RBCC Red Blood Cell Collection

GYPA (GPA) [Confidence: high (a blood group or CD marker)]
Glycophorin-A (MN sialoglycoprotein; PAS-2; Sialoglycoprotein alpha; CD235a; Flags: Precursor)

hRBCD IPI00298800
IPI00298800 Glycophorin A precursor Glycophorin A precursor membrane n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 3 1 1 Type I membrane protein. n/a found at its expected molecular weight found at molecular weight

BGMUT mns
356 mns GYPA and GYPB GYP Mi IX(1) GYP MiIX(1) (Dane,A-B-A hybrid) gene conversion breakpoint in A and B exon III; in GYPA 160-178; in GYPA nt. 160G>C; 165-167delCAC; 170C>A; 173G>C; 174A>T; 178C>A;194T>A A54P; T56del; P57H; R58T; H60N; I65N cDNA; gDNA Dane, MiIX rare 1421409 M87285 Huang et al. Blood 1992 80 2379-2387 Gene conversion; an A-B-A hybrid identical to Mi IX(2) but bearing an additional change 194T>A; an internal segment (minimum size 19 nt) of exon III of GYPA was replaced by a silent segment of GYPB; 194T>A is the accompanying variation. Blumenfeld OO, curator 2008-09-10 18:50:44.240 NA
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356 mns GYPA and GYPB GYP Mi IX(1) GYP MiIX(1) (Dane,A-B-A hybrid) gene conversion breakpoint in A and B exon III; in GYPA 160-178; in GYPA nt. 160G>C; 165-167delCAC; 170C>A; 173G>C; 174A>T; 178C>A;194T>A A54P; T56del; P57H; R58T; H60N; I65N cDNA; gDNA Dane, MiIX rare 1421409 M87285 Huang et al. Blood 1992 80 2379-2387 Gene conversion; an A-B-A hybrid identical to Mi IX(2) but bearing an additional change 194T>A; an internal segment (minimum size 19 nt) of exon III of GYPA was replaced by a silent segment of GYPB; 194T>A is the accompanying variation. Blumenfeld OO, curator 2008-09-10 18:50:44.240 NA

372 mns GYPA and GYPE GYP Sta(ERIK/TF) GYPSta(ERIK/TF) (A-E-A hybrid) A and E intron 2+intron 3: minimal sequence transferred from GYPE to GYPA: from 240nt downstrem from 3'end of intron2 + pseudoexon 3 + intron 3 1-25; in GYPA intron 2 -240A>G; -97delG; -84A>G; 79G>A; 76C>T -48A>T; -47C>T: exon III 140C>A; 160 G>C; 165 -167delCAC; 170C>A; 174A>T; 176C>T 178C>A; 194T>A 204G>C; 230C>A; 231C>T; intron 3 1G>A; 55A>G DKHKRDTYPVHSVNEVSEISVTTVSPPEEEN46-78del (sequence encoded by GYPE pseudoexon III is not expressed) cDNA; gDNA Sta/ERIK rare 10862083 AF239850 Huang et al. Gene conversion; A-E-A hybrid;transferred sequence is not expressed because it includes transfer of an inactive splicing signal; similar to Sta proteins and it bears the Sta epitope. Blumenfeld OO, curator 2008-04-09 20:51:37.983 NA

UniProt P02724
ID GLPA_HUMAN Reviewed; 150 AA.
AC P02724; A8K3E6; B8Q182; B8Q185; Q9BS51;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 22-SEP-2009, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Glycophorin-A;
DE AltName: Full=MN sialoglycoprotein;
DE AltName: Full=PAS-2;
DE AltName: Full=Sialoglycoprotein alpha;
DE AltName: CD_antigen=CD235a;
DE Flags: Precursor;
GN Name=GYPA; Synonyms=GPA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-13.
RX PubMed=3456608; DOI=10.1073/pnas.83.6.1665;
RA Siebert P.D., Fukuda M.;
RT "Isolation and characterization of human glycophorin A cDNA clones by
RT a synthetic oligonucleotide approach: nucleotide sequence and mRNA
RT structure.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:1665-1669(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS N LEU-20 AND
RP GLU-24.
RX PubMed=3196288;
RA Tate C.G., Tanner M.J.A.;
RT "Isolation of cDNA clones for human erythrocyte membrane
RT sialoglycoproteins alpha and delta.";
RL Biochem. J. 254:743-750(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ALA-13.
RX PubMed=2734312; DOI=10.1073/pnas.86.12.4619;
RA Kudo S., Fukuda M.;
RT "Structural organization of glycophorin A and B genes: glycophorin B
RT gene evolved by homologous recombination at Alu repeat sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:4619-4623(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-13.
RC TISSUE=Blood;
RX PubMed=2216775; DOI=10.1093/nar/18.19.5829;
RA Jawad K., Burness T.H.;
RT "The mechanism of production of multiple mRNAs for human glycophorin
RT A.";
RL Nucleic Acids Res. 18:5829-5836(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-13.
RC TISSUE=Blood;
RX PubMed=7798177;
RA Kudo S., Onda M., Fukuda M.;
RT "Characterization of glycophorin A transcripts: control by the common
RT erythroid-specific promoter and alternative usage of different
RT polyadenylation signals.";
RL J. Biochem. 116:183-192(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RC TISSUE=Blood;
RA Hsu K., Huang S.-Y., Chi N., Lin M.;
RT "Extensive alternative splicing of glycophorins in Southeast Asian
RT populations.";
RL Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ALA-13.
RC TISSUE=Kidney;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS N LEU-20
RP AND GLU-24.
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ALA-13,
RP AND VARIANTS N LEU-20 AND GLU-24.
RC TISSUE=Bone marrow, and Lung;
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 [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-145 (ISOFORM 1), AND VARIANT ALA-13.
RX PubMed=3809885; DOI=10.1016/S0338-4535(86)80019-8;
RA Siebert P.D., Fukuda M.;
RT "Molecular biological study of the structure and expression of human
RT glycophorin A.";
RL Rev. Fr. Transfus. Immunohematol. 29:251-266(1986).
RN [11]
RP PROTEIN SEQUENCE OF 20-150.
RX PubMed=1059087; DOI=10.1073/pnas.72.8.2964;
RA Tomita M., Marchesi V.T.;
RT "Amino-acid sequence and oligosaccharide attachment sites of human
RT erythrocyte glycophorin.";
RL Proc. Natl. Acad. Sci. U.S.A. 72:2964-2968(1975).
RN [12]
RP SEQUENCE REVISION TO 81-120.
RA Furthmayr H., Galardy R., Tomita M., Marchesi V.T.;
RL Submitted (JUN-1977) to the PIR data bank.
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 23-150.
RX PubMed=3345758; DOI=10.1111/j.1432-1033.1988.tb13866.x;
RA Rahuel C., London J., D'Auriol L., Mattei M.-G., Tournamille C.,
RA Skrzynia C., Lebouc Y., Galibert F., Cartron J.-P.;
RT "Characterization of cDNA clones for human glycophorin A. Use for gene
RT localization and for analysis of normal of glycophorin-A-deficient
RT (Finnish type) genomic DNA.";
RL Eur. J. Biochem. 172:147-153(1988).
RN [14]
RP PARTIAL PROTEIN SEQUENCE, AND VARIANT M(C) GLU-24.
RX PubMed=6166001; DOI=10.1073/pnas.78.1.631;
RA Furthmayr H., Metaxas M.N., Metaxas-Buhler M.;
RT "Mg and Mc: mutations within the amino-terminal region of glycophorin
RT A.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:631-635(1981).
RN [15]
RP PARTIAL PROTEIN SEQUENCE, AND VARIANT M(G) ASN-23.
RX PubMed=6940143; DOI=10.1073/pnas.78.2.747;
RA Blumenfeld O.O., Adamany A.M., Puglia K.V.;
RT "Amino acid and carbohydrate structural variants of glycoprotein
RT products (M-N glycoproteins) of the M-N allelic locus.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:747-751(1981).
RN [16]
RP GLYCOSYLATION.
RX PubMed=5350948;
RA Thomas D.B., Winzler R.J.;
RT "Structural studies on human erythrocyte glycoproteins. Alkali-labile
RT oligosaccharides.";
RL J. Biol. Chem. 244:5943-5946(1969).
RN [17]
RP POLYMORPHISM, AND INVOLVEMENT IN RESISTANCE TO MALARIA.
RX PubMed=7040988; DOI=10.1038/297064a0;
RA Pasvol G., Wainscoat J.S., Weatherall D.J.;
RT "Erythrocytes deficiency in glycophorin resist invasion by the
RT malarial parasite Plasmodium falciparum.";
RL Nature 297:64-66(1982).
RN [18]
RP GLYCOSYLATION.
RX PubMed=3624241;
RA Fukuda M., Lauffenburger M., Sasaki H., Rogers M.E., Dell A.;
RT "Structures of novel sialylated O-linked oligosaccharides isolated
RT from human erythrocyte glycophorins.";
RL J. Biol. Chem. 262:11952-11957(1987).
RN [19]
RP SUBUNIT.
RX PubMed=1463744; DOI=10.1021/bi00166a003;
RA Treutlein H.R., Lemmon M.A., Engelman D.M., Brunger A.T.;
RT "The glycophorin A transmembrane domain dimer: sequence-specific
RT propensity for a right-handed supercoil of helices.";
RL Biochemistry 31:12726-12732(1992).
RN [20]
RP GLYCOSYLATION AT SER-21; THR-22; THR-23; THR-29; SER-30; THR-31;
RP SER-32; THR-36; SER-38; SER-41; THR-44; ASN-45; THR-52; THR-56;
RP SER-63; SER-66 AND THR-69, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=8286855; DOI=10.1093/glycob/3.5.429;
RA Pisano A., Redmond J.W., Williams K.L., Gooley A.A.;
RT "Glycosylation sites identified by solid-phase Edman degradation: O-
RT linked glycosylation motifs on human glycophorin A.";
RL Glycobiology 3:429-435(1993).
RN [21]
RP FUNCTION AS RECEPTOR FOR PLASMODIUM EBA-175.
RX PubMed=8009226; DOI=10.1126/science.8009226;
RA Sim B.K., Chitnis C.E., Wasniowska K., Hadley T.J., Miller L.H.;
RT "Receptor and ligand domains for invasion of erythrocytes by
RT Plasmodium falciparum.";
RL Science 264:1941-1944(1994).
RN [22]
RP GLYCOSYLATION (AB BLOOD GROUP ANTIGENS).
RX PubMed=10912628;
RA Podbielska M., Krotkiewski H.;
RT "Identification of blood group A and B antigens in human
RT glycophorin.";
RL Arch. Immunol. Ther. Exp. 48:211-221(2000).
RN [23]
RP FUNCTION, AND MUTAGENESIS OF LEU-94; ILE-95; GLY-98 AND GLY-102.
RX PubMed=10926825; DOI=10.1042/0264-6021:3500053;
RA Young M.T., Beckmann R., Toye A.M., Tanner M.J.;
RT "Red-cell glycophorin A-band 3 interactions associated with the
RT movement of band 3 to the cell surface.";
RL Biochem. J. 350:53-60(2000).
RN [24]
RP SUBUNIT.
RX PubMed=11313283; DOI=10.1182/blood.V97.9.2872;
RA Auffray I., Marfatia S., de Jong K., Lee G., Huang C.H., Paszty C.,
RA Tanner M.J., Mohandas N., Chasis J.A.;
RT "Glycophorin A dimerization and band 3 interaction during erythroid
RT membrane biogenesis: in vivo studies in human glycophorin A transgenic
RT mice.";
RL Blood 97:2872-2878(2001).
RN [25]
RP SUBCELLULAR LOCATION.
RX PubMed=11402026; DOI=10.1074/jbc.M101889200;
RA Gerber D., Shai Y.;
RT "In vivo detection of hetero-association of glycophorin-A and its
RT mutants within the membrane.";
RL J. Biol. Chem. 276:31229-31232(2001).
RN [26]
RP FUNCTION, AND MUTAGENESIS OF PHE-87; SER-88; PRO-90 AND GLU-91.
RX PubMed=12813056; DOI=10.1074/jbc.M302527200;
RA Young M.T., Tanner M.J.;
RT "Distinct regions of human glycophorin A enhance human red cell anion
RT exchanger (band 3; AE1) transport function and surface trafficking.";
RL J. Biol. Chem. 278:32954-32961(2003).
RN [27]
RP REVIEW, AND VARIANTS.
RA Reid M.E., Christine Lomas-Francis C.;
RT "The blood group system.";
RL (In) Reid M.E., Christine Lomas-Francis C. (eds.);
RL The blood group antigen factsbook, pp.29-104, Academic Press, Oxford
RL (2004).
RN [28]
RP GLYCOSYLATION, AND MASS SPECTROMETRY.
RX PubMed=15313217; DOI=10.1016/j.abb.2004.06.018;
RA Podbielska M., Fredriksson S.A., Nilsson B., Lisowska E.,
RA Krotkiewski H.;
RT "ABH blood group antigens in O-glycans of human glycophorin A.";
RL Arch. Biochem. Biophys. 429:145-153(2004).
RN [29]
RP FUNCTION.
RX PubMed=14604989; DOI=10.1074/jbc.M309826200;
RA Bruce L.J., Pan R.J., Cope D.L., Uchikawa M., Gunn R.B., Cherry R.J.,
RA Tanner M.J.;
RT "Altered structure and anion transport properties of band 3 (AE1,
RT SLC4A1) in human red cells lacking glycophorin A.";
RL J. Biol. Chem. 279:2414-2420(2004).
RN [30]
RP FUNCTION AS RECEPTOR FOR FOR HEPATITIS A VIRUS.
RX PubMed=15331714; DOI=10.1128/JVI.78.18.9807-9813.2004;
RA Sanchez G., Aragones L., Costafreda M.I., Ribes E., Bosch A.,
RA Pinto R.M.;
RT "Capsid region involved in hepatitis A virus binding to glycophorin A
RT of the erythrocyte membrane.";
RL J. Virol. 78:9807-9813(2004).
RN [31]
RP INTERACTION WITH STREPTOCOCCUS GORDONII HSA PROTEIN.
RX PubMed=18380804; DOI=10.1111/j.1348-0421.2008.00015.x;
RA Yajima A., Urano-Tashiro Y., Shimazu K., Takashima E., Takahashi Y.,
RA Konishi K.;
RT "Hsa, an adhesin of Streptococcus gordonii DL1, binds to alpha2-3-
RT linked sialic acid on glycophorin A of the erythrocyte membrane.";
RL Microbiol. Immunol. 52:69-77(2008).
RN [32]
RP FUNCTION.
RX PubMed=19438409; DOI=10.1042/BJ20090345;
RA Pang A.J., Reithmeier R.A.;
RT "Interaction of anion exchanger 1 and glycophorin A in human
RT erythroleukaemic K562 cells.";
RL Biochem. J. 421:345-356(2009).
RN [33]
RP STRUCTURE BY NMR.
RX PubMed=2386609; DOI=10.1007/BF01025303;
RA Dill K., Hu S.H., Berman E., Pavia A.A., Lacombe J.M.;
RT "One- and two-dimensional NMR studies of the N-terminal portion of
RT glycophorin A at 11.7 Tesla.";
RL J. Protein Chem. 9:129-136(1990).
RN [34]
RP STRUCTURE BY NMR OF 81-120.
RX PubMed=9082985; DOI=10.1126/science.276.5309.131;
RA Mackenzie K.R., Prestegard J.H., Engelman D.M.;
RT "A transmembrane helix dimer: structure and implications.";
RL Science 276:131-133(1997).
RN [35]
RP 3D-STRUCTURE MODELING OF 93-110.
RX PubMed=8953647;
RX DOI=10.1002/(SICI)1097-0134(199611)26:3<257::AID-PROT2>3.3.CO;2-O;
RA Adams P.D., Engelman D.M., Bruenger A.T.;
RT "Improved prediction for the structure of the dimeric transmembrane
RT domain of glycophorin A obtained through global searching.";
RL Proteins 26:257-261(1996).
RN [36]
RP VARIANT ENEH/VW MET-47.
RX PubMed=1611092;
RA Huang C.-H., Spruell P., Moulds J.J., Blumenfeld O.O.;
RT "Molecular basis for the human erythrocyte glycophorin specifying the
RT Miltenberger class I (MiI) phenotype.";
RL Blood 80:257-263(1992).
RN [37]
RP VARIANT ENEH/HUT ANTIGEN LYS-47.
RX PubMed=1421409;
RA Huang C.H., Skov F., Daniels G., Tippett P., Blumenfeld O.O.;
RT "Molecular analysis of human glycophorin MiIX gene shows a silent
RT segment transfer and untemplated mutation resulting from gene
RT conversion via sequence repeats.";
RL Blood 80:2379-2387(1992).
RN [38]
RP VARIANT ERIK ARG-78.
RX PubMed=8245024;
RA Huang C.H., Reid M., Daniels G., Blumenfeld O.O.;
RT "Alteration of splice site selection by an exon mutation in the human
RT glycophorin A gene.";
RL J. Biol. Chem. 268:25902-25908(1993).
RN [39]
RP VARIANT ENEP/HAG PRO-84.
RX PubMed=10354388; DOI=10.1046/j.1365-3148.1999.00185.x;
RA Poole J., Banks J., Bruce L.J., Ring S.M., Levene C., Stern H.,
RA Overbeeke M.A., Tanner M.J.;
RT "Glycophorin A mutation Ala65 --> Pro gives rise to a novel pair of
RT MNS alleles ENEP (MNS39) and HAG (MNS41) and altered Wrb expression:
RT direct evidence for GPA/band 3 interaction necessary for normal Wrb
RT expression.";
RL Transfus. Med. 9:167-174(1999).
RN [40]
RP VARIANTS NY(A) GLU-46 AND OS(A) SER-73.
RX PubMed=10827258; DOI=10.1046/j.1537-2995.2000.40050555.x;
RA Daniels G.L., Bruce L.J., Mawby W.J., Green C.A., Petty A., Okubo Y.,
RA Kornstad L., Tanner M.J.;
RT "The low-frequency MNS blood group antigens Ny(a) (MNS18) and Os(a)
RT (MNS38) are associated with GPA amino acid substitutions.";
RL Transfusion 40:555-559(2000).
RN [41]
RP VARIANTS VR TYR-66 AND MT(A) ILE-77.
RX PubMed=10729812; DOI=10.1159/000031149;
RA Storry J.R., Coghlan G., Poole J., Figueroa D., Reid M.E.;
RT "The MNS blood group antigens, Vr (MNS12) and Mt(a) (MNS14), each
RT arise from an amino acid substitution on glycophorin A.";
RL Vox Sang. 78:52-56(2000).
CC -!- FUNCTION: Glycophorin A is the major intrinsic membrane protein of
CC the erythrocyte. The N-terminal glycosylated segment, which lies
CC outside the erythrocyte membrane, has MN blood group receptors.
CC Appears to be important for the function of SLC4A1 and is required
CC for high activity of SLC4A1. May be involved in translocation of
CC SLC4A1 to the plasma membrane. Is a receptor for influenza virus.
CC Is a receptor for Plasmodium falciparum erythrocyte-binding
CC antigen 175 (EBA-175); binding of EBA-175 is dependent on sialic
CC acid residues of the O-linked glycans. Appears to be a receptor
CC for Hepatitis A virus (HAV).
CC -!- SUBUNIT: Homodimer. Interacts with Streptococcus gordonii hsa
CC protein.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-702665, EBI-702665;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Note=Appears to be colocalized with SLC4A1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P02724-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P02724-2; Sequence=VSP_047822;
CC Name=3;
CC IsoId=P02724-3; Sequence=VSP_047823;
CC -!- PTM: The major O-linked glycan are NeuAc-alpha-(2-3)-Gal-beta-(1-
CC 3)-[NeuAc-alpha-(2-6)]-GalNAcOH (about 78 %) and NeuAc-alpha-(2-
CC 3)-Gal-beta-(1-3)-GalNAcOH (17 %). Minor O-glycans (5 %) include
CC NeuAc-alpha-(2-3)-Gal-beta-(1-3)-[NeuAc-alpha-(2-6)]-GalNAcOH
CC NeuAc-alpha-(2-8)-NeuAc-alpha-(2-3)-Gal-beta-(1-3)-GalNAcOH. About
CC 1% of all O-linked glycans carry blood group A, B and H
CC determinants. They derive from a type-2 precursor core structure,
CC Gal-beta-(1,3)-GlcNAc-beta-1-R, and the antigens are synthesized
CC by addition of fucose (H antigen-specific) and then N-
CC acetylgalactosamine (A antigen-specific) or galactose (B antigen-
CC specific). Specifically O-linked-glycans are NeuAc-alpha-(2-3)-
CC Gal-beta-(1-3)-GalNAcOH-(6-1)-GlcNAc-beta-(4-1)-[Fuc-alpha-(1-2)]-
CC Gal-beta-(3-1)-GalNAc-alpha (about 1%, B antigen-specific) and
CC NeuAc-alpha-(2-3)-Gal-beta-(1-3)-GalNAcOH-(6-1)-GlcNAc-beta-(4-1)-
CC [Fuc-alpha-(1-2)]-Gal-beta (1 %, O antigen-, A antigen- and B
CC antigen-specific).
CC -!- POLYMORPHISM: Along with GYPB, GYPA is responsible for the MNS
CC blood group system. The molecular basis of the GPA M/N bloodgroup
CC antigen is a variation at positions 20 and 24. Ser-20 and Gly-24
CC correspond to M (shown); 'Leu-20' and 'Glu-24' correspond to N.
CC -!- POLYMORPHISM: GYPA polymorphisms are involved in resistance to
CC malaria [MIM:611162].
CC -!- MISCELLANEOUS: Involved in several unequal homologous
CC recombinations or gene conversion events, predominantly with GYPB
CC and more rarely with GYPE. The resulting fusion proteins are
CC observed in different phenotypes and encode low incidence
CC bloodgroup antigens.
CC -!- SIMILARITY: Belongs to the glycophorin A family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA52624.1; Type=Erroneous initiation;
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;=mns";
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; M12857; AAA88044.1; -; mRNA.
DR EMBL; X08054; CAA30843.1; -; mRNA.
DR EMBL; M24128; AAA52768.1; -; Genomic_DNA.
DR EMBL; M24123; AAA52768.1; JOINED; Genomic_DNA.
DR EMBL; M24134; AAA52768.1; JOINED; Genomic_DNA.
DR EMBL; M24124; AAA52768.1; JOINED; Genomic_DNA.
DR EMBL; M24126; AAA52768.1; JOINED; Genomic_DNA.
DR EMBL; M24127; AAA52768.1; JOINED; Genomic_DNA.
DR EMBL; X51798; CAA36095.1; -; mRNA.
DR EMBL; L31860; AAA88051.1; -; mRNA.
DR EMBL; EU338231; ACA96789.1; -; mRNA.
DR EMBL; EU338233; ACA96791.1; -; mRNA.
DR EMBL; EU338234; ACA96792.1; -; mRNA.
DR EMBL; GU347002; ADU25340.1; -; mRNA.
DR EMBL; GU347003; ADU25341.1; -; mRNA.
DR EMBL; AK290561; BAF83250.1; -; mRNA.
DR EMBL; AC107223; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC005319; AAH05319.1; -; mRNA.
DR EMBL; BC013328; AAH13328.1; -; mRNA.
DR EMBL; M36281; AAA52624.1; ALT_INIT; mRNA.
DR PIR; A33931; A25131.
DR RefSeq; NP_002090.4; NM_002099.6.
DR RefSeq; XP_005263021.1; XM_005262964.1.
DR RefSeq; XP_005263022.1; XM_005262965.1.
DR UniGene; Hs.434973; -.
DR PDB; 1AFO; NMR; -; A/B=81-120.
DR PDB; 1MSR; Model; -; A/B=93-110.
DR PDB; 2KPE; NMR; -; A/B=89-117.
DR PDB; 2KPF; NMR; -; A/B=80-117.
DR PDBsum; 1AFO; -.
DR PDBsum; 1MSR; -.
DR PDBsum; 2KPE; -.
DR PDBsum; 2KPF; -.
DR ProteinModelPortal; P02724; -.
DR SMR; P02724; 81-120.
DR STRING; 9606.ENSP00000354003; -.
DR BindingDB; P02724; -.
DR ChEMBL; CHEMBL5806; -.
DR PhosphoSite; P02724; -.
DR UniCarbKB; P02724; -.
DR DMDM; 259016238; -.
DR PaxDb; P02724; -.
DR PRIDE; P02724; -.
DR DNASU; 2993; -.
DR Ensembl; ENST00000324022; ENSP00000324483; ENSG00000170180.
DR Ensembl; ENST00000360771; ENSP00000354003; ENSG00000170180.
DR Ensembl; ENST00000535709; ENSP00000445398; ENSG00000170180.
DR GeneID; 2993; -.
DR KEGG; hsa:2993; -.
DR UCSC; uc003ijo.4; human.
DR CTD; 2993; -.
DR GeneCards; GC04M145030; -.
DR HGNC; HGNC:4702; GYPA.
DR HPA; CAB002658; -.
DR HPA; HPA014811; -.
DR MIM; 111300; gene+phenotype.
DR MIM; 611162; phenotype.
DR neXtProt; NX_P02724; -.
DR PharmGKB; PA29080; -.
DR eggNOG; NOG114778; -.
DR HOGENOM; HOG000089933; -.
DR HOVERGEN; HBG005850; -.
DR InParanoid; P02724; -.
DR KO; K06575; -.
DR OrthoDB; EOG7ZWD4D; -.
DR EvolutionaryTrace; P02724; -.
DR GeneWiki; GYPA; -.
DR GenomeRNAi; 2993; -.
DR NextBio; 11862; -.
DR PRO; PR:P02724; -.
DR ArrayExpress; P02724; -.
DR Bgee; P02724; -.
DR CleanEx; HS_GYPA; -.
DR Genevestigator; P02724; -.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc.
DR GO; GO:0001618; F:virus receptor activity; IEA:UniProtKB-KW.
DR GO; GO:0007016; P:cytoskeletal anchoring at plasma membrane; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0047484; P:regulation of response to osmotic stress; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEA:GOC.
DR InterPro; IPR001195; Glycophorin.
DR InterPro; IPR018938; Glycophorin_CS.
DR PANTHER; PTHR13813; PTHR13813; 1.
DR Pfam; PF01102; Glycophorin_A; 1.
DR PIRSF; PIRSF002466; Glycophorin; 1.
DR PROSITE; PS00312; GLYCOPHORIN_A; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Blood group antigen;
KW Cell membrane; Complete proteome; Direct protein sequencing;
KW Glycoprotein; Host cell receptor for virus entry;
KW Host-virus interaction; Membrane; Polymorphism; Receptor;
KW Reference proteome; Sialic acid; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 19
FT CHAIN 20 150 Glycophorin-A.
FT /FTId=PRO_0000012134.
FT TOPO_DOM 20 91 Extracellular.
FT TRANSMEM 92 114 Helical.
FT TOPO_DOM 115 150 Cytoplasmic.
FT CARBOHYD 21 21 O-linked (GalNAc...).
FT CARBOHYD 22 22 O-linked (GalNAc...).
FT CARBOHYD 23 23 O-linked (GalNAc...).
FT CARBOHYD 29 29 O-linked (GalNAc...).
FT CARBOHYD 30 30 O-linked (GalNAc...).
FT CARBOHYD 31 31 O-linked (GalNAc...).
FT CARBOHYD 32 32 O-linked (GalNAc...).
FT CARBOHYD 36 36 O-linked (GalNAc...).
FT CARBOHYD 38 38 O-linked (GalNAc...).
FT CARBOHYD 41 41 O-linked (GalNAc...).
FT CARBOHYD 44 44 O-linked (GalNAc...).
FT CARBOHYD 45 45 N-linked (GlcNAc...).
FT CARBOHYD 52 52 O-linked (GalNAc...).
FT CARBOHYD 56 56 O-linked (GalNAc...).
FT CARBOHYD 63 63 O-linked (GalNAc...).
FT CARBOHYD 66 66 O-linked (GalNAc...).
FT CARBOHYD 69 69 O-linked (GalNAc...).
FT VAR_SEQ 1 26 Missing (in isoform 2).
FT /FTId=VSP_047822.
FT VAR_SEQ 13 45 Missing (in isoform 3).
FT /FTId=VSP_047823.
FT VARIANT 13 13 E -> A (in dbSNP:rs4449373).
FT /FTId=VAR_058911.
FT VARIANT 13 13 E -> G (in dbSNP:rs4449373).
FT /FTId=VAR_059977.
FT VARIANT 20 20 S -> L (in N antigen and M(g) antigen;
FT dbSNP:rs7682260).
FT /FTId=VAR_003190.
FT VARIANT 23 23 T -> N (in M(g) antigen).
FT /FTId=VAR_058912.
FT VARIANT 24 24 G -> D (in dbSNP:rs7658293).
FT /FTId=VAR_058913.
FT VARIANT 24 24 G -> E (in N antigen, in M(c) antigen and
FT in M(g) antigen; dbSNP:rs7687256).
FT /FTId=VAR_003191.
FT VARIANT 46 46 D -> E (in Ny(a) antigen).
FT /FTId=VAR_058914.
FT VARIANT 47 47 T -> K (in ENEH/Hut antigen).
FT /FTId=VAR_058915.
FT VARIANT 47 47 T -> M (in ENEH/Vw antigen).
FT /FTId=VAR_058916.
FT VARIANT 50 50 R -> W (in Or antigen).
FT /FTId=VAR_058917.
FT VARIANT 66 66 S -> Y (in Vr antigen; dbSNP:rs56077914).
FT /FTId=VAR_058918.
FT VARIANT 73 73 P -> S (in Os(a) antigen).
FT /FTId=VAR_058919.
FT VARIANT 76 76 E -> K (in Ri(a) antigen).
FT /FTId=VAR_058920.
FT VARIANT 77 77 T -> I (in Mt(a) antigen;
FT dbSNP:rs56172553).
FT /FTId=VAR_058921.
FT VARIANT 78 78 G -> R (in ERIK antigen;
FT dbSNP:rs1800582).
FT /FTId=VAR_058922.
FT VARIANT 82 82 Q -> K (in ENAV/MARS antigen).
FT /FTId=VAR_058923.
FT VARIANT 84 84 A -> P (in ENEP/HAG antigen).
FT /FTId=VAR_058924.
FT MUTAGEN 87 87 F->C: Diminishes dimerization.
FT MUTAGEN 88 88 S->C: Diminishes dimerization.
FT MUTAGEN 90 90 P->C: Diminishes dimerization.
FT MUTAGEN 91 91 E->C: Diminishes dimerization.
FT MUTAGEN 94 94 L->I: Diminishes dimerization.
FT MUTAGEN 95 95 I->A: Diminishes dimerization.
FT MUTAGEN 98 98 G->L: Diminishes dimerization.
FT MUTAGEN 102 102 G->L: Abolishes dimerization.
FT CONFLICT 30 30 S -> T (in Ref. 11; AA sequence).
FT CONFLICT 36 36 T -> S (in Ref. 11; AA sequence).
FT CONFLICT 133 133 T -> R (in Ref. 1; AAA88044).
FT STRAND 84 86
FT HELIX 91 117
SQ SEQUENCE 150 AA; 16331 MW; 48A5450E22FA99C9 CRC64;
MYGKIIFVLL LSEIVSISAS STTGVAMHTS TSSSVTKSYI SSQTNDTHKR DTYAATPRAH
EVSEISVRTV YPPEEETGER VQLAHHFSEP EITLIIFGVM AGVIGTILLI SYGIRRLIKK
SPSDVKPLPS PDTDVPLSSV EIENPETSDQ
//

MIM 111300
*RECORD*
*FIELD* NO
111300
*FIELD* TI
+111300 BLOOD GROUP--MN LOCUS; MN
GLYCOPHORIN A, INCLUDED; GPA, INCLUDED;;
GYPA, INCLUDED
read more*FIELD* TX
On the basis of studies in the family of a child with a translocation
chromosome, German et al. (1968) suggested that the MN locus is either
in the middle of chromosome 2 or near the distal end of the long arm of
chromosome 4. Using 'banding techniques,' German and Chaganti (1973)
restudied the translocation they reported in 1968 and concluded that MN
can be tentatively assigned to the area of band q14 in the proximal
portion of the long arm of chromosome 2. Weitkamp et al. (1972)
presented data suggesting that the MN locus and the beta hemoglobin
locus (141900) are linked. (This has, of course, been disproved.)
Barbosa et al. (1975) excluded a recombination fraction of less than
0.30 for MN and Hb beta. The results supported a lower recombination
fraction for males. Linkage with the Alzheimer locus (104300) and with
colonic polyposis (175100) has been suspected. Recombination data
suggested that the MN and acid phosphatase (ACP1; 171500) loci are far
apart (Weitkamp et al., 1975). Cook et al. (1978) excluded MNSs from
chromosome 9 by exclusion mapping that incorporated data both from
families with chromosome markers and from linkage studies with firmly
assigned markers. MNSs was subsequently assigned to chromosome 4. In a
further study of the propositus of the 2q;4q translocation family,
German et al. (1979) showed by banding that the breaks had occurred at
2q14 and 4q29 and that a minute segment had been lost at the site of
break. Whether the loss was from chromosome 2 or 4 was not certain
because both have several short bands at these sites and only one band
was missing in the proband. The proband lacked blood type 's' (GPB;
111740) which he should have received from his 'ss' father, had signs of
a modified red cell membrane, and had developmental abnormalities. Since
the abnormalities of phenotype appeared at the same time as the
chromosomal abnormality, German et al. (1979) suggested that deletion
was the basis of all the changes. Since Weitkamp (1978) reported
observations indicating strongly that MNSs is not near 2q14, German et
al. (1979) concluded that it must be in a band near 4q29. Cook et al.
(1980) favored 4q28 over 4q31. For males, Bias and Meyers (1979) found a
maximal lod score of 3.99 at theta 0.18 for linkage of Stoltzfus
(111800) and MNS. Acid phosphatase and Kidd both gave lods of 0.32 with
Stoltzfus at a male-theta of 0.20. Linkage of Gc and MNSs at
recombination frequencies of less than 25% in males and 30% in females
was excluded by Weitkamp (1978). For MN versus Gc, Falk et al. (1979)
found a male lod score of 3.75 at a recombination fraction of 0.30. In
females the maximal lod score was 0.34 at a recombination fraction of
0.42. From analysis of MNSs blood groups in families with chromosome 4
rearrangements, both deletion analysis and family linkage study, Cook et
al. (1981) concluded that the MNSs 'locus' lies in the region 4q28-q31.

Blumenfeld and Adamany (1978) found that the MM blood group polypeptide
differs from the NN polypeptide in two amino acids, these being serine
and glycine in MM and leucine and glutamic acid in NN. The MN individual
shows all four amino acids. The two major sialoglycoproteins of the
human red cell membrane, alpha and delta (glycophorins A and B), carry
the MNSs antigenic specificities. They have identical amino acid
sequences for the first 26 residues from the amino terminus. Alpha
expresses M or N blood group activity; delta carries only blood group N
activity. Furthermore, the asparagine at position 26 of the alpha
carries an oligosaccharide chain which is absent from the same position
of delta. The two sialoglycoproteins differ in their remaining amino
acid sequence and delta expresses Ss activity. Using antibodies directed
against different structural regions of the major sialoglycoprotein
alpha, Mawby et al. (1981) confirmed that two variant forms
(Miltenberger class V and Ph) represented hybrid sialoglycoprotein
molecules, which arose from anomalous crossover events between the genes
coding for alpha and delta. The genes appear to be closely linked, in
the order alpha-delta (5-prime to 3-prime). Thus the family data on
close linkage are confirmed. The sequence may be MN--Ss--Gc (Gedde-Dahl
and Olaisen, 1981).

One of the longest genetic intervals measured in man in the pre-RFLP era
was that between GC and MN with a lod score, in males, of 3.79 at a
recombination fraction of 0.32 (Falk, 1984). In a linkage analysis of
146 informative families for MN and Ss, Spence et al. (1984) found 7
recombinant children out of 467, including 1 confirmed recombinant
(retested and HLA-compatible) and 6 not verified. The 95% confidence
interval of the estimate of recombination was 0.0033-0.1167. By in situ
hybridization using a glycophorin A cDNA probe, Mattei et al. (1987)
mapped the gene to 4q28-q31, thus confirming the mapping by other
methods. By in situ hybridization and RFLP studies in a case of balanced
de novo translocation between chromosomes 2 and 4, Divelbiss et al.
(1989) concluded that the fibrinogen gene cluster (134830) lies proximal
to the GYPA/GYPB loci and that all of these loci lie in the 4q28 band.
In a malformed female infant with de novo interstitial deletion of 4q,
Wakui et al. (1991) found that the MN locus was intact. On the basis of
this finding and previous mapping data, they concluded that the MN locus
is in the 4q28.2-q31.1 segment.

Onda and Fukuda (1995) isolated several P1 plasmid clones with which
they characterized the organization of the glycophorin A (GPA), B (GPB),
and E (GPE; 138590) gene cluster which spans about 330 kb of chromosome
4q31. For each gene, the first intron varies in size from 25 to 29 kb,
while the intergenic interval is approximately 80 kb. The authors
proposed that the GPA-GPB-GPE cluster arose by 2 successive duplications
and a number of subsequent events, including a gene conversion between
the exon 2 region of GPA and GPE.

Red cells with the rare En(a-) variant are resistant to falciparum
malaria (Pasvol et al., 1982). Such cells lack glycophorin A, the major
red cell sialoglycoprotein (Siebert and Fukuda, 1986). The rare U(-)
variant of the Ss system, which lacks the other major sialoglycoprotein,
glycophorin B, is relatively resistant to invasion. Wr(b)-negative cells
are also resistant to invasion by P. falciparum despite the fact that
they have normal amounts of glycophorins A and B on their surface. All
of these observations, as well as experiments using antibodies to
glycophorins and certain sugars, particularly N-acetylglucosamine, have
led to a tentative model of the role of glycophorin in the red cell
invasion of P. falciparum (Pasvol and Wilson, 1982). Langlois et al.
(1986) studied the frequency of red cells with loss of expression at the
glycophorin A locus (GPA). Glycophorin A is present in about 500,000
copies per red cell. The 2 allelic forms of GPA, blood group M and blood
group N, are identical except for 2 amino acid substitutions at
positions 1 and 5 from the amino terminus (Prohaska et al., 1986). Using
monoclonal antibodies, Langlois et al. (1986) identified expression loss
mutants. They found a frequency of about 1 in 100,000 cells in normals
and a significant increase in the variant cells in cancer patients after
exposure to mutagenic chemotherapy drugs. Langlois et al. (1987)
demonstrated a linear relationship between frequency of mutations at the
glycophorin A locus and radiation exposure in atomic bomb survivors.
Grant and Bigbee (1994) discussed the use of the GPA assay to evaluate
the creation of somatic mutations by cancer chemotherapy.

Rahuel et al. (1988) characterized 2 cDNA clones encoding glycophorin A
from human fetal cDNA libraries. They used these clones to locate the
structural gene to 4q28-q32. They concluded further, by Southern blot
analysis of genomic DNA from normal En(a+) and rare En(a-) persons, that
the glycophorin A gene has a complex organization and is largely deleted
in persons of the En(a-) phenotype (Finnish type), who lack glycophorin
A on their red cells. Rahuel et al. (1988) concluded that the Finnish
variant is homozygous for a complete deletion of the glycophorin A gene
without any detectable abnormality of the genes encoding glycophorins B
or C. In the genome of the UK variant of En(a-), Rahuel et al. (1988)
identified several abnormalities of the glycophorin A and B genes,
leading them to conclude that both are largely deleted, being replaced
by a gene fusion product composed of the N-terminal portion of a blood
group M-type glycophorin A and of the C-terminal portion of glycophorin
B. Okubo et al. (1988) described 2 Japanese sisters with consanguineous
parents who were apparently homozygous for M(k). Total absence of
sialoglycoproteins A (alpha) and B (delta) from red cell membranes was
demonstrated in 1 of the sisters. This is the third reported family; one
of the other families was also Japanese. All affected individuals had
been healthy except for the proposita in the present study who had
Hodgkin disease. Huang et al. (1988) studied a family in which 3
different glycophorin mutations were present in 2 individuals of a
16-member family. The variant Dantu glycophorin showed properties
consistent with a delta-alpha (GPB/GPA) hybrid glycophorin. This gene
was linked to a gene coding for the M-specific alpha glycophorin.
Another variant glycophorin, Mi-III glycophorin, was transmitted as an
autosomal dominant trait and was associated with N blood group activity.
The inheritance pattern indicated that it could be a variant of delta
glycophorin (glycophorin B). In the persons with both Dantu and Mi-III
glycophorins, a delta glycophorin deficiency was observed, suggesting
that a deletion or alteration of the delta gene may exist on the same
chromosome as the Dantu gene. Huang et al. (1989) showed that the St(a)
(Stone) antigen is likewise determined by a fusion hybrid of the
glycophorin A and B genes.

As noted earlier, the glycophorin variant Miltenberger class V-like
molecule (MiV) is a hybrid: Kudo et al. (1990) showed that the 5-prime
half of the gene is derived from the GPA gene, whereas the 3-prime half
is derived from the GPB gene. This structure is reciprocal to the
glycophorin variant St(a), which has a GPB-GPA hybrid structure. Huang
et al. (1992) identified the molecular nature of the change responsible
for the Miltenberger class I (MiI) phenotype in a white family in which
the first homozygote was observed.

The St(a) antigen has been shown to be associated with several isoforms
of glycophorin. The St(a) alleles are genetically associated with
splicing mutations in the GPA gene or with hybrid formation between GPA
and GPB genes. Huang et al. (2000) reported the first and rare gene
conversion event in which GPE recombined with GPA, giving rise to a
novel GPA-E-A hybrid gene encoding the St(a) antigen.

Rothman et al. (1995) used the GPA assay to evaluate the effects of
occupational exposure to benzene. The GPA assay measures the frequency
of variant erythrocytes that have lost expression of the blood type M in
blood samples from heterozygous (MN) individuals. Variant cells are
detected by treating sphered, fixed erythrocytes with
fluorescent-labeled monoclonal antibodies specific for the M and N forms
and, by flow cytometry, counting variant cells that bind the anti-N
antibody but not the anti-M antibody. The variant cells possess the
phenotype N-zero (single-copy expression of N and no expression of M) or
NN (double-copy expression of N and no expression of M). These
phenotypic variants arise from different mutational mechanisms in
precursor cells: N-zero cells are thought to arise from point mutations,
deletions, or gene inactivation, whereas NN cells presumably arise from
mitotic recombination, chromosome loss and reduplication, or gene
conversion. Rothman et al. (1995) used this GPA assay to evaluate DNA
damage produced by benzene in 24 heavily exposed workers in Shanghai,
China and 23 matched controls. A significant increase in the MN GPA
variant cell frequency was found in benzene-exposed workers, but no
significant difference existed between the 2 groups for N-zero cells.
Furthermore, lifetime cumulative occupational exposure to benzene was
associated with the NN frequency, but not with the N-zero frequency,
suggesting that NN mutations occur in longer-lived bone marrow stem
cells.

Blumenfeld and Huang (1995) reviewed the molecular genetics of 25
variants of the glycophorin gene family, whose common denominator is
that they arise from unequal gene combinations or gene conversions
coupled to splice site mutations. Most rearrangements occur within a
2-kb region mainly within GPA and GPB and only rarely within the third
member, GPE. They observed that the key feature is the shuffling of
sequences within 2 specific exons (1 of which is silent), which are
homologous in the 2 parent genes. This results in expression of a mosaic
of sequences within the region, leading to polymorphism.

Bruce et al. (2004) studied the properties of band 3 (SLC4A1; 109270) in
red cells lacking glycophorin A 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.

Glycophorin A (GYPA) and B (see 111740), which determine the MN and Ss
blood types, respectively, are 2 major receptors that are expressed on
erythrocyte surfaces and interact with Plasmodium falciparum ligands. Ko
et al. (2011) analyzed nucleotide diversity of the glycophorin gene
family in 15 African populations with different levels of malaria
exposure. High levels of nucleotide diversity and gene conversion were
found at these genes. Ko et al. (2011) observed divergent patterns of
genetic variation between these duplicated genes and between different
extracellular domains of GYPA. Specifically, they identified fixed
adaptive changes at exons 3 to 4 of GYPA. By contrast, Ko et al. (2011)
observed an allele frequency spectrum skewed toward a significant excess
of intermediate-frequency alleles at GYPA exon 2 in many populations;
the degree of spectrum distortion was correlated with malaria exposure,
possibly because of the joint effects of gene conversion and balancing
selection. Ko et al. (2011) also identified a haplotype causing 3 amino
acid changes in the extracellular domain of glycophorin B. This
haplotype might have evolved adaptively in 5 populations with high
exposure to malaria.

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

*FIELD* AV
.0001
BLOOD GROUP ERIK
GPA, GLY59ARG

Huang et al. (1993) identified a G-to-A transition at the last
nucleotide position of exon 3 of the GYPA gene, which affected pre-mRNA
splicing because of partial inactivation of the adjacent 5-prime splice
site and skipping of various exons involving the alternative use of
other constitutive splice sites. Characterization of the resultant
transcripts allowed Huang et al. (1993) to elucidate the molecular basis
for the coexpression of ERIK and St(a) antigens on the erythrocyte
membrane. The full-length transcript encoded a variant glycophorin with
an arginine replacing a glycine at position 59 and defining the ERIK
epitope, whereas the exon 3-deleted transcript specified a shorter
glycophorin carrying the St(a) antigen. Whereas most mutations leading
to aberrant splicing occur as single nucleotide substitutions in the
5-prime and 3-prime splicing consensus sequences, the G-to-A change at
position -1 from the splice donor site, in the allele the authors
referred to as GPErik, has been found in a few other cases, e.g., in the
COL1A1 gene causing Ehlers-Danlos syndrome, type VIIA (120150.0026).

*FIELD* SA
Anstee (1981); Furthmayr et al. (1981); German et al. (1969); Heiberg
and Berg (1975); Mayr (1976); Rahuel et al. (1988); Springer and
Tegtmeyer (1981); Walker et al. (1977)
*FIELD* RF
1. Anstee, D. J.: The blood group MNSs-active sialoglycoproteins. Seminars
Hemat. 18: 13-31, 1981.

2. Barbosa, C. A. A.; Koury, W. H.; Krieger, H.: Linkage data on
MN and the Hb beta locus. Am. J. Hum. Genet. 27: 797-801, 1975.

3. Bias, W. B.; Meyers, D. A.: Segregation and linkage analysis of
the Stoltzfus blood group (SF). (Abstract) Cytogenet. Cell Genet. 25:
137, 1979.

4. Blumenfeld, O. O.; Adamany, A. M.: Structural (glycophorins) of
the human erythrocyte membrane. Proc. Nat. Acad. Sci. 75: 2727-2731,
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5. Blumenfeld, O. O.; Huang, C.-H.: Molecular genetics of the glycophorin
gene family, the antigens for MNSs blood groups: multiple gene rearrangements
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6. 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
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7. Cook, P. J. L.; Lindenbaum, R. H.; Salonen, R.; de la Chapelle,
A.; Daker, M. G.; Buckton, K. E.; Noades, J. E.; Tippett, P.: The
MNSs blood groups of families with chromosome 4 rearrangements. Ann.
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8. Cook, P. J. L.; Noades, J. E.; Lomas, C. G.; Buckton, K. E.; Robson,
E. B.: Exclusion mapping illustrated by the MNSs blood group. Ann.
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9. Cook, P. J. L.; Robson, E. B.; Buckton, K. E.; Slaughter, C. A.;
Gray, J. E.; Blank, C. E.; James, F. E.; Ridler, M. A. C.; Insley,
J.; Hulten, M.: Segregation of ABO, AK-1 and ACON-S in families with
abnormalities of chromosome 9. Ann. Hum. Genet. 41: 365-377, 1978.

10. Divelbiss, J.; Shiang, R.; German, J.; Moore, J.; Murray, J. C.;
Patil, S. R.: Refinement of the physical location of glycophorin
A and beta fibrinogen using in situ hybridization and RFLP analysis.
(Abstract) Cytogenet. Cell Genet. 51: 991, 1989.

11. Falk, C. T.: New family data supporting the MN/GC linkage. (Abstract) Cytogenet.
Cell Genet. 37: 466, 1984.

12. Falk, C. T.; Martin, M. D.; Walker, M. E.; Chen, T.; Rubinstein,
P.; Allen, F. H., Jr.: Family data suggesting a linkage between MN
and Gc. (Abstract) Cytogenet. Cell Genet. 25: 152, 1979.

13. Furthmayr, H.; Metaxas, M. N.; Metaxas-Buhler, M.: M(g) and M(c):
mutations within the amino-terminal region of glycophorin A. Proc.
Nat. Acad. Sci. 78: 631-635, 1981.

14. Gedde-Dahl, T., Jr.; Olaisen, B.: MN:Ss--GC more likely than
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15. German, J.; Chaganti, R. S. K.: Mapping human autosomes: assignment
of the MN locus to a specific segment in the long arm of chromosome
no. 2. Science 182: 1261-1262, 1973.

16. German, J.; Metaxas, M. N.; Metaxas-Buhler, M.; Louie, E.; Chaganti,
R. S. K.: Further evaluation of a child with the M(k) phenotype and
a translocation affecting the long arms of chromosomes 2 and 4. (Abstract) Cytogenet.
Cell Genet. 25: 160, 1979.

17. German, J.; Walker, M. E.; Steifel, F. H.; Allen, F. H., Jr.:
Autoradiographic studies of human chromosomes. II. Data concerning
the position of the MN locus. Vox Sang. 16: 130-145, 1969.

18. German, J.; Walker, M. E.; Stiefel, F. H.; Allen, F. H., Jr.:
MN blood-group locus: data concerning the possible chromosomal location. Science 162:
1014-1015, 1968.

19. Grant, S. G.; Bigbee, W. L.: Bone marrow somatic mutation after
genotoxic cancer therapy. (Letter) Lancet 343: 1507-1508, 1994.
Note: Erratum: 344: 415 only, 1994.

20. Heiberg, A.; Berg, K.: Linkage data on the MNSs blood group-red
cell acid phosphatase relationship. Hum. Hered. 25: 93-94, 1975.

21. Huang, C.-H.; Chen, Y.; Blumenfeld, O. O.: A novel St(a) glycophorin
produced via gene conversion of pseudoexon III from glycophorin E
to glycophorin A gene. Hum. Mutat. 15: 533-540, 2000.

22. Huang, C.-H.; Guizzo, M. L.; Kikuchi, M.; Blumenfeld, O. O.:
Molecular genetic analysis of a hybrid gene encoding St(a) glycophorin
of the human erythrocyte membrane. Blood 74: 836-843, 1989.

23. Huang, C.-H.; Puglia, K. V.; Bigbee, W. L.; Guizzo, M. L.; Hoffman,
M.; Blumenfeld, O. O.: A family study of multiple mutations of alpha
and delta glycophorins (glycophorins A and B). Hum. Genet. 81: 26-30,
1988.

24. Huang, C.-H.; Reid, M.; Daniels, G.; Blumenfeld, O. O.: Alteration
of splice site selection by an exon mutation in the human glycophorin
A gene. J. Biol. Chem. 268: 25902-25908, 1993.

25. Huang, C.-H.; Spruell, P.; Moulds, J. J.; Blumenfeld, O. O.:
Molecular basis for the human erythrocyte glycophorin specifying the
Miltenberger class I (MiI) phenotype. Blood 80: 257-263, 1992.

26. Ko, W.-Y.; Kaercher, K. A.; Giombini, E.; Marcatili, P.; Froment,
A.; Ibrahim, M.; Lema, G.; Nyambo, T. B.; Omar, S. A.; Wambebe, C.;
Ranciaro, A.; Hirbo, J. B.; Tishkoff, S. A.: Effects of natural selection
and gene conversion on the evolution of human glycophorins coding
for MNS blood polymorphisms in malaria-endemic African populations. Am.
J. Hum. Genet. 88: 741-754, 2011.

27. Kudo, S.; Chagnovich, D.; Rearden, A.; Mattei, M. G.; Fukuda,
M.: Molecular analysis of a hybrid gene encoding human glycophorin
variant Miltenberger V-like molecule. J. Biol. Chem. 265: 13825-13829,
1990.

28. Langlois, R. G.; Bigbee, W. L.; Jensen, R. H.: Measurements of
the frequency of human erythrocytes with gene expression loss phenotypes
at the glycophorin A locus. Hum. Genet. 74: 353-362, 1986.

29. Langlois, R. G.; Bigbee, W. L.; Kyoizumi, S.; Nakamura, N.; Bean,
M. A.; Akiyama, M.; Jensen, R. H.: Evidence for increased somatic
cell mutations at the glycophorin A locus in atomic bomb survivors. Science 236:
445-448, 1987.

30. Mattei, M. G.; London, J.; Rahuel, C.; d'Auriol, L.; Colin, Y.;
Le Van Kim, C.; Mattei, J. F.; Galibert, F.; Cartron, J. P.: Chromosome
localization by in situ hybridization of the gene for human erythrocyte
glycophorin to region 4q28-q31. (Abstract) Cytogenet. Cell Genet. 46:
658, 1987.

31. Mawby, W. J.; Anstee, D. J.; Tanner, M. J. A.: Immunochemical
evidence for hybrid sialoglycoproteins of human erythrocytes. Nature 291:
161-162, 1981.

32. Mayr, W. R.: No close linkage between MNSs and red cell acid
phosphatase. Hum. Hered. 26: 1-3, 1976.

33. Okubo, Y.; Daniels, G. L.; Parsons, S. F.; Anstee, D. J.; Yamaguchi,
H.; Tomita, T.; Seno, T.: A Japanese family with two sisters apparently
homozygous for M(k). Vox Sang. 54: 107-111, 1988.

34. Onda, M.; Fukuda, M.: Detailed physical mapping of the genes
encoding glycophorins A, B, and E, as revealed by P1 plasmids containing
human genomic DNA. Gene 159: 225-230, 1995.

35. 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.

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

37. Prohaska, R.; Koerner, T. A. W., Jr.; Armitage, I. M.; Furthmayr,
H.: Chemical and carbon-13 nuclear magnetic resonance studies of
the blood group M and N active sialoglycopeptides from human glycophorin
A. J. Biol. Chem. 256: 5781-5791, 1986.

38. Rahuel, C.; London, J.; d'Auriol, L.; Mattei, M.-G.; Tournamille,
C.; Skrzynia, C.; Lebouc, Y.; Galibert, F.; Cartron, J.-P.: Characterization
of cDNA clones for human glycophorin A: use for gene localization
and for analysis of normal of glycophorin-A-deficient (Finnish type)
genomic DNA. Europ. J. Biochem. 172: 147-153, 1988.

39. Rahuel, C.; London, J.; Vignal, A.; Cherif-Zahar, B.; Colin, Y.;
Siebert, P.; Fukuda, M.; Cartron, J.-P.: Alteration of the genes
for glycophorin A and B in glycophorin-A-deficient individuals. Europ.
J. Biochem. 177: 605-614, 1988.

40. Rothman, N.; Haas, R.; Hayes, R. B.; Li, G.-L.; Wiemels, J.; Campleman,
S.; Quintana, P. J. E.; Xi, L.-J.; Dosemeci, M.; Titenko-Holland,
N.; Meyer, K. B.; Lu, W.; Zhang, L. P.; Bechtold, W.; Wang, Y.-Z.;
Kolachana, P.; Yin, S.-N.; Blot, W.; Smith, M. T.: Benzene induces
gene-duplicating but not gene-inactivating mutations at the glycophorin
A locus in exposed humans. Proc. Nat. Acad. Sci. 92: 4069-4073,
1995.

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

42. Siebert, P. D.; Fukuda, M.: Isolation and characterization of
human glycophorin A cDNA clones by a synthetic oligonucleotide approach:
nucleotide sequence and mRNA structure. Proc. Nat. Acad. Sci. 83:
1665-1669, 1986.

43. Spence, M. A.; Field, L. L.; Marazita, M. L.; Joseph, J.; Sparkes,
M.; Crist, M.; Crandall, B. F.; Anderson, C. E.; Bateman, J. B.; Rotter,
J. I.; Kidd, K. K.; Hodge, S. E.; Sparkes, R. S.: Estimating the
recombination frequency for the MN and the Ss loci. Hum. Hered. 34:
343-347, 1984.

44. Springer, G. F.; Tegtmeyer, H.: Further evidence that carbohydrates
are the immunodeterminant structures of blood group M and N specificities. Immun.
Commun. 10: 157-171, 1981.

45. Wakui, K.; Nishida, T.; Masuda, J.; Itoh, T.; Katsumata, D.; Ohno,
T.; Fukushima, Y.: De novo interstitial deletion of 4q[46,XX,del(4)(q27q28.2)]
with intact blood group-MN locus, confining its locus to 4q28.2-4q31.1. Jpn.
J. Hum. Genet. 36: 149-153, 1991.

46. Walker, M. E.; Rubinstein, P.; Allen, F. H., Jr.: Biochemical
genetics of MN. Vox Sang. 32: 111-120, 1977.

47. Weitkamp, L. R.: Concerning the linkage relationships of the
Gc and MNSs loci. Hum. Genet. 43: 215-220, 1978.

48. Weitkamp, L. R.; Adams, M. S.; Rowley, P. T.: Linkage between
the MN and Hb beta loci. Hum. Hered. 22: 566-572, 1972.

49. Weitkamp, L. R.; Lovrien, E. W.; Olaisen, B.; Fenger, K.; Gedde-Dahl,
T., Jr.; Sorensen, S. A.; Conneally, P. M.; Bias, W. B.; Ott, J.:
Linkage relations of the loci for the MN blood group and red cell
phosphate. Birth Defects Orig. Art. Ser. XI(3): 276-280, 1975. Note:
Alternate: Cytogenet. Cell Genet. 14: 446-450, 1975.....

*FIELD* CN
Ada Hamosh - updated: 04/08/2013
Marla J. F. O'Neill - updated: 2/9/2005
Victor A. McKusick - updated: 7/19/2000
Alan F. Scott - updated: 8/9/1995

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

*FIELD* ED
alopez: 04/08/2013
terry: 11/13/2012
carol: 7/12/2005
terry: 2/9/2005
carol: 3/17/2004
alopez: 10/7/2003
carol: 10/20/2000
mcapotos: 7/20/2000
mcapotos: 7/19/2000
mcapotos: 7/17/2000
mcapotos: 7/13/2000
terry: 6/30/2000
terry: 4/30/1999
terry: 7/24/1998
terry: 7/9/1998
terry: 11/10/1997
carol: 6/23/1997
terry: 4/17/1996
mark: 3/7/1996
mark: 2/7/1996
terry: 1/31/1996
terry: 5/25/1995
jason: 6/16/1994
davew: 6/9/1994
carol: 3/29/1994
pfoster: 3/25/1994

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.

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*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