.021), and, after stratification for phenotypes, with severe anemia
(odds ratio = 1.33; p = 0.001; p corrected = 0.009), but not with
cerebral malaria or other malaria complications or with parasitemia
levels. Schuldt et al. (2010) concluded that the CRP-binding variant of
FCGR2A is associated with malarial anemia, suggesting a role for CRP
defense mechanisms in pathogenesis of this condition.

- Resistance Versus Tolerance

Hosts can in principle employ 2 different strategies to defend
themselves against parasites: resistance and tolerance. Animals
typically exhibit considerable genetic variation for resistance. Using
rodent malaria in laboratory mice as a model system and the statistical
framework developed by plant pathogen biologists, Raberg et al. (2007)
demonstrated genetic variation for tolerance, as measured by the extent
to which anemia and weight loss increased with increasing parasite
burden. Moreover, resistance and tolerance were negatively genetically
correlated. Raberg et al. (2007) concluded that their results mean that
animals, like plants, can evolve 2 conceptually different types of
defense, a finding that has important implications for the understanding
of the epidemiology and evolution of infectious diseases.

- Reviews

Nagel and Roth (1989) reviewed genetic disorders of the red cell,
including abnormal hemoglobins, G6PD deficiency, and absence of Duffy
blood group antigen, that influence resistance against malaria infection
in humans.

Kwiatkowski (2005) provided an overview of genetic resistance to
malaria.

Campino et al. (2006) reviewed mendelian and complex genetics of
susceptibility and resistance to parasitic infections, including
malaria.

ANIMAL MODEL

Ferreira et al. (2011) demonstrated that wildtype mice or mice
expressing normal human Hb, but not mice expressing sickle human Hb
(Hbs; 141900.0243), developed experimental cerebral malaria (ECM) 6 to
12 days after infection with the murine malaria parasite, Plasmodium
berghei. The Hbs mice eventually succumbed to the unrelated condition of
hyperparasitemia-induced anemia. Tolerance to Plasmodium infection was
associated with high levels of Hmox1 (141250) expression in
hematopoietic cells, and mice expressing Hbs became susceptible to ECM
when Hmox1 expression was inhibited. Hbs induced expression of Hmox1 in
an Nrf2 (NFE2L2; 600492)-dependent manner, which inhibited the
production of chemokines and Cd8-positive T cells associated with ECM
pathogenesis. Ferreira et al. (2011) concluded that sickle hemoglobin
suppresses the onset of ECM via induction of HMOX1 and the production of
carbon monoxide, which inhibits the accumulation of free heme, affording
tolerance to Plasmodium infection.

*FIELD* RF
1. Aitman, T. J.; Cooper, L. D.; Norsworthy, P. J.; Wahid, F. N.;
Gray, J. K.; Curtis, B. R.; McKeigue, P. M.; Kwiatkowski, D.; Greenwood,
B. M.; Snow, R. W.; Hill, A. V.; Scott, J.: Malaria susceptibility
and CD36 mutation. Nature 405: 1015-1016, 2000.

2. Allen, S. J.; O'Donnell, A.; Alexander, N. D. E.; Alpers, M. P.;
Peto, T. E. A.; Clegg, J. B.; Weatherall, D. J.: Alpha(+)-thalassemia
protects children against disease caused by other infections as well
as malaria. Proc. Nat. Acad. Sci. 94: 14736-14741, 1997.

3. Allen, S. J.; O'Donnell, A.; Alexander, N. D. E.; Mgone, C. S.;
Peto, T. E. A.; Clegg, J. B.; Alpers, M. P.; Weatherall, D. J.: Prevention
of cerebral malaria in children in Papua New Guinea by southeast Asian
ovalocytosis band 3. Am. J. Trop. Med. Hyg. 60: 1056-1060, 1999.

4. Auburn, S.; Diakite, M.; Fry, A. E.; Ghansah, A.; Campino, S.;
Richardson, A.; Jallow, M.; Sisay-Joof, F.; Pinder, M.; Griffiths,
M. J.; Peshu, N.; Williams, T. N.; and 9 others: Association of
the GNAS locus with severe malaria. Hum. Genet. 124: 499-506, 2008.

5. Ayodo, G.; Price, A. L.; Keinan, A.; Ajwang, A.; Otieno, M. F.;
Orago, A. S. S.; Patterson, N.; Reich, D.: Combining evidence of
natural selection with association analysis increases power to detect
malaria-resistance variants. Am. J. Hum. Genet. 81: 234-242, 2007.

6. Baer, A.: Elliptocytosis, malaria, and fertility in Malaysia. Hum.
Biol. 60: 909-915, 1988.

7. Bellamy, R.; Kwiatkowski, D.; Hill, A. V. S.: Absence of an association
between intercellular adhesion molecule 1, complement receptor 1 and
interleukin 1 receptor antagonist gene polymorphisms and severe malaria
in a West African population. Trans. R. Soc. Trop. Med. Hyg. 92:
312-316, 1998.

8. Booth, P. B.; McLoughlin, K.: The Gerbich blood group system,
especially in Melanesians. Vox Sang. 22: 73-84, 1972.

9. Campino, S.; Kwiatkowski, D.; Dessein, A.: Mendelian and complex
genetics of susceptibility and resistance to parasitic infections. Semin.
Immun. 18: 411-422, 2006.

10. Cappadoro, M.; Giribaldi, G.; O'Brien, E.; Turrini, F.; Mannu,
F.; Ulliers, D.; Simula, G.; Luzzatto, L.; Arese, P.: Early phagocytosis
of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes
parasitized by Plasmodium falciparum may explain malaria protection
in G6PD deficiency. Blood 92: 2527-2534, 1998.

11. Clatworthy, M. R.; Willcocks, L.; Urban, B.; Langhorne, J.; Williams,
T. N.; Peshu, N.; Watkins, N. A.; Floto, R. A.; Smith, K. G. C.:
Systemic lupus erythematosus-associated defects in the inhibitory
receptor Fc-gamma-RIIb reduce susceptibility to malaria. Proc. Nat.
Acad. Sci. 104: 7169-7174, 2007.

12. Cockburn, I. A.; Mackinnon, M. J.; O'Donnell, A.; Allen, S. J.;
Moulds, J. M.; Baisor, M.; Bockarie, M.; Reeder, J. C.; Rowe, J. A.
: A human complement receptor 1 polymorphism that reduces Plasmodium
falciparum rosetting confers protection against severe malaria. Proc.
Nat. Acad. Sci. 101: 272-277, 2004.

13. Crosnier, C.; Bustamante, L. Y.; Bartholdson, S. J.; Bei, A. K.;
Theron, M.; Uchikawa, M.; Mboup, S.; Ndir, O.; Kwiatkowski, D. P.;
Duraisingh, M. T.; Rayner, J. C.; Wright, G. J.: Basigin is a receptor
essential for erythrocyte invasion by Plasmodium falciparum. Nature 480:
534-537, 2011.

14. Cserti-Gazdewich, C. M.; Dhabangi, A.; Musoke, C.; Ssewanyana,
I.; Ddungu, H.; Nakiboneka-Ssenabulya, D.; Nabukeera-Barungi, N.;
Mpimbaza, A.; Dzik, W. H.: Cytoadherence in paediatric malaria: ABO
blood group, CD36, and ICAM1 expression and severe Plasmodium falciparum
infection. Br. J. Haemat. 159: 223-236, 2012.

15. Fairhurst, R. M.; Baruch, D. I.; Brittain, N. J.; Ostera, G. R.;
Wallach, J. S.; Hoang, H. L.; Hayton, K.; Guindo, A.; Makobongo, M.
O.; Schwartz, O. M.; Tounkara, A.; Doumbo, O. K.; Diallo, D. A.; Fujioka,
H.; Ho, M.; Wellems, T. E.: Abnormal display of PfEMP-1 on erythrocytes
carrying haemoglobin C may protect against malaria. Nature 435:
1117-1121, 2005.

16. Fernandez-Reyes, D.; Craig, A. G.; Kyes, S. A.; Peshu, N.; Snow,
R. W.; Berendt, A. R.; Marsh, K.; Newbold, C. I.: A high frequency
African coding polymorphism in the N-terminal domain of ICAM-1 predisposing
to cerebral malaria in Kenya. Hum. Molec. Genet. 6: 1357-1360, 1997.

17. Ferreira, A.; Marguti, I.; Bechmann, I.; Jeney, V.; Chora, A.;
Palha, N. R.; Rebelo, S.; Henri, A.; Beuzard, Y.; Soares, M. P.:
Sickle hemoglobin confers tolerance to Plasmodium infection. Cell 145:
398-409, 2011.

18. Flori, L.; Sawadogo, S.; Esnault, C.; Delahaye, N. F.; Fumoux,
F.; Rihet, P.: Linkage of mild malaria to the major histocompatibility
complex in families living in Burkina Faso. Hum. Molec. Genet. 12:
375-378, 2003.

19. Fortin, A.; Stevenson, M. M.; Gros, P.: Susceptibility to malaria
as a complex trait: big pressure from a tiny creature. Hum. Molec.
Genet. 11: 2469-2478, 2002.

20. Friedman, M. J.; Trager, W.: The biochemistry of resistance to
malaria. Sci. Am. 244(3): 154-164, 1981.

21. Hadley, T.; Saul, A.; Lamont, G.; Hudson, D. E.; Miller, L. H.;
Kidson, C.: Resistance of Melanesian elliptocytes (ovalocytes) to
invasion by Plasmodium knowlesi and Plasmodium falciparum malaria
parasites in vitro. J. Clin. Invest. 71: 780-782, 1983.

22. Hill, A. V. S.; Allsopp, C. E. M.; Kwiatkowski, D.; Anstey, N.
M.; Twumasi, P.; Rowe, P. A.; Bennett, S.; Brewster, D.; McMichael,
A. J.; Greenwood, B. M.: Common West African HLA antigens are associated
with protection from severe malaria. Nature 352: 595-600, 1991.

23. Hill, A. V. S.; Elvin, J.; Willis, A. C.; Aidoo, M.; Allsopp,
C. E. M.; Gotch, F. M.; Gao, X. M.; Takiguchi, M.; Greenwood, B. M.;
Townsend, A. R. M.; McMichael, A. J.; Whittle, H. C.: Molecular analysis
of the association of HLA-B53 and resistance to severe malaria. Nature 360:
434-439, 1992.

24. Hobbs, M. R.; Udhayakumar, V.; Levesque, M. C.; Booth, J.; Roberts,
J. M.; Tkachuk, A. N.; Pole, A.; Coon, H.; Kariuki, S.; Nahlen, B.
L.; Mwaikambo, E. D.; Lai, A. L.; Granger, D. L.; Anstey, N. M.; Weinberg,
J. B.: A new NOS2 promoter polymorphism associated with increased
nitric oxide production and protection from severe malaria in Tanzanian
and Kenyan children. Lancet 360: 1468-1475, 2002. Note: Erratum:
Lancet 361: 438 only, 2003.

25. Khor, C. C.; Chapman, S. J.; Vannberg, F. O.; Dunne, A.; Murphy,
C.; Ling, E. Y.; Frodsham, A. J.; Walley, A. J.; Kyrieleis, O.; Khan,
A.; Aucan, C.; Segal, S.; and 22 others: A Mal functional variant
is associated with protection against invasive pneumococcal disease,
bacteremia, malaria and tuberculosis. Nature Genet. 39: 523-528,
2007.

26. Kidson, C.; Lamont, G.; Saul, A.; Nurse, G. T.: Ovalocytic erythrocytes
from Melanesians are resistant to invasion by malaria parasites in
culture. Proc. Nat. Acad. Sci. 78: 5829-5832, 1981.

27. Knight, J. C.; Udalova, I.; Hill, A. V. S.; Greenwood, B. M.;
Peshu, N.; Marsh, K.; Kwiatkowski, D.: A polymorphism that affects
OCT-1 binding to the TNF promoter region is associated with severe
malaria. Nature Genet. 22: 145-150, 1999.

28. Kun, J. F. J.; Mordmuller, B.; Lell, B.; Lehman, L. G.; Luckner,
D.; Kremsner, P. G.: Polymorphism in promoter region of inducible
nitric oxide synthase gene and protection against malaria. Lancet 351:
265-266, 1998.

29. Kwiatkowski, D. P.: How malaria has affected the human genome
and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77:
171-192, 2005.

30. Louicharoen, C.; Patin, E.; Paul, R.; Nuchprayoon, I.; Witoonpanich,
B.; Peerapittayamongkol, C.; Casademont, I.; Sura, T.; Laird, N. M.;
Singhasivanon, P.; Quintana-Murci, L.; Sakuntabhai, A.: Positively
selected G6PD-Mahidol mutation reduces Plasmodium vivax density in
Southeast Asians. Science 326: 1546-1549, 2009.

31. Maier, A. G.; Duraisingh, M. T.; Reeder, J. C.; Patel, S. S.;
Kazura, J. W.; Zimmerman, P. A.; Cowman, A. F.: Plasmodium falciparum
erythrocyte invasion through glycophorin C and selection for Gerbich
negativity in human populations. Nature Med. 9: 87-92, 2003.

32. Marquet, S.; Doumbo, O.; Cabantous, S.; Poudiougou, B.; Argiro,
L.; Safeukui, I.; Konate, S.; Sissoko, S.; Chevereau, E.; Traore,
A.; Keita, M. M.; Chevillard, C.; Abel, L.; Dessein, A. J.: A functional
promoter variant in IL12B predisposes to cerebral malaria. Hum. Molec.
Genet. 17: 2190-2195, 2008.

33. Martin, S. K.; Miller, L. H.; Alling, D.; Okoye, V. C.; Esan,
G. J. F.; Osunkoya, B. O.; Deane, M.: Severe malaria and glucose-6-phosphate-de
hydrogenase deficiency: a reappraisal of the malaria-G6PD hypothesis. Lancet 313:
524-526, 1979. Note: Originally Volume I.

34. McGuire, W.; Hill, A. V. S.; Allsopp, C. E. M.; Greenwood, B.
M.; Kwiatkowski, D.: Variation in the TNF-alpha promoter region associated
with susceptibility to cerebral malaria. Nature 371: 508-511, 1994.

35. Moulds, J. M.; Moulds, J. J.: Blood group associations with parasites,
bacteria, and viruses. Trans. Med. Rev. 14: 302-311, 2000.

36. Nagel, R. L.; Roth, E. F., Jr.: Malaria and red cell genetic
defects. Blood 74: 1213-1221, 1989.

37. Nuchnoi, P.; Ohashi, J.; Kimura, R.; Hananantachai, H.; Naka,
I.; Krudsood, S.; Looareesuwan, S.; Tokunaga, K.; Patarapotikul, J.
: Significant association between TIM1 promoter polymorphisms and
protection against cerebral malaria in Thailand. Ann. Hum. Genet. 72:
327-336, 2008.

38. Omi, K.; Ohashi, J.; Patarapotikul, J.; Hananantachai, H.; Naka,
I.; Looareesuwan, S.; Tokunaga, K.: CD36 polymorphism is associated
with protection from cerebral malaria. Am. J. Hum. Genet. 72: 364-374,
2003.

39. Pasvol, G.; Wainscoat, J. S.; Weatherall, D. J.: Erythrocytes
deficient in glycophorin resist invasion by the malarial parasite
Plasmodium falciparum. Nature 297: 64-66, 1982.

40. Pasvol, G.; Wilson, R. J. M.: The interaction of malaria parasites
with red blood cells. Brit. Med. Bull. 38: 133-140, 1982.

41. Patel, S. S.; Mehlotra, R. K.; Kastens, W.; Mgone, C. S.; Kazura,
J. W.; Zimmerman, P. A.: The association of the glycophorin C exon
3 deletion with ovalocytosis and malaria susceptibility in the Wosera,
Papua New Guinea. Blood 98: 3489-3491, 2001.

42. Raberg, L.; Sim, D.; Read, A. F.: Disentangling genetic variation
for resistance and tolerance to infectious diseases in animals. Science 318:
812-817, 2007.

43. Rihet, P.; Flori, L.; Tall, F.; Traore, A. S.; Fumoux, F.: Hemoglobin
C is associated with reduced Plasmodium falciparum parasitemia and
low risk of mild malaria attack. Hum. Molec. Genet. 13: 1-6, 2004.

44. Rihet, P.; Traore, Y.; Abel, L.; Aucan, C.; Traore-Leroux, T.;
Fumoux, F.: Malaria in humans: Plasmodium falciparum blood infection
levels are linked to chromosome 5q31-q33. Am. J. Hum. Genet. 63:
498-505, 1998.

45. Roth, E. F., Jr.; Raventos-Suarez, C.; Rinaldi, A.; Nagel, R.
L.: Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro
growth of Plasmodium falciparum. Proc. Nat. Acad. Sci. 80: 298-299,
1983.

46. Rowe, J. A.; Handel, I. G.; Thera, M. A.; Deans, A.-M.; Lyke,
K. E.; Kone, A.; Diallo, D. A.; Raza, A.; Kai, O.; Marsh, K.; Plowe,
C. V.; Doumbo, O. K.; Moulds, J. M.: Blood group O protects against
severe Plasmodium falciparum malaria through the mechanism of reduced
rosetting. Proc. Nat. Acad. Sci. 104: 17471-17476, 2007.

47. Rowe, J. A.; Moulds, J. M.; Newbold, C. I.; Miller, L. H.: P-falciparum
rosetting mediated by a parasite-variant erythrocyte membrane protein
and complement-receptor 1. Nature 388: 292-295, 1997.

48. Ruwando, C.; Khea, S. C.; Snow, R. W.; Yates, S. N. R.; Kwiatkoweld,
D.; Gupta, S.; Warn, P.; Alisopp, G. E. M.; Gilbert, S. C.; Peschu,
N.; Newbold, C. I.; Greenwood, S. M.; Marsh, K.; Hill, A. V. S.:
Natural selection of hemi- and heterozygotes for G6PD deficiency in
Africa by resistance to severe malaria. Nature 376: 246-249, 1995.

49. Schuldt, K.; Esser, C.; Evans, J.; May, J.; Timmann, C.; Ehmen,
C.; Loag, W.; Ansong, D.; Ziegler, A.; Agbenyega, T.; Meyer, C. G.;
Horstmann, R. D.: FCGR2A functional genetic variant associated with
susceptibility to severe malarial anaemia in Ghanaian children. J.
Med. Genet. 47: 471-475, 2010.

50. Serjeantson, S. W.; White, B. S.; Bhatia, K.; Trent, R. J.: A
3.5 kb deletion in the glycophorin C gene accounts for the Gerbich-negative
blood group in Melanesians. Immun. Cell Biol. 72: 23-27, 1994.

51. Sikora, M.; Ferrer-Admetlla, A.; Laayouni, H.; Menendez, C.; Mayor,
A.; Bardaji, A.; Sigauque, B.; Mandomando, I.; Alonso, P. L.; Bertranpetit,
J.; Casals, F.: A variant in the gene FUT9 is associated with susceptibility
to placental malaria infection. Hum. Molec. Genet. 18: 3136-3144,
2009.

52. Sjoberg, K.; Lepers, J. P.; Raharimalala, L.; Larsson, A.; Olerup,
O.; Marbiah, N. T.; Troye-Blomberg, M.; Perlmann, P.: Genetic regulation
of human anti-malarial antibodies in twins. Proc. Nat. Acad. Sci. 89:
2101-2104, 1992.

53. Tham, W.-H.; Wilson, D. W.; Lopaticki, S.; Schmidt, C. Q.; Tetteh-Quarcoo,
P. B.; Barlow, P. N.; Richard, D.; Corbin, J. E.; Beeson, J. G.; Cowman,
A. F.: Complement receptor 1 is the host erythrocyte receptor for
Plasmodium falciparum PfRh4 invasion ligand. Proc. Nat. Acad. Sci. 107:
17327-17332, 2010.

54. Timmann, C.; Evans, J. A.; Konig, I. R.; Kleensang, A.; Ruschendorf,
F.; Lenzen, J.; Sievertsen, J.; Becker, C.; Enuameh, Y.; Kwakye, K.
O.; Opoku, E.; Browne, E. N. L.; Ziegler, A.; Nurnberg, P.; Horstmann,
R. D.: Genome-wide linkage analysis of malaria infection intensity
and mild disease. PLoS Genet. 3: e48, 2007. Note: Electronic Article.

55. Timmann, C.; Thye, T.; Vens, M.; Evans, J.; May, J.; Ehmen, C.;
Sievertsen, J.; Muntau, B.; Ruge, G.; Loag, W.; Ansong, D.; Antwi,
S.; and 13 others: Genome-wide association study indicates two
novel resistance loci for severe malaria. Nature 489: 443-446, 2012.

56. Tripathi, A. K.; Sha, W.; Shulaev, V.; Stins, M. F.; Sullivan,
D. J., Jr.: Plasmodium falciparum-infected erythrocytes induce NF-kappa-B
regulated inflammatory pathways in human cerebral endothelium. Blood 114:
4243-4252, 2009.

57. Turner, L.; Lavstsen, T.; Berger, S. S.; Wang, C. W.; Petersen,
J. E. V.; Avril, M.; Brazier, A. J.; Freeth, J.; Jespersen, J. S.;
Nielsen, M. A.; Magistrado, P.; Lusingu, J.; Smith, J. D.; Higgins,
M. K.; Theander, T. G.: Severe malaria is associated with parasite
binding to endothelial protein C receptor. Nature 498: 502-505,
2013.

58. Willcocks, L. C.; Carr, E. J.; Niederer, H. A.; Rayner, T. F.;
Williams, T. N.; Yang, W.; Scott, J. A. G.; Urban, B. C.; Peshu, N.;
Vyse, T. J.; Lau, Y. L.; Lyons, P. A.; Smith, K. G. C.: A defunctioning
polymorphism in FCGR2B is associated with protection against malaria
but susceptibility to systemic lupus erythematous. Proc. Nat. Acad.
Sci. 107: 7881-7885, 2010.

59. Williams, T. N.; Maltland, K.; Bennett, S.; Ganczakowski, M.;
Peto, T. E. A.; Newbold, C. I.; Bowden, D. K.; Weatherall, D. J.;
Clegg, J. S.: High incidence of malaria in alpha-thalassaemic children. Nature 383:
522-525, 1996.

*FIELD* CN
Paul J. Converse - updated: 12/9/2013
Paul J. Converse - updated: 8/22/2013
Paul J. Converse - updated: 7/29/2013
Paul J. Converse - updated: 9/26/2012
Paul J. Converse - updated: 6/19/2012
Paul J. Converse - updated: 1/18/2012
Paul J. Converse - updated: 11/11/2011
Paul J. Converse - updated: 5/5/2011
Paul J. Converse - updated: 4/29/2011
George E. Tiller - updated: 6/28/2010
Ada Hamosh - updated: 1/6/2010
Paul J. Converse - updated: 11/24/2009
Paul J. Converse - updated: 11/2/2009
Paul J. Converse - updated: 1/26/2009
Paul J. Converse - updated: 1/8/2009
Paul J. Converse - updated: 8/21/2008
Ada Hamosh - updated: 11/21/2007
Paul J. Converse - updated: 7/17/2007
George E. Tiller - updated: 7/6/2007
Paul J. Converse - updated: 7/5/2007

*FIELD* CD
Matthew B. Gross: 7/2/2007

*FIELD* ED
mgross: 01/06/2014
mcolton: 12/9/2013
mgross: 10/25/2013
carol: 10/24/2013
mgross: 8/22/2013
alopez: 8/7/2013
alopez: 7/29/2013
mgross: 9/27/2012
terry: 9/26/2012
terry: 7/3/2012
mgross: 6/19/2012
mgross: 1/18/2012
mgross: 11/17/2011
terry: 11/11/2011
terry: 5/20/2011
mgross: 5/11/2011
terry: 5/5/2011
mgross: 5/3/2011
terry: 4/29/2011
mgross: 12/21/2010
wwang: 7/21/2010
terry: 6/28/2010
alopez: 6/10/2010
alopez: 1/19/2010
terry: 1/6/2010
alopez: 11/24/2009
mgross: 11/2/2009
wwang: 8/24/2009
terry: 4/8/2009
carol: 3/31/2009
mgross: 1/26/2009
mgross: 1/8/2009
mgross: 8/21/2008
terry: 8/21/2008
mgross: 4/1/2008
alopez: 11/28/2007
terry: 11/21/2007
mgross: 8/27/2007
terry: 7/17/2007
mgross: 7/9/2007
wwang: 7/6/2007
mgross: 7/5/2007

MIM 611590
*RECORD*
*FIELD* NO
611590
*FIELD* TI
#611590 RENAL TUBULAR ACIDOSIS, DISTAL, WITH HEMOLYTIC ANEMIA
;;RTA, DISTAL, AUTOSOMAL RECESSIVE, WITH HEMOLYTIC ANEMIA
read moreRENAL TUBULAR ACIDOSIS, DISTAL, WITH NORMAL RED CELL MORPHOLOGY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
distal renal tubular acidosis (dRTA) with hemolytic anemia is caused by
mutation in the SLC4A1 gene (109270).

For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal recessive distal RTA, see 267300.

CLINICAL FEATURES

Tanphaichitr et al. (1998) described a Thai brother and sister with
autosomal recessive distal RTA and hemolytic anemia. The male proband
presented at age 3.5 years with a history of lethargy, anorexia, and
slow growth. Physical examination showed height and weight less than the
third percentile, pallor, and hepatosplenomegaly. Hypokalemia,
hyperchloremic metabolic acidosis, and normal creatinine were
accompanied by isosthenuria and alkaline urinary pH, bilateral
nephrocalcinosis, and rachitic bone changes. Mild anemia (hematocrit 11
g/dl) with microcytosis, reticulocytosis, and a peripheral smear
consistent with a xerocytic type of hemolytic anemia were accompanied by
homozygosity for hemoglobin E, a clinically benign hemoglobin frequently
encountered in Southeast Asia. The sister showed similar findings.

MOLECULAR GENETICS

Tanphaichitr et al. (1998) described novel SLC4A1 mutations in a Thai
family with a recessive syndrome of distal renal tubular acidosis and
hemolytic anemia in which red cell anion transport was normal. A brother
and sister were triply homozygous for 2 benign mutations, M31T and K56E
(109270.0001), and for a loss-of-function mutation, G701D (109270.0016).
The genetic and functional data suggested that the homozygous SLC4A1
G701D mutation caused recessively transmitted dRTA in this kindred with
apparently normal erythroid anion transport.

Bruce et al. (2000) studied 3 Malaysian and 6 Papua New Guinean families
with dRTA and Southeast Asian ovalocytosis (SAO; see 109270). The SAO
deletion mutation (109270.0002) in the SLC4A1 gene occurred in many of
the families but did not itself result in dRTA. Compound heterozygotes
of each of 3 dRTA mutations (G701D; A858D, 109270.0020; and delV850,
109270.0021) with SAO all had dRTA, evidence of hemolytic anemia, and
abnormal red cell properties. The A858D mutation showed dominant
inheritance and the recessive delV850 and G701D mutations showed a
pseudodominant phenotype when the transport-inactive SAO allele was also
present.

Sritippayawan et al. (2004) reported 2 Thai families with recessive dRTA
due to different compound heterozygous mutations of the SLC4A1 gene. In
the first family, the proband was a 5-year-old boy with dRTA, rickets,
failure to thrive, nephrocalcinosis, and hypokalemic/hyperchloremic
metabolic acidosis with a urine pH of 7.00. He had a normal hemoglobin
level and normal red cell morphology. The proband was found to have
compound heterozygous G701D (109270.0016)/S773P (109270.0026) mutations,
inherited from his clinically normal mother and father, respectively. In
the second family, a 19-year-old man and his 15-year-old sister had dRTA
and Southeast Asian ovalocytosis, and were compound heterozygotes for
the SAO deletion mutation (109270.0002) and an R602H mutation
(109270.0027). Their mother had SAO and an unaffected brother was
heterozygous for the R602P mutation. Sritippayawan et al. (2004) noted
that the second patient had a severe form of dRTA whereas his sister had
only mild metabolic acidosis, indicating that other modifying factors or
genes might play a role in governing the severity of the disease.

POPULATION GENETICS

Yenchitsomanus et al. (2002) found that all Thai patients with autosomal
recessive dRTA caused by homozygosity for the G701D mutation originated
from northeastern Thailand. Yenchitsomanus et al. (2003) confirmed the
higher allele frequency of the G701D mutation in this population. This
suggested that the G701D allele might have arisen in northeastern
Thailand. The presence of patients with dRTA who were compound
heterozygotes for the Southeast Asian ovalocytosis deletion mutation and
G701D in southern Thailand and Malaysia and their apparent absence in
northeastern Thailand indicated that the G701D allele may have migrated
to the southern peninsula region where SAO is common, resulting in
pathogenic allelic interaction.

*FIELD* RF
1. Bruce, L. J.; Wrong, O.; Toye, A. M.; Young, M. T.; Ogle, G.; Ismail,
Z.; Sinha, A. K.; McMaster, P.; Hwaihwanje, I.; Nash, G. B.; Hart,
S.; Lavu, E.; Palmer, R.; Othman, A.; Unwin, R. J.; Tanner, M. J.
A.: Band 3 mutations, renal tubular acidosis and South-East Asian
ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band
3 transport in red cells. Biochem. J. 350: 41-51, 2000.

2. Sritippayawan, S.; Sumboonnanonda, A.; Vasuvattakul, S.; Keskanokwong,
T.; Sawasdee, N.; Paemanee, A.; Thuwajit, P.; Wilairat, P.; Nimmannit,
S.; Malasit, P.; Yenchitsomanus, P.: Novel compound heterozygous
SLC4A1 mutations in Thai patients with autosomal recessive distal
renal tubular acidosis. Am. J. Kidney Dis. 44: 64-70, 2004.

3. Tanphaichitr, V. S.; Sumboonnanonda, A.; Ideguchi, H.; Shayakul,
C.; Brugnara, C.; Takao, M.; Veerakul, G.; Alper, S. L.: Novel AE1
mutations in recessive distal renal tubular acidosis: loss-of-function
is rescued by glycophorin A. J. Clin. Invest. 102: 2173-2179, 1998.

4. Yenchitsomanus, P.; Sawasdee, N.; Paemanee, A.; Keskanokwong, T.;
Vasuvattakul, S.; Bejrachandra, S.; Kunachiwa, W.; Fucharoen, S.;
Jittphakdee, P.; Yindee, W.; Promwong, C.: Anion exchanger 1 mutations
associated with distal renal tubular acidosis in the Thai population. J.
Hum. Genet. 48: 451-456, 2003.

5. Yenchitsomanus, P.; Vasuvattakul, S.; Kirdpon, S.; Wasanawatana,
S.; Susaengrat, W.; Sreethiphayawan, S.; Chuawatana, D.; Mingkum,
S.; Sawasdee, N.; Thuwajit, P.; Wilairat, P.; Malasit, P.; Nimmannit,
S.: Autosomal recessive distal renal tubular acidosis caused by G701D
mutation of anion exchanger 1 gene. Am. J. Kidney Dis. 40: 21-29,
2002.

*FIELD* CD
Marla J. F. O'Neill: 11/8/2007

*FIELD* ED
carol: 11/08/2007

MIM 612653
*RECORD*
*FIELD* NO
612653
*FIELD* TI
#612653 SPHEROCYTOSIS, TYPE 4; SPH4
;;SPHEROCYTOSIS, HEREDITARY, 4; HS4
*FIELD* TX
read moreA number sign (#) is used with this entry because spherocytosis type 4
is caused by mutation in the band 3 gene (SLC4A1, EPB3; 109270).

For a general description and a discussion of genetic heterogeneity of
spherocytosis, see SPH1 (182900).

CLINICAL FEATURES

Prchal et al. (1991) studied a family with autosomal dominant hereditary
spherocytosis associated with deficiency of erythrocyte band 3 protein.

Del Giudice et al. (1992) reported a family in which a dominantly
inherited form of hereditary spherocytosis was associated with
deficiency of band 3, resulting in an increased spectrin/band 3 ratio.
Since deficiency of spectrin is a much more frequent cause of hereditary
spherocytosis, the usual finding is a decreased spectrin/band 3 ratio.
An increased spectrin/band 3 ratio, pointing to a band 3 defect, was
found in 2 families with hereditary spherocytosis studied by Lux et al.
(1990).

Del Giudice et al. (1993) described a family in which both hereditary
spherocytosis due to band 3 deficiency and beta-0-thalassemia trait due
to codon 39 (C-T) mutation (141900.0312) were segregating. Two subjects
with HS alone had a typical clinical form of spherocytosis with anemia,
reticulocytosis, and increased red cell osmotic fragility. Two who
coinherited HS and beta-thalassemia trait were not anemic and showed a
slight, well-compensated hemolysis. Thus, the beta-thalassemic trait
partially corrected or 'silenced' HS caused by band 3 deficiency.

PATHOGENESIS

Saad et al. (1991) examined the mechanism underlying band 3 deficiency
in a subset of patients with hereditary spherocytosis.

MAPPING

Prchal et al. (1991) performed linkage analysis in a family with
autosomal dominant hereditary spherocytosis associated with deficiency
of erythrocyte band 3 protein. They excluded linkage with alpha-spectrin
(182860), beta-spectrin (182870), and ankyrin (612641), but found a
suggestion of linkage to EPB3 (SLC4A1). They used RFLPs not only in the
EPB3 gene but also in the NGFR gene (162010) which, like EPB3, maps to
17q21-q22. A maximum lod score of 11.40 at theta = 0.00 was observed.
Study of 42 members from 4 generations revealed a consistent linkage of
spherocytosis with 1 particular haplotype generated by the 4 probes that
were used.

MOLECULAR GENETICS

In a 28-year-old female with congenital spherocytic hemolytic anemia,
Jarolim et al. (1991) identified a missense mutation in the SLC4A1 gene
(109270.0003).

Jarolim et al. (1994) described duplication of 10 nucleotides in the
SLC4A1 gene (109270.0005) in a family with 5 individuals affected by
spherocytosis in 3 generations. Before splenectomy, the affected
subjects had a compensated hemolytic disease with reticulocytosis,
hyperbilirubinemia, and increased osmotic fragility.

Eber et al. (1996) found that band 3 frameshift and nonsense null
mutations occurred in dominant hereditary spherocytosis. In studies of
46 HS families, 12 ankyrin-1 mutations and 5 band 3 mutations were
identified.

Among 80 hereditary spherocytosis kindreds studied using denaturing
electrophoretic separation of solubilized erythrocyte membrane proteins,
Dhermy et al. (1997) recognized 3 prominent subsets: HS with isolated
spectrin deficiency, HS with combined spectrin and ankyrin deficiency,
and HS with band 3 deficiency. These 3 subsets represented more than 80%
of the HS kindreds studied. In 8 dominant HS kindreds with band 3
deficiency mutations were sought. In each, linkage analysis confirmed
the band 3 gene as the culprit gene. Five different mutations were found
in the 8 kindreds. Dhermy et al. (1997) found that the amount of band 3
appeared to be slightly, but significantly, more reduced in HS patients
with missense mutations and presence of the mutant transcripts than in
HS patients with premature termination of translation and absence of
mutant transcripts. This led to speculation that missense mutations may
have a dominant negative effect.

Bruce et al. (2005) identified 11 human pedigrees with dominantly
inherited hemolytic anemias in both the hereditary stomatocytosis and
spherocytosis classes. Affected individuals in these families had an
increase in membrane permeability to sodium and potassium ion that was
particularly marked at zero degree centigrade. They found that disease
in these pedigrees was associated with a series of single amino acid
substitutions in the intramembrane domain of the band 3 anion exchanger,
AE1. Anion movements were reduced in the abnormal red cells. The 'leak'
cation fluxes were inhibited by chemically diverse inhibitors of band 3.
Expression of the mutated genes in Xenopus laevis oocytes induced
abnormal NA and K fluxes in the oocytes, and the induced chloride
transport was low. These data were considered consistent with the
suggestion that the substitutions convert the protein from an anion
exchanger into an unregulated cation channel. Only 1 of the gene
changes, R760Q (109270.0028), had previously been reported (Jarolim et
al., 1995). All the mutations were in exon 17 of the SLC4A1 gene.

*FIELD* RF
1. Bruce, L. J.; Robinson, H. C.; Guizouarn, H.; Borgese, F.; Harrison,
P.; King, M.-J.; Goede, J. S.; Coles, S. E.; Gore, D. M.; Lutz, H.
U.; Ficarella, R.; Layton, D. M.; Iolascon, A.; Ellory, J. C.; Stewart,
G. W.: Monovalent cation leaks in human red cells caused by single
amino-acid substitutions in the transport domain of the band 3 chloride-bicarbon
ate exchanger, AE1. Nature Genet. 37: 1258-1263, 2005.

2. del Giudice, E.; Perrotta, S.; Pinto, L.; Cappellini, M. D.; Fiorelli,
G.; Cutillo, S.; Iolascon, A.: Hereditary spherocytosis characterized
by increased spectrin/band 3 ratio. Brit. J. Haemat. 80: 133-136,
1992.

3. del Giudice, E. M.; Perrotta, S.; Nobili, B.; Pinto, L.; Cutillo,
L.; Iolascon, A.: Coexistence of hereditary spherocytosis (HS) due
to band 3 deficiency and beta-thalassaemia trait: partial correction
of HS phenotype. Brit. J. Haemat. 85: 553-557, 1993.

4. Dhermy, D.; Galand, C.; Bournier, O.; Boulanger, L.; Cynober, T.;
Schismanoff, P. O.; Bursaux, E.; Tchernia, G.; Boivin, P.; Garbarz,
M.: Heterogenous band 3 deficiency in hereditary spherocytosis related
to different band 3 gene defects. Brit. J. Haemat. 98: 32-40, 1997.
Note: Erratum: Brit. J. Haemat. 99: 474 only, 1997.

5. Eber, S. W.; Gonzalez, J. M.; Lux, M. L.; Scarpa, A. L.; Tse, W.
T.; Dornwell, M.; Herbers, J.; Kugler, W.; Ozcan, R.; Pekrun, A.;
Gallagher, P. G.; Schroter, W.; Forget, B. G.; Lux, S. E.: Ankyrin-1
mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature
Genet. 13: 214-218, 1996.

6. Jarolim, P.; Palek, J.; Rubin, H. L.; Prchal, J. T.; Korsgren,
C.; Cohen, C. M.: Band 3 Tuscaloosa: pro327-to-arg327 substitution
in the cytoplasmic domain of erythrocyte band 3 protein associated
with spherocytic hemolytic anemia and partial deficiency of protein
4.2. (Abstract) Blood 78 (suppl.): 252a, 1991.

7. Jarolim, P.; Rubin, H. L.; Brabec, V.; Chrobak, L.; Zolotarev,
A. S.; Alper, S. L.; Brugnara, C.; Wichterle, H.; Palek, J.: Mutations
of conserved arginines in the membrane domain of erythroid band 3
lead to a decrease in membrane-associated band 3 and to the phenotype
of hereditary spherocytosis. Blood 85: 634-640, 1995.

8. Jarolim, P.; Rubin, H. L.; Liu, S.-C.; Cho, M. R.; Brabec, V.;
Derick, L. H.; Yi, S. J.; Saad, S. T. O.; Alper, S.; Brugnara, C.;
Golan, D. E.; Palek, J.: Duplication of 10 nucleotides in the erythroid
band 3 (AE1) gene in a kindred with hereditary spherocytosis and band
3 protein deficiency (band 3-Prague). J. Clin. Invest. 93: 121-130,
1994.

9. Lux, S.; Bedrosian, C.; Shalev, O.; Morris, M.; Chasis, J.; Davies,
K.; Savvides, P.; Telen, M.: Deficiency of band 3 in dominant hereditary
spherocytosis with normal spectrin content. (Abstract) Clin. Res. 38:
300A, 1990.

10. Prchal, J. T.; Guan, Y.; Jarolim, P.; Palek, J.; Showe, L.; Bertoli,
L.: Hereditary spherocytosis in a large family is linked with the
band 3 gene and not with alpha-spectrin, beta-spectrin or ankyrin.
(Abstract) Blood 78 (suppl.): 81a, 1991.

11. Saad, S. T. O.; Liu, S. C.; Golan, D.; Corbett, J. B.; Thatte,
H. S.; Derick, L.; Hanspal, M.; Jarolim, P.; Fibach, E.; Palek, J.
: Mechanism underlying band 3 deficiency in a subset of patients with
hereditary spherocytosis (HS). (Abstract) Blood 78 (suppl.): 81a,
1991.

*FIELD* CD
Carol A. Bocchini: 3/10/2009

*FIELD* ED
terry: 07/05/2012
carol: 3/11/2009
carol: 3/10/2009