RBCC Red Blood Cell Collection

PTPRC (CD45) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Receptor-type tyrosine-protein phosphatase C; 3.1.3.48 (Leukocyte common antigen; L-CA; T200; CD45; Flags: Precursor)

UniProt P08575
ID PTPRC_HUMAN Reviewed; 1304 AA.
AC P08575; A8K7W6; Q16614; Q9H0Y6;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 19-JUL-2003, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Receptor-type tyrosine-protein phosphatase C;
DE EC=3.1.3.48;
DE AltName: Full=Leukocyte common antigen;
DE Short=L-CA;
DE AltName: Full=T200;
DE AltName: CD_antigen=CD45;
DE Flags: Precursor;
GN Name=PTPRC; Synonyms=CD45;
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 ALTERNATIVE SPLICING.
RC TISSUE=Lymphocyte;
RX PubMed=2824653; DOI=10.1084/jem.166.5.1548;
RA Streuli M., Hall L.R., Saga Y., Schlossman S.F., Saito H.;
RT "Differential usage of three exons generates at least five different
RT mRNAs encoding human leukocyte common antigens.";
RL J. Exp. Med. 166:1548-1566(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RX PubMed=2956090;
RA Ralph S.J., Thomas M.L., Morton C.C., Trowbridge I.S.;
RT "Structural variants of human T200 glycoprotein (leukocyte-common
RT antigen).";
RL EMBO J. 6:1251-1257(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 146-192.
RX PubMed=2531281;
RA Tsai A.Y.M., Streuli M., Saito H.;
RT "Integrity of the exon 6 sequence is essential for tissue-specific
RT alternative splicing of human leukocyte common antigen pre-mRNA.";
RL Mol. Cell. Biol. 9:4550-4555(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 191-1304.
RC TISSUE=Placenta;
RX PubMed=2971730;
RA Hall L.R., Streuli M., Schlossman S.F., Saito H.;
RT "Complete exon-intron organization of the human leukocyte common
RT antigen (CD45) gene.";
RL J. Immunol. 141:2781-2787(1988).
RN [6]
RP FUNCTION.
RX PubMed=2845400; DOI=10.1073/pnas.85.19.7182;
RA Charbonneau H., Tonks N.K., Walsh K.A., Fischer E.H.;
RT "The leukocyte common antigen (CD45): a putative receptor-linked
RT protein tyrosine phosphatase.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:7182-7186(1988).
RN [7]
RP MUTAGENESIS.
RX PubMed=1695146;
RA Streuli M., Krueger N.X., Thai T., Tang M., Saito H.;
RT "Distinct functional roles of the two intracellular phosphatase like
RT domains of the receptor-linked protein tyrosine phosphatases LCA and
RT LAR.";
RL EMBO J. 9:2399-2407(1990).
RN [8]
RP INTERACTION WITH SKAP1, MUTAGENESIS OF CYS-851, AND FUNCTION.
RX PubMed=11909961; DOI=10.1128/MCB.22.8.2673-2686.2002;
RA Wu L., Fu J., Shen S.-H.;
RT "SKAP55 coupled with CD45 positively regulates T-cell receptor-
RT mediated gene transcription.";
RL Mol. Cell. Biol. 22:2673-2686(2002).
RN [9]
RP INTERACTION WITH DPP4, AND SUBCELLULAR LOCATION.
RX PubMed=12676959; DOI=10.1074/jbc.M212978200;
RA Salgado F.J., Lojo J., Alonso-Lebrero J.L., Lluis C., Franco R.,
RA Cordero O.J., Nogueira M.;
RT "A role for interleukin-12 in the regulation of T cell plasma membrane
RT compartmentation.";
RL J. Biol. Chem. 278:24849-24857(2003).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-973, AND MASS
RP SPECTROMETRY.
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-232 AND ASN-335, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-232; ASN-240; ASN-276;
RP ASN-284; ASN-335; ASN-419; ASN-488 AND ASN-497, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-
RT linked cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-973 AND SER-1297, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 622-1231 ALONE AND IN COMPLEX
RP WITH PHOSPHOPEPTIDE.
RX PubMed=15684325; DOI=10.1084/jem.20041890;
RA Nam H.J., Poy F., Saito H., Frederick C.A.;
RT "Structural basis for the function and regulation of the receptor
RT protein tyrosine phosphatase CD45.";
RL J. Exp. Med. 201:441-452(2005).
RN [16]
RP INVOLVEMENT IN SUSCEPTIBILITY TO MS.
RX PubMed=11101853; DOI=10.1038/82659;
RA Jacobsen M., Schweer D., Ziegler A., Gaber R., Schock S.,
RA Schwinzer R., Wonigeit K., Lindert R.-B., Kantarci O.,
RA Schaefer-Klein J., Schipper H.I., Oertel W.H., Heidenreich F.,
RA Weinshenker B.G., Sommer N., Hemmer B.;
RT "A point mutation in PTPRC is associated with the development of
RT multiple sclerosis.";
RL Nat. Genet. 26:495-499(2000).
RN [17]
RP VARIANT T(-)B(+)NK(+) SCID 362-GLU-TYR-363 DEL, AND CHARACTERIZATION
RP OF VARIANT T(-)B(+)NK(+) SCID 362-GLU-TYR-363 DEL.
RX PubMed=11145714;
RA Tchilian E.Z., Wallace D.L., Wells R.S., Flower D.R., Morgan G.,
RA Beverley P.C.L.;
RT "A deletion in the gene encoding the CD45 antigen in a patient with
RT SCID.";
RL J. Immunol. 166:1308-1313(2001).
RN [18]
RP VARIANTS [LARGE SCALE ANALYSIS] ALA-228 AND ARG-863.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Protein tyrosine-protein phosphatase required for T-cell
CC activation through the antigen receptor. Acts as a positive
CC regulator of T-cell coactivation upon binding to DPP4. The first
CC PTPase domain has enzymatic activity, while the second one seems
CC to affect the substrate specificity of the first one. Upon T-cell
CC activation, recruits and dephosphorylates SKAP1 and FYN.
CC Dephosphorylates LYN, and thereby modulates LYN activity (By
CC similarity).
CC -!- CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein
CC tyrosine + phosphate.
CC -!- SUBUNIT: Binds GANAB and PRKCSH (By similarity). Interacts with
CC SKAP1. Interacts with DPP4; the interaction is enhanced in a
CC interleukin-12-dependent manner in activated lymphocytes.
CC -!- INTERACTION:
CC P41240:CSK; NbExp=3; IntAct=EBI-1341, EBI-1380630;
CC P35222:CTNNB1; NbExp=2; IntAct=EBI-1341, EBI-491549;
CC P04626:ERBB2; NbExp=2; IntAct=EBI-1341, EBI-641062;
CC P20701:ITGAL; NbExp=2; IntAct=EBI-1341, EBI-961214;
CC P06239:LCK; NbExp=7; IntAct=EBI-1341, EBI-1348;
CC P06240:Lck (xeno); NbExp=2; IntAct=EBI-1341, EBI-1401;
CC P09382:LGALS1; NbExp=2; IntAct=EBI-1341, EBI-1048875;
CC Q02763:TEK; NbExp=3; IntAct=EBI-1341, EBI-2257090;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein. Membrane raft. Note=Colocalized with DPP4 in membrane
CC rafts.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=At least 8 isoforms are produced;
CC Name=1;
CC IsoId=P08575-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P08575-2; Sequence=VSP_007780;
CC -!- DOMAIN: The first PTPase domain interacts with SKAP1.
CC -!- PTM: Heavily N- and O-glycosylated.
CC -!- DISEASE: Severe combined immunodeficiency autosomal recessive T-
CC cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+)
CC SCID) [MIM:608971]: A form of severe combined immunodeficiency
CC (SCID), a genetically and clinically heterogeneous group of rare
CC congenital disorders characterized by impairment of both humoral
CC and cell-mediated immunity, leukopenia, and low or absent antibody
CC levels. Patients present in infancy recurrent, persistent
CC infections by opportunistic organisms. The common characteristic
CC of all types of SCID is absence of T-cell-mediated cellular
CC immunity due to a defect in T-cell development. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Multiple sclerosis (MS) [MIM:126200]: A multifactorial,
CC inflammatory, demyelinating disease of the central nervous system.
CC Sclerotic lesions are characterized by perivascular infiltration
CC of monocytes and lymphocytes and appear as indurated areas in
CC pathologic specimens (sclerosis in plaques). The pathological
CC mechanism is regarded as an autoimmune attack of the myelin
CC sheath, mediated by both cellular and humoral immunity. Clinical
CC manifestations include visual loss, extra-ocular movement
CC disorders, paresthesias, loss of sensation, weakness, dysarthria,
CC spasticity, ataxia and bladder dysfunction. Genetic and
CC environmental factors influence susceptibility to the disease.
CC Note=Disease susceptibility may be associated with variations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Receptor class 1/6 subfamily.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 2 tyrosine-protein phosphatase domains.
CC -!- WEB RESOURCE: Name=PTPRCbase; Note=PTPRC mutation db;
CC URL="http://bioinf.uta.fi/PTPRCbase/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CD45 entry;
CC URL="http://en.wikipedia.org/wiki/CD45";
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DR EMBL; Y00638; CAA68669.1; -; mRNA.
DR EMBL; Y00062; CAA68269.1; -; mRNA.
DR EMBL; AK292131; BAF84820.1; -; mRNA.
DR EMBL; M23492; AAD15273.2; -; Genomic_DNA.
DR EMBL; M23496; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23466; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23467; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23468; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23469; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23470; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23471; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23472; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23473; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23474; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23475; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23476; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23477; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23478; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23479; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23480; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23481; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23482; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23483; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23484; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23485; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23486; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23487; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23488; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23489; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23490; AAD15273.2; JOINED; Genomic_DNA.
DR EMBL; M23491; AAD15273.2; JOINED; Genomic_DNA.
DR PIR; A46546; A46546.
DR RefSeq; NP_002829.3; NM_002838.4.
DR RefSeq; NP_563578.2; NM_080921.3.
DR UniGene; Hs.654514; -.
DR PDB; 1YGR; X-ray; 2.90 A; A/B=622-1231.
DR PDB; 1YGU; X-ray; 2.90 A; A/B=622-1231.
DR PDBsum; 1YGR; -.
DR PDBsum; 1YGU; -.
DR ProteinModelPortal; P08575; -.
DR SMR; P08575; 623-1228.
DR DIP; DIP-224N; -.
DR IntAct; P08575; 39.
DR MINT; MINT-1130341; -.
DR STRING; 9606.ENSP00000356346; -.
DR BindingDB; P08575; -.
DR ChEMBL; CHEMBL3243; -.
DR GuidetoPHARMACOLOGY; 1852; -.
DR PhosphoSite; P08575; -.
DR UniCarbKB; P08575; -.
DR DMDM; 33112650; -.
DR PaxDb; P08575; -.
DR PRIDE; P08575; -.
DR Ensembl; ENST00000367376; ENSP00000356346; ENSG00000081237.
DR Ensembl; ENST00000573477; ENSP00000461074; ENSG00000262418.
DR Ensembl; ENST00000573679; ENSP00000458322; ENSG00000262418.
DR Ensembl; ENST00000594404; ENSP00000471843; ENSG00000081237.
DR GeneID; 5788; -.
DR KEGG; hsa:5788; -.
DR CTD; 5788; -.
DR GeneCards; GC01P198607; -.
DR HGNC; HGNC:9666; PTPRC.
DR HPA; CAB000052; -.
DR HPA; CAB002800; -.
DR HPA; CAB056154; -.
DR HPA; HPA000440; -.
DR MIM; 126200; phenotype.
DR MIM; 151460; gene.
DR MIM; 608971; phenotype.
DR neXtProt; NX_P08575; -.
DR Orphanet; 169157; T-B+ severe combined immunodeficiency due to CD45 deficiency.
DR PharmGKB; PA34011; -.
DR eggNOG; COG5599; -.
DR HOGENOM; HOG000049064; -.
DR HOVERGEN; HBG000066; -.
DR InParanoid; P08575; -.
DR KO; K06478; -.
DR OMA; EPEHSAN; -.
DR PhylomeDB; P08575; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P08575; -.
DR ChiTaRS; PTPRC; human.
DR EvolutionaryTrace; P08575; -.
DR GeneWiki; PTPRC; -.
DR GenomeRNAi; 5788; -.
DR NextBio; 22518; -.
DR PRO; PR:P08575; -.
DR ArrayExpress; P08575; -.
DR Bgee; P08575; -.
DR CleanEx; HS_PTPRC; -.
DR Genevestigator; P08575; -.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR GO; GO:0005925; C:focal adhesion; ISS:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; ISS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0005001; F:transmembrane receptor protein tyrosine phosphatase activity; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0042100; P:B cell proliferation; ISS:UniProtKB.
DR GO; GO:0050853; P:B cell receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0048539; P:bone marrow development; IMP:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; ISS:UniProtKB.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IMP:UniProtKB.
DR GO; GO:0002378; P:immunoglobulin biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006933; P:negative regulation of cell adhesion involved in substrate-bound cell migration; IMP:UniProtKB.
DR GO; GO:0001960; P:negative regulation of cytokine-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IDA:UniProtKB.
DR GO; GO:0001915; P:negative regulation of T cell mediated cytotoxicity; ISS:UniProtKB.
DR GO; GO:0050857; P:positive regulation of antigen receptor-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0030890; P:positive regulation of B cell proliferation; IMP:UniProtKB.
DR GO; GO:2000473; P:positive regulation of hematopoietic stem cell migration; IMP:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; NAS:UniProtKB.
DR GO; GO:2000648; P:positive regulation of stem cell proliferation; IMP:UniProtKB.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB.
DR GO; GO:0051209; P:release of sequestered calcium ion into cytosol; ISS:UniProtKB.
DR GO; GO:0048864; P:stem cell development; IMP:UniProtKB.
DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IDA:UniProtKB.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR016335; Leukocyte_common_ag.
DR InterPro; IPR024739; PTP_recept_N.
DR InterPro; IPR000387; Tyr/Dual-sp_Pase.
DR InterPro; IPR016130; Tyr_Pase_AS.
DR InterPro; IPR000242; Tyr_Pase_rcpt/non-rcpt.
DR Pfam; PF12567; CD45; 1.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF12453; PTP_N; 2.
DR Pfam; PF00102; Y_phosphatase; 2.
DR PIRSF; PIRSF002004; Leukocyte_common_antigen; 1.
DR PRINTS; PR00700; PRTYPHPHTASE.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00194; PTPc; 2.
DR SUPFAM; SSF49265; SSF49265; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 2.
DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Disease mutation; Glycoprotein; Hydrolase; Membrane; Phosphoprotein;
KW Polymorphism; Protein phosphatase; Reference proteome; Repeat; SCID;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 23
FT CHAIN 24 1304 Receptor-type tyrosine-protein
FT phosphatase C.
FT /FTId=PRO_0000025470.
FT TOPO_DOM 24 575 Extracellular (Potential).
FT TRANSMEM 576 597 Helical; (Potential).
FT TOPO_DOM 598 1304 Cytoplasmic (Potential).
FT DOMAIN 389 481 Fibronectin type-III 1.
FT DOMAIN 482 574 Fibronectin type-III 2.
FT DOMAIN 651 910 Tyrosine-protein phosphatase 1.
FT DOMAIN 942 1226 Tyrosine-protein phosphatase 2.
FT REGION 851 857 Substrate binding (By similarity).
FT ACT_SITE 851 851 Phosphocysteine intermediate.
FT ACT_SITE 1167 1167 Phosphocysteine intermediate (By
FT similarity).
FT BINDING 819 819 Substrate (By similarity).
FT BINDING 895 895 Substrate (By similarity).
FT MOD_RES 973 973 Phosphoserine.
FT MOD_RES 1297 1297 Phosphoserine.
FT CARBOHYD 78 78 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 90 90 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 95 95 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 184 184 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 190 190 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 197 197 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 232 232 N-linked (GlcNAc...).
FT CARBOHYD 240 240 N-linked (GlcNAc...); atypical.
FT CARBOHYD 260 260 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 270 270 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 276 276 N-linked (GlcNAc...).
FT CARBOHYD 284 284 N-linked (GlcNAc...); atypical.
FT CARBOHYD 335 335 N-linked (GlcNAc...).
FT CARBOHYD 378 378 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 419 419 N-linked (GlcNAc...).
FT CARBOHYD 468 468 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 488 488 N-linked (GlcNAc...).
FT CARBOHYD 497 497 N-linked (GlcNAc...); atypical.
FT CARBOHYD 529 529 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 32 192 Missing (in isoform 2).
FT /FTId=VSP_007780.
FT VARIANT 191 191 T -> A (in dbSNP:rs4915154).
FT /FTId=VAR_036860.
FT VARIANT 228 228 E -> A (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035653.
FT VARIANT 294 294 I -> L (in dbSNP:rs2230606).
FT /FTId=VAR_051763.
FT VARIANT 362 363 Missing (in T(-)B(+)NK(+) SCID;
FT associated with lack of surface
FT expression).
FT /FTId=VAR_021205.
FT VARIANT 421 421 T -> I (in dbSNP:rs6696162).
FT /FTId=VAR_051764.
FT VARIANT 568 568 H -> Q (in dbSNP:rs12136658).
FT /FTId=VAR_051765.
FT VARIANT 863 863 G -> R (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035654.
FT VARIANT 1283 1283 S -> R (in dbSNP:rs2298872).
FT /FTId=VAR_020303.
FT MUTAGEN 851 851 C->S: Loss of activity. Abolishes
FT interaction with SKAP1.
FT CONFLICT 650 650 L -> P (in Ref. 1; CAA68669).
FT CONFLICT 1207 1207 P -> L (in Ref. 1; CAA68669).
FT TURN 633 635
FT HELIX 636 656
FT STRAND 663 665
FT TURN 668 670
FT HELIX 673 678
FT TURN 688 690
FT STRAND 691 693
FT STRAND 698 700
FT TURN 701 704
FT STRAND 705 711
FT STRAND 714 716
FT STRAND 720 723
FT TURN 728 730
FT HELIX 731 740
FT STRAND 745 748
FT STRAND 752 754
FT STRAND 757 759
FT TURN 767 769
FT STRAND 771 774
FT STRAND 777 786
FT STRAND 788 802
FT STRAND 807 814
FT HELIX 826 836
FT STRAND 847 850
FT STRAND 852 855
FT HELIX 856 869
FT HELIX 871 874
FT STRAND 875 877
FT HELIX 879 887
FT HELIX 897 913
FT HELIX 920 922
FT HELIX 923 930
FT HELIX 941 948
FT HELIX 960 962
FT HELIX 966 968
FT TURN 979 981
FT STRAND 1018 1022
FT STRAND 1029 1034
FT TURN 1038 1040
FT HELIX 1041 1050
FT STRAND 1055 1058
FT STRAND 1062 1064
FT STRAND 1067 1070
FT STRAND 1088 1093
FT STRAND 1095 1105
FT STRAND 1113 1120
FT STRAND 1125 1127
FT HELIX 1132 1143
FT STRAND 1163 1171
FT HELIX 1174 1189
FT STRAND 1190 1192
FT HELIX 1195 1205
FT TURN 1207 1210
FT HELIX 1213 1225
SQ SEQUENCE 1304 AA; 147254 MW; A08FC22D6069BAF7 CRC64;
MYLWLKLLAF GFAFLDTEVF VTGQSPTPSP TGLTTAKMPS VPLSSDPLPT HTTAFSPAST
FERENDFSET TTSLSPDNTS TQVSPDSLDN ASAFNTTGVS SVQTPHLPTH ADSQTPSAGT
DTQTFSGSAA NAKLNPTPGS NAISDVPGER STASTFPTDP VSPLTTTLSL AHHSSAALPA
RTSNTTITAN TSDAYLNASE TTTLSPSGSA VISTTTIATT PSKPTCDEKY ANITVDYLYN
KETKLFTAKL NVNENVECGN NTCTNNEVHN LTECKNASVS ISHNSCTAPD KTLILDVPPG
VEKFQLHDCT QVEKADTTIC LKWKNIETFT CDTQNITYRF QCGNMIFDNK EIKLENLEPE
HEYKCDSEIL YNNHKFTNAS KIIKTDFGSP GEPQIIFCRS EAAHQGVITW NPPQRSFHNF
TLCYIKETEK DCLNLDKNLI KYDLQNLKPY TKYVLSLHAY IIAKVQRNGS AAMCHFTTKS
APPSQVWNMT VSMTSDNSMH VKCRPPRDRN GPHERYHLEV EAGNTLVRNE SHKNCDFRVK
DLQYSTDYTF KAYFHNGDYP GEPFILHHST SYNSKALIAF LAFLIIVTSI ALLVVLYKIY
DLHKKRSCNL DEQQELVERD DEKQLMNVEP IHADILLETY KRKIADEGRL FLAEFQSIPR
VFSKFPIKEA RKPFNQNKNR YVDILPYDYN RVELSEINGD AGSNYINASY IDGFKEPRKY
IAAQGPRDET VDDFWRMIWE QKATVIVMVT RCEEGNRNKC AEYWPSMEEG TRAFGDVVVK
INQHKRCPDY IIQKLNIVNK KEKATGREVT HIQFTSWPDH GVPEDPHLLL KLRRRVNAFS
NFFSGPIVVH CSAGVGRTGT YIGIDAMLEG LEAENKVDVY GYVVKLRRQR CLMVQVEAQY
ILIHQALVEY NQFGETEVNL SELHPYLHNM KKRDPPSEPS PLEAEFQRLP SYRSWRTQHI
GNQEENKSKN RNSNVIPYDY NRVPLKHELE MSKESEHDSD ESSDDDSDSE EPSKYINASF
IMSYWKPEVM IAAQGPLKET IGDFWQMIFQ RKVKVIVMLT ELKHGDQEIC AQYWGEGKQT
YGDIEVDLKD TDKSSTYTLR VFELRHSKRK DSRTVYQYQY TNWSVEQLPA EPKELISMIQ
VVKQKLPQKN SSEGNKHHKS TPLLIHCRDG SQQTGIFCAL LNLLESAETE EVVDIFQVVK
ALRKARPGMV STFEQYQFLY DVIASTYPAQ NGQVKKNNHQ EDKIEFDNEV DKVKQDANCV
NPLGAPEKLP EAKEQAEGSE PTSGTEGPEH SVNGPASPAL NQGS
//

MIM 126200
*RECORD*
*FIELD* NO
126200
*FIELD* TI
#126200 MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO; MS
;;DISSEMINATED SCLEROSIS
MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 1, INCLUDED; MS1, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
susceptibility to multiple sclerosis-1 (MS1) is associated with
variation in certain HLA genes on chromosome 6p21, including HLA-A
(142800), HLA-DRB1 (142857), HLA-DQB1 (604305), HLA-DRA (142860), on
chromosome 6p21.3.

An HLA-DRB1*1501-DQB1*0602 haplotype (HLA-DR15) has been repeatedly
demonstrated in high-risk populations of Northern European descent.

Additional MS susceptibility loci include MS2 (612594) on chromosome
10p15, MS3 (612595) on chromosome 5p13, MS4 (612596) on chromosome 1p36,
and MS5 (614810), influenced by variation in the TNFRSF1A gene (191190)
on chromosome 12p13.2.

Svejgaard (2008) provided a detailed review of the immunogenetics of
multiple sclerosis, with special emphasis on the association with HLA
molecules.

INHERITANCE

Familial aggregation in this disease is not strong; however, in a series
of 91 cases, Bas (1964) found 3 instances of affected mother and
daughter. From an extensive review, McAlpine (1965) concluded that the
risk to a first-degree relative of a patient with multiple sclerosis is
at least 15 times that for a member of the general population but that
no definite genetic pattern is discernible. MacKay and Myrianthopoulos
(1966) found that concordance is slightly higher in monozygotic than in
dizygotic twins and that multiple sclerosis is about 20 times more
frequent among relatives of probands than in the general population. The
frequency declined as the relationship to the proband became more
remote. They concluded that the family data were consistent with
autosomal recessive inheritance with reduced penetrance but that
exogenous factors must be very strong. Ebers et al. (1986) surveyed 10
multiple sclerosis clinics across Canada and found 27 monozygotic and 43
dizygotic twin pairs with multiple sclerosis in at least 1 of each pair.
Seven (25.9%) of the monozygotic pairs and 1 (2.3%) of the dizygotic
pairs were concordant for multiple sclerosis. The concordance rate for
nontwin sibs was 1.9%. Kinnunin et al. (1986) also reported a nationwide
series of twins. The higher concordance rate in monozygotic twins
despite the low recurrence risk in families is consistent with a
polygenic model (Ebers, 1988). The situation may be the same as that for
Hodgkin disease; see 236000.

Ebers et al. (1995) concluded that familial aggregation in MS is
genetically determined. They could detect no effect of shared
environment in a study of adopted index cases and MS cases with adopted
relatives. Waksman (1995), in a commentary, reviewed evidence suggesting
that environmental factors are not completely excluded.

Sadovnick et al. (1996) studied familial aggregation of multiple
sclerosis in a sample of 16,000 multiple sclerosis cases in Canada. The
age-adjusted multiple sclerosis rate in half sibs of index cases was
1.32%, compared with 3.46% in full sibs. There were similar risks in
half sibs raised together and those raised apart. The risk for maternal
and paternal half sibs was similar. They quoted previous studies which
indicated a 300-fold increase of risk for monozygotic twins of index
cases (Ebers et al., 1986) and 20- to 40-fold increase for biologic
first-degree relatives (Mumford et al., 1994). Together, these studies
suggested that familial aggregation in multiple sclerosis is genetic.
However, since most monozygotic twins remain discordant, nongenetic risk
factors are clearly important.

From a review of genomic screens, Dyment et al. (1997) concluded that a
number of genes with interacting effects are likely and that no single
region has a major influence on familial risk. An HLA haplotype
associated with the disease has been identified, but HLA contributes
only modestly to overall susceptibility.

The Multiple Sclerosis Genetics Group (1998) reported demographic and
clinical characteristics of 89 multiplex families. The mean difference
in age of onset between probands and affected sibs was 8.87 years. There
was a higher concordance rate among sister pairs than among brother
pairs, but there was no difference in affection rate between sons and
daughters of either affected mothers or affected fathers.

Chataway et al. (1998) reported a follow-up on the studies in progress
in the U.K. for a systematic genome screen to determine the genetic
basis of MS. They stated that a gene of major effect had been excluded
from 95% of the genome and one with a moderate role from 65%. The
results to date suggested that multiple sclerosis depends on independent
or epistatic effects of several genes, each with small individual
effects, rather than a very few genes of major biologic importance.

Sadovnick et al. (1999) provided familial risk data in a practical
format for use during genetic counseling for MS.

Noseworthy et al. (2000) included genetic factors in an extensive review
of multiple sclerosis.

Marrosu et al. (2002) examined the recurrence risk in sibs of 901
Sardinian MS patients and factors influencing risk, such as patient and
sib sex, patient age at onset, sib birth cohort, and presence of
affected relatives other than sibs. To evaluate the presence of distant
familial relationships among patients, extended pedigrees were traced
for all patients who were born in 1 Sardinian village. The authors found
that 23 brothers and 36 sisters of the 2,971 sibs were affected with MS.
Recurrence risk was greater in sibs of index patients with onset age
less than 30 years (increased risk 2.33 times) and with a relative with
MS other than a sib or parent (increased risk 2.90 times). Pedigree
analysis of patients from the 1 village showed that all 11 patients
descended from 3 pairs of ancestors, whereas no cases occurred in the
remaining 2,346 inhabitants. In descendants from the 3 couples, MS
prevalence was dramatically greater than the regional average and 1.5
times greater than that observed in sibs of affected cases.

In a longitudinal population-based study of twins with MS in Canada,
Willer et al. (2003) analyzed 370 index cases from 354 pairs and
obtained a probandwise concordance rate of 25.3% in monozygotic twin
pairs, 5.4% in dizygotic pairs, and 2.9% for their nontwin sibs. The
excess concordance in monozygotes was derived primarily from female
pairs with a probandwise concordance rate of 34% for female monozygotic
pairs compared to 3.8% for female dizygotic pairs. Willer et al. (2003)
did not demonstrate a monozygotic/dizygotic difference in males, but
they noted that the sample size was small.

Ristori et al. (2006) analyzed data from 216 Italian twin pairs in which
at least 1 twin had MS, including 198 pairs from continental Italy and
18 pairs from Sardinia. These regions have estimated disease prevalences
of 61.1 and 147.1 per 100,000 individuals, respectively. They found a
twinning rate of 0.62% among MS patients, which was significantly less
than the twinning rate of the general population. In continental Italy,
concordance for MS was 14.5% and 4.0% for mono- and dizygotic twins,
respectively. In Sardinia, concordance for MS was 22.2% for monozygotic
twins and zero for dizygotic twins. Results from a questionnaire on
nonheritable risk factors given to a subset of patients suggested a link
to infection. Ristori et al. (2006) concluded that nonheritable
variables play a role in the development of MS in Mediterranean regions,
and they suggested a role for protective factors in particular.

In a study of 79 MS-discordant monozygotic twin pairs, Islam et al.
(2007) found that childhood sun exposure offered protection against
disease development. Depending on sun exposure, the odds ratio ranged
from 0.25 to 0.57. The authors concluded that early sun exposure is
protective against MS, independent of genetic susceptibility. The effect
was significant only for female twins; however, there were only 13 male
twin pairs. Islam et al. (2007) hypothesized that exposure to
ultraviolet radiation may induce immunosuppression via several
mechanisms.

In a cohort of 807 avuncular MS families with 938 affected
aunt/uncle-niece/nephew pairs ascertained from a longitudinal,
population-based Canadian database, Herrera et al. (2008) observed an
increased number of avuncular pairs connected through unaffected mothers
compared to unaffected fathers (p = 0.008). To restrict confounders
introduced by families with multiple pairs, the overall number of
maternal and paternal families were compared, and the comparison
revealed a significantly higher number of maternal families (p = 0.038).
The findings indicated a maternal parent-of-origin effect in
susceptibility to MS.

Baranzini et al. (2010) reported the genome sequences of one
MS-discordant monozygotic twin pair, and mRNA transcriptome and
epigenome sequences of CD4+ lymphocytes from 3 MS-discordant,
monozygotic twin pairs. No reproducible differences were detected
between cotwins among approximately 3.6 million SNPs or approximately
0.2 million insertion-deletion polymorphisms. Nor were any reproducible
differences observed between sibs of the 3 twin pairs in HLA haplotypes,
confirmed MS susceptibility SNPs, copy number variations, mRNA and
genomic SNP and insertion-deletion genotypes, or the expression of
approximately 19,000 genes in CD4+ T cells. Only 2 to 176 differences in
the methylation of approximately 2 million CpG dinucleotides were
detected between sibs of the 3 twin pairs, in contrast to approximately
800 methylation differences between T cells of unrelated individuals and
several thousand differences between tissues or between normal and
cancerous tissues. In the first systematic effort to estimate sequence
variation among monozygotic cotwins, Baranzini et al. (2010) did not
find evidence for genetic, epigenetic, or transcriptome differences that
explained disease discordance. Baranzini et al. (2010) noted that these
were the first female, twin, and autoimmune disease individual genome
sequences reported.

CLINICAL MANAGEMENT

In patients with multiple sclerosis, treatment with interferon-beta
reduces clinical exacerbations and disease burden via multiple
immunomodulatory actions, including augmentation of apoptosis. In 10 of
18 patients with MS who responded to interferon-beta therapy, Sharief
and Semra (2002) found a significant decline in cellular survivin
expression after 6 and 12 months. Specifically, T-cell susceptibility to
etoposide-induced apoptosis was increased in these patients, findings
that were confirmed by in vitro experiments. These results suggested at
least 1 mechanism by which interferon-beta treatment is effective in
some patients with MS.

Miller et al. (2003) and Ghosh et al. (2003) reported clinical trials of
natalizumab, a recombinant anticlonal antibody against alpha-4-integrins
(192975), for the treatment of multiple sclerosis and Crohn disease (see
266600), respectively. Miller et al. (2003) reported that a group of
patients with multiple sclerosis who received monthly injections of
natalizumab had significantly fewer new inflammatory central nervous
system lesions than the placebo group (a reduction of approximately 90%)
and had approximately half as many clinical relapses. Ghosh et al.
(2003) reported that patients with Crohn disease also had a favorable
response to natalizumab, with remission rates that were approximately
twice as high in patients who received 2 injections of the antibody as
in patients from the placebo group. The rate of adverse events did not
differ significantly between the natalizumab and placebo groups in
either trial. Von Andrian and Engelhardt (2003) stated that natalizumab
probably has therapeutic effects because it blocks the ability of
alpha-4/beta-1 and alpha-4/beta-7 to bind to their respective
endothelial counter-receptors, VCAM1 (192225) and MADCAM1 (102670). In
both disorders, lesions result from autoimmune responses involving
activated lymphocytes and monocytes. Alpha-4-integrin is expressed on
the surface of these cells and plays an integral part in their adhesion
to the vascular endothelium and migration into the parenchyma.

Williams and Johnson (2004) reported that 3 (8.6%) of 35 consecutive
patients with neuroretinitis had previously been diagnosed with MS,
suggesting that neuroretinitis is a late finding in MS rather than an
initial presenting event. All 3 patients had been treated with
interferon-beta before or concurrently with the development of
neuroretinitis, which raised the question of whether interferon-beta
might have been a causative agent of neuroretinitis in the patients.

Hoffmann et al. (2008) used high-resolution HLA class I and II typing to
identify 2 HLA class II alleles associated with the development of
antibodies to interferon-B in the treatment of multiple sclerosis. In 2
independent continuous and binary-trait association studies,
HLA-DRB1*0401 and HLA-DRB1*0408 (odds ratio: 5.15), but not other HLA
alleles, were strongly associated with the development of binding and
neutralizing antibodies to interferon-B. The associated HLA-DRB1*04
alleles differ from nonassociated HLA-DRB1*04 alleles by a
glycine-to-valine substitution in position 86 of the epitope-binding
alpha-helix of the HLA class II molecule. The peptide-binding motif of
HLA-DRB1*0401 and *0408 might promote binding and presentation of an
immunogenic peptide, which may eventually break T cell tolerance and
facilitate antibody development to interferon-beta. In summary, Hoffmann
et al. (2008) identified genetic factors determining the immunogenicity
of interferon-beta, a protein-based disease-modifying agent for the
treatment of MS.

Kumpfel et al. (2008) identified 20 patients with MS who carried a
heterozygous variant (R92Q) in the TNFRSF1A gene (191190) and had
clinical features consistent with late-onset of the tumor necrosis
factor receptor 1-associated periodic syndrome (TRAPS; 142680),
including myalgias, arthralgias, headache, fatigue, and skin rashes.
Most of these patients experienced severe side effects during
immunomodulatory therapy for MS. Kumpfel et al. (2008) concluded that
patients with coexistence of MS and features of TRAPS should be
carefully observed during treatment.

Comabella et al. (2009) performed a genomewide association study in 53
MS patients who responded to beta-interferon treatment and 53
nonresponders in an attempt to identify a genetic basis influencing the
variable response observed in patients. The discovery study and a
replication study in 49 additional responders and 45 additional
nonresponders pointed to 18 SNPs in various genes that showed a possible
association (uncorrected p values of less than 0.05). The findings
indicated that response to beta-interferon is a complex and polygenic
trait.

Hla and Brinkmann (2011) and Soliven et al. (2011) provided reviews of
the neurobiology of sphingosine 1-phosphate (S1P) signaling in the CNS
via the S1P receptors (S1PRs), of which there are 5 subtypes (see, e.g.,
S1PR1; 601974), and discussed the benefit of the S1PR modulator,
fingolimod (FTY720), in the treatment of MS. FTY720 was approved in 2010
as the first oral treatment for relapsing MS in the U.S. One effect of
FTY720 is to downmodulate S1PR1 to retain circulating naive and central
memory T and B lymphocytes in lymph nodes, while sparing effector memory
T cells. The result is to reduce the infiltration of autoreactive
lymphocytes into the CNS, causing a slowing of the disease process (Hla
and Brinkmann, 2011). In addition, S1PR1 is expressed in
oligodendrocytes, astrocytes, neurons, and microglia, where it may
modulate cell survival, process dynamics, migration, differentiation,
activation, and crosstalk. The presence of S1PRs on multiple cell lines
in the CNS may represent a mechanism by which FTY720 may contribute to
observed neurologic benefit in patients with MS via neuroprotective and
regenerative effects (Soliven et al., 2011).

POPULATION GENETICS

Pugliatti et al. (2002) demonstrated a hotspot of MS in the southwestern
part of Sassari province in Sardinia, bordering with the commune of
Macomer, where MS was once hypothesized as having occurred as an
epidemic. These areas of MS clustering comprised the Common Logudorese
linguistic domain. The Catalan area, which is linguistically and
genetically distant from the remaining Sardinian domains, did not show
such high estimates.

MAPPING

Bell and Lathrop (1996) reviewed the work on linkage analysis in
multiple sclerosis.

- MS1 Locus Associated with HLA on Chromosome 6p21.3

Terasaki et al. (1976) described a high frequency of a B-lymphocyte
antigen (group 4) in multiple sclerosis. Associations with HLA-A3,
HLA-B7, and HLA-Dw2 have been demonstrated also. The association with
Dw2 seems to be especially strong and probably indicates an
immune-response mechanism.

Zipp et al. (1995) compared the production of lymphotoxin (tumor
necrosis factor-beta (TNFB; 153440) and tumor necrosis factor-alpha
(TNFA; 191160)) by T-cell lines isolated from multiple sclerosis
patients in normal controls. There was greater production in those lines
derived from HLA-DR2-positive donors than from those that were
HLA-DR2-negative. Although both lymphotoxin and tumor necrosis
factor-alpha are encoded within the HLA region, there was no significant
association of cytokine production with individual lymphotoxin or TNF
alleles. The authors suggested that the association of multiple
sclerosis with HLA-DR2 results from a propensity of T cells to produce
increased amounts of lymphotoxic TNF, controlled by a polymorphic gene
in this region.

In a linkage analysis of 72 pedigrees, Tiwari et al. (1980) found
evidence of linkage between HLA and a hypothesized multiple sclerosis
susceptibility gene (MSSG) for both dominant and recessive models of
inheritance and for a wide range of penetrance values. They suggested
that the MSSG is located 15-20 recombination units from HLA, probably on
the B-D side. The analysis showed no evidence of linkage heterogeneity,
and the lod scores appeared not to be inflated artificially by the
association of multiple sclerosis with HLA-B7. In linkage studies with
HLA, Haile et al. (1980) assumed a dominant model of inheritance. With a
penetrance value of 0.05, a maximal lod score of 2.411 was obtained for
recombination fraction of 0.10. With high penetrance values, lod scores
did not support linkage. Francis et al. (1987) did a study of familial
MS: 10 affected sib pairs and 4 instances of affected parent and
offspring, together with 1 family with 3 affected sibs and another with
2 affected sibs and an affected parent. They concluded that an MS
susceptibility gene exists in the HLA complex in linkage disequilibrium
with HLA-D.

In a 2-stage genome screen, Sawcer et al. (1996) found 2 principal
regions of linkage with multiple sclerosis: 17q22 and the HLA region on
6p21. The results were considered compatible with genetic models
involving epistatic interaction between these and several additional
genes. A similar complete genomic screen by the Multiple Sclerosis
Genetics Group (1996) yielded results suggesting a multifactorial
etiology, including both environmental and multiple genetic factors of
moderate effect. The results supported a role for the MHC region on 6p.

Ebers et al. (1996) found maximum lod scores (MLS) greater than 1 for MS
at 5 loci on chromosomes 2, 3, 5, 11, and X. Two additional datasets
containing 44 and 78 sib pairs respectively, were used to further
evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS
of 4.24. Markers within 6p21 gave an MLS of 0.65. However, D6S461, just
outside the HLA region, showed significant evidence for linkage
disequilibrium by the transmission disequilibrium test (TDT), in all 3
datasets, suggesting to the investigators a modest susceptibility locus
in this region. The chromosome 5p results from 3 datasets (222 sib
pairs) yielded a multipoint MLS of 1.6. Ebers et al. (1996) concluded
that the results support the genetic epidemiologic evidence that several
genes interact epistatically to determine heritable susceptibility.

In a collaborative study, Haines et al. (1998) studied a data set of 98
multiplex MS families to test for an association to the HLA-DR2 allele
in familial MS and to determine if genetic linkage to the major
histocompatibility complex (MHC) was due solely to such an association.
Three highly polymorphic markers (HLA-DR, D6S273, and TNF-beta) in the
MHC demonstrated strong genetic linkage (parametric lod scores of 4.60,
2.20, and 1.24, respectively) and a specific association with the
HLA-DR2 allele was confirmed; the transmission/disequilibrium test (TDT)
yielded a P value of less than 0.001. Stratifying the results by HLA-DR2
status showed that the linkage results were limited to families
segregating HLA-DR2 alleles. These results demonstrated that genetic
linkage to the MHC can be explained by the HLA-DR2 allelic association.
They also indicated that sporadic and familial MS share a common genetic
susceptibility. In addition, preliminary calculations suggested that the
MHC explains between 17% and 62% of the genetic etiology of MS. This
heterogeneity is also supported by the minority of families showing no
linkage or association with loci within the MHC. In a study of the
Sardinian population, Marrosu et al. (1998) tested the role of other
class II HLA loci in MS predisposition.

Fernandez-Arquero et al. (1999) found a significant correlation between
a TNFA-376 promoter polymorphism with susceptibility to multiple
sclerosis in a study of 238 patients and 324 controls. This association
was independent of HLA class II association and synergistically
increased risk in the presence of HLA-DRB1*1501. In a follow-up
case-control study of 241 Spanish patients with MS, Martinez et al.
(2004) confirmed an association between MS and the TNFA-376
polymorphism. Noting that another study (Weinshenker et al., 2001) had
failed to replicate the findings in a mostly Northern European
population, Martinez et al. (2004) concluded that the positive
association is specific to the Spanish white population or that only
studies in this population have sufficient power because of the higher
frequency of the TNFA-376 allele.

Ligers et al. (2001) assessed the importance of the HLA-DR locus to
multiple sclerosis susceptibility in 542 sib pairs with MS and in their
families. By genotyping 1,978 individuals for HLA-DRB1 (142857) alleles,
they confirmed the well-established association of MS with HLA-DRB1*15
(HLA-DRB1*1501 and HLA-DRB5*0101, 604776), by the
transmission/disequilibrium test. They obtained significant evidence of
linkage throughout the whole dataset (mlod = 4.09; 59.9% sharing).
Surprisingly, similar sharing was also observed in 58 families in which
both parents lacked the DRB1*15 allele (mlod = 1.56; 62.7% sharing; p =
0.0081). The findings suggested that the notion that HLA-DRB1*15 is the
sole MHC determinant of susceptibility in northern European populations
with MS may be incorrect. The possibility remained that the association
of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby
locus and/or to the presence of disease-influencing allele(s) in
DRB1*15-negative haplotypes.

Lang et al. (2002) examined the association of MS with HLA-DRB1*1501 and
-DRB5*0101 polymorphisms by determining the antigen-recognition profile
of an MS patient with a relapsing-remitting disease course. A T-cell
receptor (TCR) from the patient recognized both DRB1*1501-restricted
myelin basic protein (MBP; 159430) (residues 85 to 99) and
DRB5*0101-restricted Epstein-Barr virus DNA polymerase peptide. The
crystal structure of both DRB-antigen complexes revealed a marked degree
of structural equivalence at the surface presented for TCR recognition,
with 4 identical TCR-peptide contacts. Lang et al. (2002) concluded that
these similarities support the concept of molecular mimicry (in
structural terms, a similarity of charge distribution) involving HLA
molecules and suggested that these structural details may explain the
preponderance of MHC class II associations in HLA-associated diseases.
They noted the findings of Madsen et al. (1999) with transgenic mice,
which also showed that MBP(85 to 99) associated with HLA-DRB1*1501 was
involved in the development of an MS-like disease.

Models of disease susceptibility in MS often assume a dominant action
for the HLA-DRB1*1501 (see 142857) allele and its associated haplotype,
DRB1*1501-DQB1*0602, also known as DR2. Barcellos et al. (2003) found a
dosage effect of HLA-DR2 haplotypes on MS susceptibility. Two copies of
a susceptibility haplotype further increased disease risk. They also
reported that DR2 haplotypes modify disease expression. There was a
paucity of benign MS and an increase of severe MS in individuals
homozygous for DR2.

Mattila et al. (2001) genotyped 97 patients with MS and 100 healthy
controls and found an association between the pp polymorphism in the
ESR1 (133430) gene on chromosome 6q25 in combination with the previously
described association of HLA-DR2 in women with MS (odds ratio for MS in
women with both ESR1pp and HLA-DR2 was 19.4 vs 5.1 with DR2 alone).

Marrosu et al. (2001) scanned an 11.4-Mb region encompassing the whole
HLA complex on chromosome 6p21.3 for MS association in the founder
population of Sardinia. Using 19 microsatellite markers,
single-nucleotide polymorphisms (SNPs) within 12 candidate genes, and
the extended transmission disequilibrium test (ETDT), a peak of
association represented by the 3 adjacent DRB1, -DQA1, and -DQB1 loci
was detected in the class II region. Two additional less significant
areas of association were detected, respectively, in the centromeric
side of the class II region at the DPB1 locus and, telomeric of the
classically defined class I loci, at the D6S1683 microsatellite.
Conditional ETDT analysis indicated that these regions of association
could be independent of each other. Within the main peak of association,
DRB1 and DQB1 contributed to the disease association independently of
each other, whereas DQA1 had no detectable primary genetic effects. Five
DQB1-DRB1 haplotypes positively associated with MS in Sardinia, which
consistently included all the haplotypes previously found associated
with MS in the various human populations. The authors concluded that
their results are consistent with a multilocus model of the MHC-encoded
susceptibility to MS.

In 30 patients with relapsing-remitting MS, which the authors termed
'benign,' and 25 patients with secondary-progressive MS, which the
authors termed 'malignant,' from a region in northeast Italy, Perini et
al. (2001) found a positive association between the HLA-DR13 haplotype
(particularly the DRB1*1302 allele) and 'benign' MS. The DR13 haplotype
was detected in 40% of patients with 'benign' MS, in 4% with 'malignant'
MS, and in 16% of normal controls.

Association of MS with the HLA-DRB1*1501-DQB1*0602 haplotype has been
repeatedly demonstrated in high-risk (northern European) populations.
African populations are characterized by greater haplotypic diversity
and distinct patterns of linkage disequilibrium compared with northern
Europeans. To better localize the HLA gene responsible for MS
susceptibility, Oksenberg et al. (2004) performed case-control and
family-based association studies for the DRB1 and DQB1 loci in a large
and well-characterized African American dataset. A selective association
with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1
locus in MS independent of DQB1*0602. This finding was unlikely to be
solely explained by admixture, since a substantial proportion of the
susceptibility chromosomes from African American patients with MS
displayed haplotypes consistent with an African origin.

Genetic susceptibility to multiple sclerosis is associated with genes of
the major histocompatibility complex (MHC), particularly HLA-DRB1 and
HLA-DQB1. To clarify whether HLA-DRB1 itself, nearby genes in the region
encoding the MHC, or combinations of these loci underlie susceptibility
to multiple sclerosis, Lincoln et al. (2005) genotyped 1,185 Canadian
and Finnish families with multiple sclerosis with a high-density SNP
panel spanning the genes encoding the MHC and flanking genomic regions.
Strong associations in Canadian and Finnish samples were observed with
blocks in the HLA-II genomic region, but the strongest association was
with HLA-DRB1. Conditioning on either HLA-DRB1 or the most significant
HLA class II haplotype block found no additional block or SNP
association independent of the HLA class II genomic region. This study
therefore indicated that MHC-associated susceptibility to multiple
sclerosis is determined by HLA class II alleles, their interactions, and
closely neighboring variants.

Dyment et al. (2004) reported a multistage genome scan of 552 sib pairs
from 442 MS families. Only markers at chromosome 6p showed significant
evidence for linkage (MLOD = 4.40), while other regions were only
suggestive. The replication analysis involving all 552 affected sib
pairs confirmed suggestive evidence for 5 locations, namely, 2q27, 5p15,
18p11, 9q21, and 1p31. The overall excess allele sharing observed for
the entire sample was due to increased allele sharing within the DRB1*15
negative subgroup alone. The authors concluded that their observations
supported a model of genetic heterogeneity between HLA and other genetic
loci.

Gregersen et al. (2006) reported that the MHC HLA-DR2 haplotype
comprised of DRB1*1501 (DR2b) and DRB5*0101 (DR2a), which predisposes to
multiple sclerosis, shows more extensive linkage disequilibrium than
other common Caucasian HLA haplotypes in the DR region and thus seems
likely to have been maintained through positive selection.
Characterization of 2 multiple sclerosis-associated HLA-DR alleles at
separate loci by a functional assay in humanized mice indicates that the
linkage disequilibrium between the 2 alleles may be due to a functional
epistatic interaction, whereby 1 allele modifies the T-cell response
activated by the second allele through activation-induced cell death.
This functional epistasis is associated with a milder form of multiple
sclerosis-like disease. Gregersen et al. (2006) suggested that such
epistatic interaction might prove to be an important general mechanism
for modifying exuberant immune responses that are deleterious to the
host and could also help to explain the strong linkage disequilibrium in
this and perhaps other HLA haplotypes.

The International Multiple Sclerosis Genetics Consortium (2007) found
evidence that variation in the HLA-C gene (142840) influences
susceptibility to MS independent of the HLA-DRB1 gene. Using a
combination of microsatellite, SNP, and HLA typing in a family-based and
case-control cohort beginning with a sample of 1,201 MS patients, the
authors analyzed 264 patients without the common DRB1*1501, DRB1*03, and
DRB1*0103 alleles. Significant association was found with the HLA-C
locus (p = 5.9 x 10(-5)). Specifically, the HLA-C*05 allele was
underrepresented in patients compared to controls (p = 3.3 x 10(-5)),
suggesting a protective effect.

In a multistage genomewide association study involving a total of 1,540
multiple sclerosis family trios, 2,322 case subjects, and 5,418 control
subjects, the International Multiple Sclerosis Genetics Consortium
(2007) used the HLA-DRA (142860) A/G SNP dbSNP rs3135388 as a proxy for
the DRB1*1501 allele (complete concordance between the dbSNP rs3135388 A
allele and DRB1*1501 was found in 2,730 of 2,757 subjects for whom data
were available) and confirmed unequivocally that the HLA-DRA locus was
associated with MS (p = 8.94 X 10(-81); OR, 1.99).

Baranzini et al. (2009) conducted a genomewide association study in 978
well-characterized individuals with MS and 883 group-matched controls.
The authors compared allele frequencies and assessed genotypic
influences on susceptibility, age of onset, disease severity, as well as
brain lesion load and normalized brain volume from MRI exams. Top SNPs
were located in the MHC class-II subregion likely reflecting linkage
disequilibrium with the HLA-DRB1*1501 allele. Logistic regression
analysis adjusting for gender, study site, and DRB1*1501 suggested an
independent association in the HLA-class I region localized around
TRIM26 (600830), TRIM15, and TRIM10 (605701).

In a collaborative GWAS involving 9,772 cases of European descent
collected by 23 research groups working in 15 different countries, the
International Multiple Sclerosis Genetics Consortium and Wellcome Trust
Case Control Consortium 2 (2011) replicated almost all of the previously
suggested associations and identified at least a further 29 novel
susceptibility loci for multiple sclerosis. Within the MHC the
International Multiple Sclerosis Genetics Consortium and Wellcome Trust
Case Control Consortium 2 (2011) refined the identity of the HLA-DRB1
risk alleles as DRB1*1501 (142857.0002) and DRB1*1303, and confirmed
that variation in the HLA-A gene (142800) underlies the independent
protective effect attributable to the class I region. Immunologically
relevant genes were significantly overrepresented among those mapping
close to the identified loci and particularly implicated T helper cell
differentiation in the pathogenesis of multiple sclerosis.

Disanto et al. (2011) found that 64 (24%) of 266 children with an
initial attack of demyelination (acquired demyelinating syndrome, ADS)
met criteria for a diagnosis of MS during a mean follow-up of 3.2 years.
ADS children with 1 or more DRB1*15 alleles were more likely to be
diagnosed with MS (OR of 2.7) compared to children without this allele.
The association was most apparent in those children of European descent
(OR of 3.3). Presence of DRB1*15 did not convey an increased risk for MS
in ADS children of non-European descent. The findings indicated that
DRB1*15 alleles confer increased susceptibility to pediatric-onset MS,
supporting a fundamental similarity in genetic contribution to risk of
chronic MS in both pediatric- and adult-onset disease.

- Associations Pending Confirmation

Mycko et al. (1998) found an increased frequency of the K469 allele of
intercellular adhesion molecule-1 (ICAM1; 147840) in 79 Polish multiple
sclerosis patients compared with 68 ethnically matched controls (68% vs
49%). Homozygosity for this variant was also increased (53% vs 34%).

Vandenbroeck et al. (1998) found evidence that the interferon-gamma gene
(IFNG; 147570) on chromosome 12q14 is a susceptibility factor for
multiple sclerosis in those Sardinians who are at low risk by virtue of
their HLA status.

In a genomewide association study (GWAS) involving 1,618 MS patients and
3,413 controls, with replication in an independent set of 2,256 cases
and 2,310 controls, the Australia and New Zealand Multiple Sclerosis
Genetics Consortium ANZgene (2009) identified several risk-associated
SNPs on chromosome 12q13-14, including dbSNP rs703842 in the METTL1 gene
(604466) (p = 5.4 x 10(-11)); dbSNP rs10876994, p = 2.7 x 10(-10); and
dbSNP rs12368653, p = 1.0 x 10(-7). The region encompassed 17 putative
genes. Gandhi et al. (2010) determined that the MS-associated SNP dbSNP
rs703842 identified by the Australia and New Zealand Multiple Sclerosis
Genetics Consortium ANZgene (2009) was also associated with expression
of the FAM119B gene (615258), the MS susceptibility allele being the
low-expressor of FAM119B.

Schrijver et al. (1999) found that patients with multiple sclerosis who
were carriers of the IL1RN*2 allele (see 147679) and noncarriers of the
IL1B*2 allele (see 147720) had a higher rate of progression than those
with other allele combinations.

In 3 of 4 independent case-control studies, Jacobsen et al. (2000)
demonstrated an association of a SNP in the PTPRC gene (151460) with MS.
Furthermore, they found that the PTPRC mutation was linked to and
associated with the disease in 3 MS nuclear families. However, studies
by Vorechovsky et al. (2001) Barcellos et al. (2001), Cocco et al.
(2004), and Szvetko et al. (2009) found no association between the PTPRC
SNP and multiple sclerosis.

Dyment et al. (2001) analyzed and performed genotyping in 219 sib pairs
assembled in connection with 4 published genome screens that had
identified a number of markers with increased sharing in MS families but
which did not reach statistical significance.

Dyment et al. (2001) used 105 markers previously identified as showing
increased sharing in genome screens of Canadian, British, Finnish, and
American MS families, but which did not reach statistical significance
for linkage, in a genotype analysis of a Canadian sample of 219 sibs
pairs. None of the markers met the criteria for significant linkage.
Markers located at 5p14 and 17q22 were analyzed in a total of 333 sib
pairs and attained maximum lod scores of 2.27 and 1.14, respectively.
The known HLA-DRB1 association with MS was confirmed (p less than
0.0001). A significant transmission disequilibrium was also observed for
D17S789 at 17q22 (p = 0.0015). The authors noted that the study
highlighted the difficulty of searching for genes with only mild to
moderate effects on susceptibility, although large effects of specific
loci may still be present in individual families. They suggested that
progress in the genetics of this complex trait may be helped by (1)
focusing on more ethnically homogeneous samples, (2) using an increased
number of MS families, and (3) using transmission disequilibrium
analysis in candidate regions rather than the affected relative pair
linkage analysis.

Xu et al. (2001) investigated 27 microsatellite markers from 8
chromosomal regions syntenic to loci of importance for experimental
autoimmune diseases in the rat in 74 Swedish MS families. Possible
linkage was observed with markers in the 7q35 (highest NPL score of
1.16) and 12p13.3 (highest NPL score of 1.16) regions, which are
syntenic to the rat Cia3 (collagen-induced arthritis) and Oia2
(oil-induced arthritis) loci, respectively. Both regions overlapped with
areas showing evidence for linkage in previous MS genomic screens.

The prevalence of MS in Sardinia (approximately 140 per 100,000) is
significantly higher than in surrounding Mediterranean countries,
suggesting that the isolated growth of this population has concentrated
genetic susceptibility factors for the disease. Coraddu et al. (2001)
performed a genomewide screen for linkage in 49 Sardinian multiplex
families (46 sib pairs and 3 sib trios) using 327 markers. Nonparametric
multipoint linkage analysis revealed suggestive linkage (MLS greater
than 1.8) to chromosome regions 1q31, 10q23, and 11p15. Coraddu et al.
(2001) concluded that the individual effects of genes determining
susceptibility to MS are modest.

Pericak-Vance et al. (2001) reviewed linkage studies in multiple
sclerosis. Genomic screens had suggested over 50 regions that might
harbor MS susceptibility genes, but there had been little agreement
between studies. The one region suggested by all 4 screens resided
within chromosome 19q13. They examined this region in detail in an
expanded dataset of MS families from the United States. Genetic linkage
and association were tested with multiple markers in this region using
both parametric and nonparametric analyses. Additional support for an MS
susceptibility locus was observed, primarily in families with the
MS-associated HLA-DR2 allele. While consistent, this effect appeared to
be modest, probably representing no more than 10% of the overall genetic
effect in MS.

Haines et al. (2002) studied a population of 266 individuals with MS
belonging to 98 multiplex families. Their analysis continued to support
linkage to chromosomes 6p21, 6q27, and 19q13 with lod scores higher than
3.0, and suggested that regions on chromosomes 12q23-q24 and 16p13 may
also harbor susceptibility loci for MS. Analysis taking into account the
known HLA-DR2 association identified additional potential linkage
regions on chromosomes 7q21-22 and 13q33-34.

Vitale et al. (2002) identified a pedigree of Pennsylvania Dutch
extraction in which MS segregated with an autosomal dominant inheritance
pattern. Eighteen individuals, of whom 7 were affected, were serotyped
for HLA class I and II and also analyzed by a genomewide screen for
linkage analysis. There was suggestive linkage to markers on 12p12 with
a maximum multipoint lod score of 2.71, conditional on the presence of
HLA-DR15*DQ6. Contingency table analysis showed that all MS affected
individuals had both the DR15*DQ6 allele and the 12p12 haplotype,
whereas the unaffected individuals had either 1 or neither of these
markers (P = 0.00011). The authors concluded that both HLA-DR15*DQ6 and
a novel locus on chromosome 12p12 may be necessary for development of MS
in this family.

He et al. (2002) studied a genetically isolated population in the
Overkalix community of northern Sweden, which demonstrates a high
incidence of MS. This ethnically homogeneous population was probably
founded in the 17th century by a few couples. A genealogic analysis
established that 19 of the MS patients originated from a single common
ancestral couple. Five affected individuals from 4 nuclear families were
selected for genomewide genotyping with 390 microsatellite markers.
Seven shared haplotypes in 6 different chromosomal regions were
identified. Only 1 of the suggested haplotypes was confirmed to be
identical-by-descent after analysis of additional markers in 15 MS
patients, and the identified region at 17p11 consisted of 4 markers
spanning 7 cM. A significant excess of transmission of alleles to
affected individuals (p less than 0.05) was observed for 3 of the
markers by TDT. No increased sharing of haplotypes was observed for the
HLA-DR and -DQ loci. The results suggested the presence of a
susceptibility gene for MS in chromosome 17p11.

Saarela et al. (2002) carried out linkage analyses in 22 Finnish
multiplex MS families originating from a regional subisolate that showed
an exceptionally high prevalence of MS. The authors identified a 4-cM
region flanked by the markers D17S1792 and ATA43A10 in 17 of 22
families. Using the combined power of linkage, association, and shared
haplotype analyses, the authors restricted the MS locus on chromosome
17q to a region corresponding to a physical interval of 2.5 Mb.

By genomewide analysis of 779 Finnish MS patients and 1,165 controls,
including those from an isolate in Southern Ostrobothnia, Jakkula et al.
(2010) found an association between multiple sclerosis and the A allele
of dbSNP rs744166 in the STAT3 gene (102582) on 17q21; the A allele was
protective. The findings were replicated in a total of 3,859 cases and
9,110 controls from various populations, including Norway, Denmark, the
Netherlands, Switzerland, and the United States, yielding an overall p
value of 2.75 x 10(-10) and an odds ratio of 0.87 (CI, 0.83-0.91). To
validate the findings of Jakkula et al. (2010), Lill et al. (2012)
performed a genetic association study of 2 SNPs in the STAT3 gene in a
German case-control sample of 2,932 MS patients and 2,972 controls.
There was a nominally significant association between the G allele of
dbSNP rs744166 and MS (OR of 1.09, p = 0.012), and no association with
dbSNP rs2293152. Lill et al. (2012) noted that dbSNP rs744166 occurs in
an intron and is not likely to have functional significance.

Kenealy et al. (2004) used a panel of 390 microsatellite markers for a
genome screen in 245 U.S. and French multiplex families (the largest
genomic screen for MS to that time). Four regions were thought to
warrant further study.

Admixture mapping is a method for scanning the genome for gene variants
that affect the risk for common, complex disease. The method has high
statistical power to detect factors that differ markedly in frequency
across human populations. Multiple sclerosis was an excellent candidate
for admixture mapping because it is more prevalent in European Americans
than in African Americans (Kurtzke et al., 1979, Wallin et al. (2004)).
Reich et al. (2005) performed a high-powered admixture scan, focusing on
605 African American cases of multiple sclerosis and 1,043 African
American controls. The individuals in their study had, on average, 21%
European and 79% African ancestry. The goal was to identify genetic
regions where individuals with multiple sclerosis tended to have an
unusually high proportion of ancestry from either Europeans or Africans,
indicative of the presence of a multiple sclerosis risk variant that
differs in frequency between the ancestral populations. Reich et al.
(2005) hypothesized that if there are genetic risk factors for multiple
sclerosis that explain the epidemiology, they should be identifiable as
regions with a high proportion of European ancestry in African Americans
with multiple sclerosis compared with the average. They reported a locus
on chromosome 1 that is significantly associated with multiple
sclerosis. The 95% credible interval on chromosome 1 was estimated to be
between 114.9 Mb and 144.7 Mb from 1pter, a region containing 68 known
genes.

Among 242 patients with multiple sclerosis and 207 controls from a
central Ohio population, Zhou et al. (2003) found that homozygosity for
an ala57-to-val (A57V) SNP in the CD24 gene (600074) on chromosome 6q21
was associated with a 2-fold increased risk of MS in the general
population, and the V57 allele was preferentially transmitted to
affected individuals among familial MS cases. Most V57 homozygotes
reached an expanded disability status within 5 years, whereas
heterozygotes and A57 homozygotes reached this milestone in 16 and 13
years, respectively. Flow cytometric analysis demonstrated that CD24 was
more highly expressed on T cells of V57 homozygous patients than A57
homozygous patients. Zhou et al. (2003) concluded that the A57V CD24
polymorphism genetically modifies susceptibility and progression of MS,
perhaps by affecting the efficiency of CD24 expression. However, Goris
et al. (2006) were unable to confirm the association between the A57V
SNP and multiple sclerosis in a combined cohort of 1,180 cases and 1,168
unrelated and family-based controls from Belgium and the United Kingdom.
Among 135 Spanish Basque patients with MS and 285 controls, Otaegui et
al. (2006) found evidence for trend of association between the V56
allele and MS, but the results did not reach significance for an
association study.

By fine mapping of a candidate locus at chromosome 1p13 in 1,278 trio
families with MS and replication in an additional 3,341 MS patients, De
Jager et al. (2009) observed a significant association between
protection against MS and the G allele of dbSNP rs2300747 in the CD58
gene (153420) (combined p of 1.1 x 10(-6); OR of 0.82). The protective G
allele was associated with a dose-dependent increase in CD58 mRNA
expression in lymphoblastic cells lines from MS patients (p = 1.1 x
10(-10)), suggesting a functional effect. De Jager et al. (2009) found
that CD58 mRNA expression was higher in MS patients during clinical
remission.

In a metaanalysis of genomewide association studies including 2,624
patients with MS and 7,220 controls, followed by replication in an
independent set of 2,215 patients MS and 2,116 controls, De Jager et al.
(2009) identified loci for MS susceptibility on chromosome 12p13 in the
TNFRSF1A gene (191190) (dbSNP rs1800693; see MS5, 614810), on chromosome
16 (dbSNP rs17445836) near the IRF8 gene (601565) (p = 3.73 x 10(-9)),
and on chromosome 11q13 (dbSNP rs17824933) in the CD6 gene (186720) (p =
3.79 x 10(-9)). In addition, the authors replicated the findings of an
association between MS and SNP dbSNP rs2300747 in the CD58 gene (p =
3.10 x 10(-10)). D'Netto et al. (2009) found an association between the
C allele of dbSNP rs12044852 in the CD58 gene and MS in 211 patients and
521 unaffected relatives from 43 multiplex MS families (OR, 1.05; p =
0.014), and in a case-control with the 211 patients and 182 unrelated
controls (OR, 2.63; p = 8.5 x 10(-5)).

In a multistage genomewide association study (GWAS) involving a total of
1,540 multiple sclerosis family trios, 2,322 case subjects, and 5,418
control subjects, the International Multiple Sclerosis Genetics
Consortium (2007) found an association between the G allele of dbSNP
rs6498169 in the KIAA0350 gene (611303) on chromosome 16p13 and MS (OR,
1.14; p = 3.83 x 10(-6)). D'Netto et al. (2009) found an association
between MS and dbSNP rs6498169 in a study of 211 MS patients and 182
controls (OR, 1.47; p = 0.014). However, significant associations with
this SNP were not found among the 211 patients and 521 unaffected
relatives from 43 multiplex MS families.

In a GWAS involving 1,618 MS patients and 3,413 controls, with
replication in an independent set of 2,256 cases and 2,310 controls, the
Australia and New Zealand Multiple Sclerosis Genetics Consortium ANZgene
(2009) identified risk-associated SNPs on chromosome 20q13 (dbSNP
rs6074022, p = 1.3 x 10(-7) and dbSNP rs1569723, p = 2.9 x 10(-7)). Both
SNPs are located upstream of the CD40 gene (109535). Gandhi et al.
(2010) determined that, of the 30 SNPs genotyped from the chromosome 20
CD40 linkage block by the Australia and New Zealand Multiple Sclerosis
Genetics Consortium ANZgene (2009), dbSNP rs6074022 had the strongest
association with CD40 expression. The CD40 haplotype associated with
increased MS susceptibility has decreased gene expression in MS.

Baranzini et al. (2009) conducted a GWAS in 978 well-characterized
individuals with MS and 883 group-matched controls. The authors compared
allele frequencies and assessed genotypic influences on susceptibility,
age of onset, disease severity, as well as brain lesion load and
normalized brain volume from MRI exams. They identified an association
with SNP dbSNP rs9523762 in the GPC5 gene (602446) (adjusted log p value
= 5.155), which was replicated in an independent group of 974 MS
patients (adjusted log p value = 2.42).

The International Multiple Sclerosis Genetics Consortium (2010)
genotyped approximately 30,000 single-nucleotide polymorphisms (SNPs)
that demonstrated mild to moderate levels of significance (p less than
or equal to 0.10) in an initial GWAS of an independent set of 1,343
multiple sclerosis (MS) cases and 1,379 controls. The consortium further
replicated several of the most significant findings in another
independent data set of 2,164 MS cases and 2,016 controls. There was
considerable evidence for a number of novel susceptibility loci
including KIF21B (608322) (dbSNP rs12122721, combined p = 6.56 x
10(-10), odds ratio = 1.22) and TMEM39A (dbSNP rs1132200, p = 3.09 x
10(-8), odds ratio = 1.24), both of which met genomewide significance.

The Wellcome Trust Case Control Consortium and The
Australo-Anglo-American Spondylitis Consortium (2007) and Ban et al.
(2009) reported a possible protective effect in MS of a rare functional
variant within the TYK2 gene, dbSNP rs34536443. Because of the low
frequency (0.04) of the minor allele (C), genomewide-significant
association was not established. Mero et al. (2010) genotyped 5,429
Nordic MS cases and 6,167 healthy controls for this TYK2 nonsynonymous
SNP, which encodes a proline-to-alanine substitution in exon 21, and
then combined the Nordic genotype data with raw genotypes from the
studies of the Wellcome Trust Case Control Consortium and The
Australo-Anglo-American Spondylitis Consortium (2007) and Ban et al.
(2009). The combined Nordic analysis showed significant association with
MS (p = 5 x 10(-4), odds ratio 0.78), and by mega-analysis of 10,642 MS
patients, 10,620 controls, and 2,110 MS trios, the association at
genomewide significance level (p = 5.08 x 10(-9), odds ratio 0.77) was
shown.

- Association with APOE

The contribution of the major histocompatibility complex (MHC) to the
pathogenesis of MS has been established in numerous genetic linkage and
association studies. In addition to MHC, the chromosome 19p13 region
surrounding the apolipoprotein E gene (APOE; 107741) has shown
consistent evidence of involvement in MS when family-based analyses were
conducted. Some clinical studies have suggested an association between
the APOE4 allele and more severe disease and faster progression of
disability (Fazekas et al., 2001; Chapman et al., 2001). Noting that the
APOE4 allele has been associated with earlier age of onset in AD, but
not disease progression, and with faster disease progression in MS, but
not age of onset, Chapman et al. (2001) suggested that these apparent
effects are influenced by whether the diagnosis is made late in disease
course (as in AD) or relatively early in disease course (as in MS). The
authors hypothesized that the APOE4 genotype influences neuronal disease
in general via alterations in the efficacy of neuronal maintenance and
repair, and that the apparent effects of the genotype on these 2
parameters are related to the threshold at which the disease manifests
itself clinically.

Lucotte and French MS Consortium (2002) conducted a genomewide linkage
analysis in 18 families with multiple cases of MS. An MS locus was
linked to markers located in the 19q13.3 region (multipoint lod score =
2.1). They suggested that APOE, which is located in this region, is an
excellent candidate gene for MS.

To examine further the role of APOE in MS, Schmidt et al. (2002)
genotyped its functional alleles, as well as 7 single nucleotide
polymorphisms (SNPs) located primarily within 13 kb of APOE, in 398
families. Using family-based association analysis, they found
statistically significant evidence that a SNP haplotype near APOE is
associated with MS susceptibility (p = 0.005). An analysis of disease
progression in 614 patients with MS from 379 families indicated that
APOE4 carriers are more likely to be affected with severe disease (p =
0.03), whereas a higher proportion of APOE2 carriers exhibited a mild
disease course (p = 0.02). Kantarci et al. (2004) presented evidence
suggesting that the APOE2 allele is associated with lesser disease
severity in women with MS, as indicated by a longer time to reach an
expanded disability status scale (EDSS) score of 6. In contrast, Zwemmer
et al. (2004) reported no favorable role for the E2 allele in a study of
250 women with MS. In fact, they found a trend in the opposite
direction: time to an EDSS score of 6 was shorter (6.8 years) in E2
carriers than in noncarriers (10.0 years). In addition, E2 carriers had
a higher lesion load on MRI compared to noncarriers. In a response,
Weinshenker and Kantarci (2004) noted that the study by Zwemmer et al.
(2004) had a higher number of more severe primary progressive cases (22%
of subjects) than that reported by Kantarci et al. (2004) (6.4% of
subjects), which may explain the discrepancy.

In MS, a reduction in concentration of N-acetylaspartate (NAA), which
has been shown to be contained almost exclusively in mature neurons,
reflects neuronal loss, axonal loss, and generalized neuronal
dysfunction. Moreover, the degree of reduction of NAA has been
correlated with disease severity and extent of tissue destruction. In 72
patients with relapsing-remitting MS, Enzinger et al. (2003) showed by
proton magnetic resonance spectroscopy (MRS) that patients with the
APOE4 allele had a higher degree of disability and a significantly lower
NAA:creatine ratio than patients without the E4 allele. During follow-up
in 44 patients, the drop in the NAA:creatine ratio of E4 carriers was
significantly larger and was paralleled by a higher number of relapses
and a faster disease progression. Enzinger et al. (2003) concluded that
the findings indicated more extensive axonal damage associated with the
APOE4 allele.

Among 125 Greek MS patients, Koutsis et al. (2007) found that carriers
of the APOE E4 allele had a 6-fold increase in the relative risk of
verbal learning deficits compared to noncarriers. The effect was
specific and was not observed in other cognitive domains.

Among 1,006 Australian patients with relapsing-remitting MS or secondary
progressive MS, van der Walt et al. (2009) found no association between
APOE allele status or promoter region heterogeneity at positions -219G-T
(107741.0030) or +113C-G and clinical disease severity, cognition, or
cerebral atrophy.

Ghaffar et al. (2010) found no differences in 11 cognitive outcome
variables, including attention, processing speed, verbal and visual
memory, and executive functions in a comparison of 50 MS patients with
the E4 allele and 50 MS patients without the E4 allele who were
well-matched regarding education and disease course and duration. The
presence of cognitive impairment overall was 41%.

MOLECULAR GENETICS

Among 163 patients with sporadic MS, DeLuca et al. (2007) observed an
association between relatively benign outcome and HLA-DRB1*01. The
allele was present in 19% of 112 patients with milder disease compared
to 3.9% of 51 patients with severe disease, yielding an odds ratio of
4.85. Severity analysis of a cohort of affected sib pairs discordant for
the DRB1*01 allele confirmed the protective effect, but only reached
significance when combined in the DRB1*1501 allele. Another group of
Sardinian MS patients showed that 19 with benign disease had the DRB1*01
allele, compared to none with malignant disease. DeLuca et al. (2007)
suggested that the DRB1*01 allele acts as a modifier of disease
progression in MS.

Epidemiologic evidence implicating epigenetic factors in MS includes
complex distortion of disease transmission seen in
aunt/uncle-niece/nephew (AUNN) pairs. In AUNN families, Chao et al.
(2009) found that allele frequencies for HLA-DRB1*1501 were different
between the first and second generations affected. Affected aunts had
significantly lower HLA-DRB1*15 frequency compared with their affected
nieces (P = 0.0016), whereas HLA-DRB1*15 frequency in affected males
remained unaltered across the 2 generations (P = 0.63). The authors
compared transmissions for the HLA-DRB1*15 allele using a family-based
transmission disequilibrium test approach in 1,690 individuals from 350
affected sib-pair (ASP) families and 960 individuals from 187 AUNN
families. Transmissions differed between the ASP and the AUNN families
(P = 0.0085). The risk carried by HLA-DRB1*15 was increased in families
with affected second-degree relatives (AUNN: OR = 4.07) when compared
with those consisting only first-degree relatives (ASP: OR = 2.17),
establishing heterogeneity of risk among HLA-DRB1*15 haplotypes based on
whether collateral parental relatives are affected. The authors proposed
gene-environment interactions in susceptibility and more specifically,
that epigenetic modifications may differentiate among human leukocyte
antigen class II risk haplotypes and may be involved in the
determination of the gender bias in MS. The authors suggested that the
female-specific increasing risk of MS is mediated through these alleles
or adjacent variation.

- Modifier Genes

Among 939 German patients with multiple sclerosis, Kroner et al. (2005)
reported an association between the A allele of a SNP in the PDCD1 gene
(600244) and disease progression. Of 94 patients with primary
progressive MS, 44% had the G/G genotype, and 53% had the A/G genotype.
Of 5 MS patients who were homozygous for the A allele, 3 had primary
progressive MS, and 1 had secondary progressive MS. In vitro studies
showed that PDCD1-mediated inhibition of T-cell activation and cytokine
secretion was impaired in cells from patients with the A allele compared
to cells from patients with only the G allele. Presence of the A allele
did not confer susceptibility to disease development.

Barcellos et al. (2000) found that patients with multiple sclerosis
carrying the CCR5 (601373)-delta-32 deletion showed an age at onset
approximately 3 years later than did patients without the deletion.
Studying 256 Israeli patients with MS, Kantor et al. (2003) presented
evidence suggesting that the CCR5-delta-32 deletion may contribute to a
slower rate of disease progression in MS.

PATHOGENESIS

Genetically determined susceptibility to a viral infection in childhood
or adolescence has long been suspected based on the occurrence of
several 'MS epidemics' (Kurtzke and Hyllested, 1979; Sheremata et al.,
1985). One of the epidemiologic facts that is compatible with viral
etiology is that there is a direct correlation between latitude and
frequency, i.e., the disease is most frequent in northern climes. A
notable exception is in Japan, which is at the same latitude as the east
coast of the United States from southern Maine to South Carolina. The
basis of the exception may be the relative lack of Dw2 in Japan (except
as introduced by Caucasians). MS is also rare in Africans. MS in
American blacks is accounted for, to a considerable extent, by Caucasian
admixture with acquisition of Dw2, which is low or absent in Africa.

Steinman (1996) reviewed what was known about the molecular mechanisms
in the pathogenesis of multiple sclerosis, the most common autoimmune
disease involving the nervous system. It is estimated that in the United
States approximately 250,000 individuals suffer from MS. The concordance
rate among monozygotic twins is 30%, a 10-fold increase over that in
dizygotic twins or first-degree relatives. It is hoped that as
understanding of the pathophysiology of MS increases, rational therapies
will be devised that will arrest the immunologic attack on myelin
without causing widespread immune suppression. Once the immune response
is silenced, it will be important to repair the damaged myelin sheath.
Steinman (1996) stated that possible methods to accomplish this repair
by use of oligodendroglial transplants and growth factors to reinitiate
myelination were under intense investigation. Vyse and Todd (1996) gave
a general review of genetic analysis of autoimmune disease, including
this one.

Reasoning that there could be an antigen present in the white matter of
MS brain that is not found in normal white matter and that specifically
activates T cells, van Noort et al. (1995) separated the proteins of the
myelin sheath using reversed-phase HPLC and discovered that a particular
fraction in the myelin of MS brain, but not in the myelin taken from
healthy brain, stimulated proliferation of T cells. They showed that
alpha-crystallin B (CRYAB; 123590) is expressed in glial cells from MS
lesions but not in white matter from healthy individuals or in
unaffected white matter from MS brain. This small heat-shock protein was
found in oligodendroglial cells as well as in astrocytes in plaques from
patients with acute and chronic MS. In light of the findings of van
Noort et al. (1995), Steinman (1995) discussed the significance of the
immune reaction against alpha-crystallin B in the pathology of MS. He
stated that the efforts to determine which antigens trigger the
pathologic response in MS brain may yield results that make it possible
to induce immunologic tolerance to these proteins using strategies such
as alteration of peptide ligands that bind to the T-cell receptor and
the blockade of costimulatory molecules on T cells.

Chabas et al. (2001) performed large-scale sequencing of cDNA libraries
derived from plaques dissected from brains of patients with multiple
sclerosis and detected an abundance of transcripts for osteopontin
(166490) that were completely absent from control brains.

During mammalian CNS development, contact-mediated activation of NOTCH1
(190198) receptors on oligodendrocyte precursors by the ligand JAG1
(601920) induces HES5 (607348), which inhibits maturation of these
cells. John et al. (2002) tested whether the NOTCH pathway is
reexpressed in the adult CNS in multiple sclerosis and found that
TGF-beta-1 (190180), a cytokine upregulated in MS, specifically
reinduced JAG1 in primary cultures of human astrocytes. Within and
around active MS plaques lacking remyelination, JAG1 was expressed at
high levels by hypertrophic astrocytes, whereas NOTCH1 and HES5
localized to cells with an immature oligodendrocyte phenotype, and
TGF-beta-1 was associated with perivascular extracellular matrix in the
same areas. In contrast, there was negligible JAG1 expression in
remyelinated lesions. In vitro experiments showed that JAG1 signaling
inhibited process outgrowth from primary human oligodendrocytes.

Progressive oligodendrocyte loss is part of the pathogenesis of MS.
Oligodendrocytes are vulnerable to a variety of mediators of cell death,
including free radicals, proteases, inflammatory cytokines, and
glutamate excitotoxicity. Proinflammatory cytokine release in MS is
mediated in part by microglial activation. Takahashi et al. (2003) found
that interleukin-1-beta (IL1B), a prominent microglia-derived cytokine,
caused oligodendrocyte death in coculture with astrocytes and microglia,
but not in pure culture of oligodendrocytes alone. Because IL1B had been
shown to impair the activity of astrocytes in the uptake and metabolism
of glutamate, Takahashi et al. (2003) hypothesized that the indirect
toxic effect of microglia-derived IL1B on oligodendrocytes involved
increased glutamate excitotoxicity via modulation of astrocyte activity.
In support, antagonists at glutamate receptors blocked the toxicity.
Similar studies of TNF-alpha, another microglia-derived cytokine,
yielded the same results. The findings provided a mechanistic link
between microglial activation in MS with glutamate-induced
oligodendrocyte destruction.

Bomprezzi et al. (2003) distinguished gene expression profiles of
peripheral blood monocytes from MS patients versus healthy controls
using cDNA microarrays. The authors hypothesized that activation of
autoreactive T cells may be of primary importance in MS.

Among 939 German patients with MS Kroner et al. (2005) reported an
association between an intronic SNP in the PDCD1 gene (600244.0001) and
disease progression. The SNP did not confer susceptibility to disease
development.

Alpha-B-crystallin (CRYAB; 123590) is the most abundant gene transcript
present in early active multiple sclerosis lesions, whereas such
transcripts are absent in normal brain tissue. This crystallin has
antiapoptotic and neuroprotective functions. CRYAB is the major target
of CD4+ T cell immunity to the myelin sheath from multiple sclerosis
brain. Ousman et al. (2007) demonstrated that CRYAB is a potent negative
regulator acting as a brake on several inflammatory pathways in both the
immune system and central nervous system. Cryab-null mice showed worse
experimental autoimmune encephalomyelitis at the acute and progressive
phases, with higher Th1 and Th17 cytokine secretion from T cells and
macrophages, and more intense CNS inflammation, compared with their
wildtype counterparts. Furthermore, Cryab-null astrocytes showed more
cleaved caspase-3 (600636) and more TUNEL staining, indicating an
antiapoptotic function of Cryab. Antibody to CRYAB was detected in
cerebrospinal fluid from multiple sclerosis patients and in sera from
mice with autoimmune encephalomyelitis. Administration of recombinant
CRYAB ameliorated autoimmune encephalomyelitis. Thus, Ousman et al.
(2007) concluded that the immune response against the negative regulator
of inflammation, CRYAB, in multiple sclerosis, would exacerbate
inflammation and demyelination. They suggested that this can be
countered by giving CRYAB itself for therapy of ongoing disease.

Using a proteomics approach, Derfuss et al. (2009) identified CNTN2
(190197) as a candidate autoantigen in 3 of 5 serum samples from
patients with multiple sclerosis. A larger sample of MS patients showed
significantly increased T-cell and IgG immune responses to CNTN2
compared to controls. Increased levels of IFN-gamma (147570) and IL17
(603149) were also observed in MS patients. Adoptive transfer of
Cntn2-specific T cells induced experimental autoimmune encephalitis in
rats that was characterized by a preferential inflammation of gray
matter of the spinal cord and cortex. Cotransfer of these T cells with a
myelin oligodendrocyte glycoprotein-specific monoclonal antibody
generated focal perivascular demyelinating lesions in the cortex and
extensive demyelination in spinal cord gray and white matter. These
findings indicated that CNTN2 is an autoantigen targeted by T cells and
autoantibodies in MS and suggested that a CNTN2-specific T-cell response
contributes to the development of gray matter pathology in MS.

Viral pathogens have been implicated in the etiology and pathogenesis of
MS. Plasmacytoid dendritic cells (PDCs) sense viral DNA and produce
increased levels of alpha-interferon (IFNA1; 147660) in response to
functional processed TLR9 (605474), which is generated by cleaving the N
terminus to generate a functional C-terminal TLR9. Balashov et al.
(2010) found that PDCs from untreated patients with relapsing-remitting
MS had increased levels of IFNA1 compared to PDCs from 14 patients
treated with beta-interferon (IFNB1; 147640). PDCs from IFNB1-treated
patients had significantly reduced levels of processed TLR9 protein but
normal levels of full-length TLR9 and TLR9 gene expression compare to
untreated patients. In vitro cellular studies showed that IFNB1
inhibited the processing of TLR9 in PDCs. Balashov et al. (2010)
suggested that the findings represented a new immunomodulatory mechanism
of beta-interferon.

Bittner et al. (2010) demonstrated that a T-cell potassium channel TASK2
(KCNK5; 603493) was significantly upregulated (2-fold) on peripheral
CD4+ T cells derived from patients with relapsing-remitting MS compared
to those from MS patients with stable disease and to controls. TASK2
expression on peripheral CD8+ T cells was more significantly increased
in MS patients with acute relapse (7.6-fold) and in those with stable
disease (3.3-fold). CSF-derived and CNS lesion-derived cytotoxic T cells
from MS patients showed an even greater increase in TASK2 expression
compared to peripheral cells. No increase in TASK2 expression was seen
in patients with neuromyelitis optica, another neurologic inflammatory
disease believed to be mediated by B cells. Pharmacologic or
siRNA-mediated knockdown of TASK2 in T cells reduced proliferation and
cytokine production, indicating that TASK2 is a key mediator of T-cell
physiology.

Srivastava et al. (2012) screened serum IgG from persons with MS to
identify antibodies that are capable of binding to brain tissue and
observed specific binding of IgG to glial cells in a subgroup of
patients. Using a proteomics approach focused on membrane proteins,
Srivastava et al. (2012) identified the ATP-sensitive inwardly
rectifying potassium channel KIR4.1 (602208) as the target of the IgG
antibodies. Serum levels of antibodies to KIR4.1 were higher in persons
with MS than in persons with other neurologic diseases and healthy
donors (p less than 0.001 for both comparisons). This finding was
replicated in 2 independent groups of persons with MS or other
neurologic diseases (p less than 0.001 for both comparisons). Analysis
of the combined data sets indicated the presence of serum antibodies to
KIR4.1 in 186 of 397 persons with MS (46.9%), in 3 of 329 persons with
other neurologic diseases (0.9%), and in none of the 59 healthy donors.
These antibodies bound to the first extracellular loop of KIR4.1.
Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a
profound loss of KIR4.1 expression, altered expression of glial
fibrillary acidic protein in astrocytes, and activation of the
complement cascade at sites of KIR4.1 expression in the cerebellum.
Srivastava et al. (2012) concluded that KIR4.1 is a target of the
autoantibody response in a subgroup of individuals with multiple
sclerosis.

- Association With Vitamin D

In a population-based study examining month of birth of 17,874 Canadian
MS patients and 11,502 British MS patients, with the addition of data
from 6,276 Danish and 6,393 Swedish patients, Willer et al. (2005) found
that significantly more (9.1% more) people with MS were born in May and
significantly fewer (8.5% fewer) were born in November. This represented
a 19% decreased risk of MS for those born in November compared to those
born in May. The effect was greatest in Scotland. Willer et al. (2005)
discussed possible interpretations of the data, including interactions
between genes and environment related to climate, such as variation in
sun exposure and vitamin D levels.

Munger et al. (2006) observed an association between increased serum
25-hydroxyvitamin D levels and protection from multiple sclerosis among
whites from a military registry. Among 148 cases and 296 controls, the
risk of multiple sclerosis significantly decreased with increasing
levels of 25-hydroxyvitamin D (odds ratio (OR) of 0.59). The inverse
relation with multiple sclerosis risk was particularly strong for
25-hydroxyvitamin D levels measured before age 20 years. No significant
associations were found between 109 black and Hispanic cases compared to
218 controls, although these groups had lower 25-hydroxyvitamin D levels
compared to whites. The results suggested that high circulating levels
of vitamin D are associated with a lower risk of multiple sclerosis.

Ramagopalan et al. (2009) identified a vitamin D response element (VDRE)
in the promoter region of HLA-DRB1. Sequencing of this promoter in
HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE
on HLA-DRB1*15 haplotypes in 322 MS-affected and unaffected individuals.
In contrast, there was striking variation among 168 individuals with
non-MS-associated haplotypes. Electrophoretic mobility shift assays
showed specific recruitment of vitamin D receptor to the VDRE in the
HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation
experiments using lymphoblastoid cells homozygous for HLA-DRB1*15.
Transient transfection of the promoter in B cells showed increased
expression on stimulation with 1,25-dihydroxyvitamin D3 that was lost
both on deletion of the VDRE. This study further implicated vitamin D as
a strong environmental candidate in MS by demonstrating direct
functional interaction with the major locus determining genetic
susceptibility. These findings support a connection between the main
epidemiologic and genetic features of this disease.

Torkildsen et al. (2008) reported 3 Norwegian patients from 2 families
with childhood-onset vitamin D hydroxylation-deficient rickets (VDDR1A;
264700) due to mutations in the CYP27B1 gene (609506) who all developed
multiple sclerosis. Since this form of vitamin D-dependent rickets is
very uncommon, the authors proposed a link between defects in vitamin D
metabolism and increased risk of multiple sclerosis. Ramagopalan et al.
(2010) found that all 3 Norwegian patients with VDDR1A and MS reported
by Torkildsen et al. (2008) had the MS risk allele HLA-DRB1*15, with the
vitamin D response element in the promoter. Two patients were homozygous
for the HLA risk allele.

By whole-exome sequencing of 43 probands with multiple sclerosis, each
from a family in which 4 or more individuals had MS, Ramagopalan et al.
(2011) failed to find a common loss of function or predicted damaging
variant. However, 1 patient had a heterozygous loss-of-function
arg389-to-his (R389H; 609506.0012) substitution (dbSNP rs118204009) in
the CYP27B1 gene that was found to be present in all 4 (100%) affected
family members and 33% of genotyped unaffected family members. This
variant was also found to be overtransmitted in an analysis of 3,046
parent-affected child MS trios (p = 1 x 10(-5)) and in a further 422
parent-affected sib MS pairs (p = 0.046). None of the individuals had
evidence of vitamin D hydroxylation-deficient rickets. Two additional
pathogenic variants in the CYP27B1 gene, E189G (609506.0017) and L343F
(609506.0016), were found to be overtransmitted in the larger trio
cohort. None of the individuals with any of these mutations were of
French Canadian origin. Serum from 1 individual with the R389H mutation
showed low calcitriol levels compared to controls, and 3 of 96
additional MS patients with low calcitriol levels were found to carry
putative pathogenic CYP27B1 variants, suggesting that heterozygosity for
loss of function alleles results in lower calcitriol levels. Overall,
the findings supported a causative role for variation in the CYP27B1
gene in MS risk, which correlated with the geographic latitude gradient
that appeared to influence disease risk.

Ban et al. (2013) found no significant association between the R389H and
L343F variants in the CYP27B1 gene and MS among 495 multiplex families,
2,092 single affected families, and 4,594 patients with the disorder
compared to 3,583 controls. The populations were from the U.K., U.S.,
and Norway. Barizzone et al. (2013) also found no association between
the R389H variant and MS among 2,608 patients and 1,987 controls from
Italy and Belgium. Plasma measurement of 1 MS patient and 1 unaffected
individual, both of whom had a heterozygous R389H variant, showed no
decrease in 1,25-dihydroxyvitamin D levels. Screening of the CYP27B1
coding sequence in 134 Italian multiplex MS families revealed no
mutations. Ban et al. (2013) and Barizzone et al. (2013) independently
concluded that mutant CYP27B1 alleles do not influence the risk of
developing MS.

Gandhi et al. (2010) measured the whole blood mRNA transcriptome for 99
untreated MS patients, comprising 43 with primary progressive MS, 20
with secondary progressive MS, and 36 with relapsing remitting MS, and
45 age-matched healthy controls. The authors genotyped more than 300,000
SNPs for 115 of these samples. Transcription from genes regulating
translation, oxidative phosphorylation, immune synapse, and antigen
presentation pathways was markedly increased in all forms of MS.
Expression of genes predominantly expressed in T cells was also
upregulated in MS. A T-cell gene signature predicted disease state with
a concordance index of 0.79 with age and gender as covariables, but the
signature was not associated with clinical course or disability. The
authors concluded that dysregulation of T cells can be detected in the
whole blood of untreated MS patients, and they supported targeting of
activated T-cells in therapy for all forms of MS.

DIAGNOSIS

There appear to be rare forms of multiple sclerosis or multiple
sclerosis-like diseases that are mendelian; see 169500. Also see spastic
ataxia (108600) for a disorder that closely resembles disseminated
sclerosis. Ekbom (1966) described a familial form of multiple sclerosis
associated with narcolepsy (223300): in 1 family 2 brothers had MS,
combined in 1 with narcolepsy; in another family 3 sisters had MS, and
of the 3 one had narcolepsy. As noted in 161400, narcolepsy shows a
strong association with HLA-DR2.

Natowicz and Bejjani (1994) provided a review of genetic disorders that
masquerade as multiple sclerosis. They usefully divided these into
biochemically defined disorders and clinically defined disorders. The
former included Leber hereditary optic neuropathy with associated
neurologic features; the latter included hereditary spastic paraparesis
and hereditary adult-onset leukodystrophy (169500).

In CSF samples from 19 of 29 patients with MS, Irani et al. (2006)
identified a 12.5-kD cleavage product of cystatin C (CST3; 604312)
formed by the removal of the last 8 amino acids from the C terminus. The
12.5-kD peak was not identified in CSF samples from 27 patients with
unrelated neurologic disorders or 27 additional patients with acute
transverse myelitis, but lower levels than that of MS patients were
found in some patients with HIV infection. Overall, the presence of the
12.5-kD peak provided 66% sensitivity and 100% specificity for the
detection of MS. Irani et al. (2006) suggested that cleavage of cystatin
C may be an adaptive host response.

Del Boccio et al. (2007) and Hansson et al. (2007) independently
identified a 12.5-kD product of cystatin C that is formed by degradation
of the first 8 N-terminal amino acids resulting from inappropriate
storage at -20 degrees Celsius. Compared to controls, no significant
differences in cystatin C fragments were observed in the CSF of 21 and
43 MS patients, respectively. Both groups concluded that CSF cystatin C
is not a useful marker for the diagnosis of MS. In a response, Wheeler
et al. (2007) stated that they had stored the CSF samples at -80 degrees
Celsius (Irani et al., 2006), and that the cleavage site identified by
them was at the C-terminal. A more accurate measurement indicated that
the C-terminal fragment was 12,546.6 Da and the N-terminal fragment was
12,561.3 Da, suggesting that there are 2 similarly sized, yet distinct
fragments of cystatin C.

Sawcer et al. (2010) discussed the utility of genetic screening for
predicting risk of multiple sclerosis and refining diagnosis or
predicting prognosis of multiple sclerosis. They noted that the
epidemiologic and genetic evidence on MS supported a polygenic/biometric
model with a multiplicative model of risk. The authors concluded that
very few individuals would carry a level of genetically determined risk
that would allow confident prediction. Sawcer et al. (2010) emphasized
that the overall prevalence of MS in the general population is low, that
familial clustering is modest, and that, with the exception of the MHC
locus, most all MS risk alleles identified are anonymous variants,
thereby reducing the utility of genetic screening efforts at this time.

HISTORY

- Exclusion Studies

Salier et al. (1986) found a combined influence on MS of 2 genetic loci
that are unlinked but related to immune response: Gm (IGHG1; 147100) and
HLA. Gaiser et al. (1987) found a negative association with a RFLP
related to a genomic Ig gamma-1 probe. Among patients with myasthenia
gravis and others with Graves disease, the frequency of the marker was
the same as in controls. In a study using 15 immunoglobulin heavy chain
constant and variable region polymorphisms in 34 sib pairs concordant
for MS and in 23 sporadic MS patients, Walter et al. (1991) found no
significant association between MS and constant region genes but a
significant correlation between MS and a polymorphism of the VH2-5 gene
segment. This segment is located in the proximal part of the variable
region within a distance of 180 to 360 kb from the constant region.

Hall (1983) raised a question of arthrogryposis (e.g., 208100) occurring
causally in offspring of women with MS. McKusick (1983) saw clubfoot in
3 children and full-blown arthrogryposis multiplex congenita in the
youngest of these, the fourth child of a woman with MS.

Beall et al. (1989) and Seboun et al. (1989) presented evidence that a
MS susceptibility gene lies near or within the T-cell receptor
beta-chain locus (TCRB; see 186930). Charmley et al. (1991) presented
further evidence based on the patterns of linkage disequilibrium. Utz et
al. (1993) analyzed the role of T-cell receptor (TCR) genes in multiple
sclerosis by comparing TCR usage in monozygotic twins who were either
concordant or discordant in response to self and foreign antigens. They
found that after stimulation with myelin basic protein or tetanus
toxoid, control twin sets as well as concordant twin sets selected
similar V-alpha chains. Only the discordant twin sets selected different
TCRs after stimulation with antigens. The study involved 6 monozygotic
twin pairs. Two were concordant (both affected) and 2 discordant (1 twin
affected) for MS. One control twin set was discordant for bipolar mental
disorder and a second was clinically healthy. It is not clear whether
the discordance was due to the effect of the disease or represented a
preexisting condition. One possibility is that it was preexisting and
contributed to the susceptibility of the affected twin; another
possibility is the occurrence of somatic changes during development,
especially alterations in the TCR genes.

By study of 49 MS sib pairs using restriction fragment length
polymorphisms and of 82 sib pairs using a microsatellite repeat
polymorphism, Eoli et al. (1994) found no evidence of linkage between
the TCRA locus (see 186880) and the disease; in neither case did
genotype or haplotype sharing differ significantly from expected rates.
Stratification of patients according to DR15 status did not alter the
distribution of haplotypes in affected sibs.

Adopting a candidate gene approach, Tienari et al. (1992) used
polymorphism of the myelin basic protein (MBP; 159430) gene, which is
located on chromosome 18, in genetic linkage and association studies in
a Finnish population. They investigated 21 MS families, 51 additional
unrelated patients with definite MS, and 85 controls. All subjects were
from an area with an exceptional familial clustering of MS. Magnetic
resonance imaging (MRI) was used to examine subclinical disease in
symptom-free family members. In the association analysis, the allele
frequencies between MS patients and controls differed significantly (p =
0.000049), the difference being attributable mainly to a higher
frequency of a 1.27-kb allele among patients. In the linkage analysis,
based on an autosomal dominant model and penetrance of 0.05, a maximum
lod score of 3.42 at theta = 0.00 was obtained when patients with optic
neuritis and their symptom-free sibs with abnormal MRI findings were
classified as 'affected.' In the set of Finnish multiplex families in
which they had previously found linkage between MS susceptibility and 2
independent loci, MBP and HLA, Tienari et al. (1994) performed linkage
analysis conditional on 2 loci contributing to the disease. Responding
to a comment by Colover (1993), Tienari et al. (1993) suggested that if
demyelination in multiple sclerosis is secondary to reduced
remyelination capacity and if MBP is a candidate gene, several
genetically determined factors might be involved: low levels of MBP
expression in multiple sclerosis patients; differences in MBP isoforms;
and amino acid variation in MBP leading to a functionally defective
protein. In Utah, Rose et al. (1993) likewise studied linkage between MS
and the polymorphic tetranucleotide repeat region immediately 5-prime to
exon 1 of MBP used in the Finnish study. In studies of 14 multiplex
families with 36 affected individuals, linkage analysis, using either an
autosomal dominant or an autosomal recessive model, showed negative
cumulative lod scores. Thus, linkage between MS and MBP could not be
demonstrated. Eoli et al. (1994) studied the multiallelic polymorphism
adjacent to the gene for MBP in Italian patients. In a study of 54
sporadic patients, 55 control subjects, and 18 families with 2 or more
affected individuals, they found no evidence for either association or
linkage according to autosomal dominant or autosomal recessive modes of
inheritance between MBP and MS in the Italian population. Wood et al.
(1994) used 2 adjacent amplification fragment length polymorphisms to
examine the relationship of myelin basic protein to multiple sclerosis
in the United Kingdom. No allelic association was found in a comparison
of 77 cases and 88 controls, nor was there evidence for linkage in 73
affected sib pairs, using the methods of identity by descent and
identity by state.

ANIMAL MODEL

The chronic variant of experimental allergic encephalomyelitis (EAE), a
T cell-mediated autoimmune disease in rodents, represents a relevant
animal model for MS given the chronic relapsing disease course and
inflammatory changes observed in the CNS in these demyelinating
disorders. Kuokkanen et al. (1996) tested human chromosomal regions
homologous to murine loci predisposing to EAE as candidate regions for
genetic susceptibility to MS. Three chromosomal regions (1p23-q22,
5p14-p12, and Xq13.2-q22) were screened in 21 Finnish multiplex MS
families, most originating from a high-risk region in western Finland.
Several markers yielded positive lod scores on 5p14-p12, syntenic to the
murine locus Eae2. Thus, Kuokkanen et al. (1996) concluded that there
may be a predisposing locus for MS in this chromosomal region.

In transgenic mice, Madsen et al. (1999) expressed 3 human components
involved in T-cell recognition of an MS-related autoantigen presented by
the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II
candidate MS susceptibility gene found among individuals of European
descent; a T-cell receptor (TCR) from an MS patient-derived T-cell clone
specific for the HLA-DR2-bound immunodominant myelin basic protein (MBP;
159430) 84-101 peptide; and the human CD4 coreceptor (186940). The amino
acid sequence of MBP 84-102 peptide was the same in both human and mouse
MBP. Following administration of the MBP peptide, together with adjuvant
and pertussis toxin, transgenic mice developed focal central nervous
system inflammation and demyelination that led to clinical
manifestations and disease courses resembling those seen in MS.
Spontaneous disease was observed in 4% of mice. When DR2 and TCR double
transgenic mice were backcrossed twice to RAG2 (179616)-deficient mice,
the incidence of spontaneous disease increased, demonstrating that T
cells specific for the HLA-DR2-bound MBP peptide are sufficient and
necessary for the development of disease. Madsen et al. (1999) concluded
that their study provided evidence that HLA-DR2 can mediate both induced
and spontaneous disease resembling MS by presenting a MBP self-peptide
to T cells.

The cytokine ciliary neurotrophic factor (CNTF; 118945), which was
originally identified as a survival factor for isolated neurons,
promotes differentiation, maturation, and survival of oligodendrocytes.
To investigate the role of endogenous CNTF in inflammatory demyelinating
disease, Linker et al. (2002) studied myelin oligodendrocyte
glycoprotein (MOG)-induced EAE in CNTF-deficient and wildtype C57BL/6
mice. Disease was more severe in CNTF-deficient mice and recovery was
poor, with a 60% decrease in the number of proliferating oligodendrocyte
precursor cells and a more than 50% increase in the rate of
oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and
axonal damage were more severe in CNTF-deficient mice. These specific
pathologic features could be prevented by treatment with an antiserum
against tumor necrosis factor-alpha, suggesting that endogenous CNTF may
counterbalance this effect of TNF-alpha. Thus, Linker et al. (2002)
identified a factor that modulates, in an inflammatory environment,
glial cell survival and is an outcome determinant of EAE.

Kalyvas and David (2004) found high expression of phospholipase A2
(PLA2; see 172411) in endothelial and immune cells within CNS lesions
from EAE mice throughout the disease course. Inhibition of PLA2 resulted
in a significant reduction in the onset and progression of the disease,
and was correlated with decreased expression of multiple chemokine and
chemokine receptor genes. Kalyvas and David (2004) suggested that
cytosolic PLA2 plays a central role in inflammation in EAE.

Arnett et al. (2004) demonstrated that Olig1 (606385) has an essential
role in oligodendrocyte differentiation and consequent remyelination in
the context of white matter injury. Olig1 -/- mice exhibited failure of
remyelination of induced lesions, contrasting dramatically with the
extensive remyelination of normal controls. The authors demonstrated a
genetic requirement for Olig1 in repairing the types of lesions that
occur in patients with multiple sclerosis.

IL12 is composed of p35 (IL12A; 161560) and p40 (IL12B) subunits, while
IL23 is composed of a p19 subunit (IL23A; 605580) and the IL12 p40
subunit. Cua et al. (2003) generated mice lacking only IL23 (p19 -/-),
only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them
with MOG in an EAE model of multiple sclerosis. The p19 -/- mice were
generated by completely removing the p19 locus. Mice lacking p19 or p40
were resistant to development of EAE, whereas mice lacking only p35 were
at least as susceptible as wildtype mice. Exogenous IL23 delivered into
the CNS, but not intravenously, 2 days before expected onset of disease
reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in
the latter was delayed and disease was less severe. Administration of
recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8,
also induced intense EAE, suggesting that IL12 promotes the development
of Th1 cells, while IL23 is required for subsequent inflammatory events.
MOG immunization induced Th1 cells and proinflammatory cytokines in p19
-/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was
observed. Flow cytometric and real-time PCR analyses demonstrated the
entry of Th1 cells into the CNS in the absence of IL23, without the
recruitment of additional T cells or macrophages or the activation of
resident microglia. During EAE, IL23R (607562) and IL12RB1 (601604) were
coexpressed by inflammatory macrophages, whereas resident microglia
expressed only IL12RB1. Although resident microglia and inflammatory
macrophages produced IL23, only inflammatory macrophages responded to
IL23. In contrast, IL12 was produced primarily by inflammatory
macrophages, and both macrophages and microglia had the potential to
respond to IL12. Cua et al. (2003) concluded that IL12 promotes the
development of naive T cells, while IL23 mediates late-stage
inflammation and seems to be necessary for chronic inflammation.

Friese et al. (2008) noted that HLA-A3 and HLA-B7 had been found in
increased frequencies in individuals with MS, but that these
associations were later thought to be due to strong linkage
disequilibrium with HLA-DR2, encoded by HLA-DRB1*1501, which showed an
even stronger association with MS. However, HLA-A*310, which encodes
HLA-A3, was found to double the risk of MS, independently of HLA-DR2. In
contrast, risk conferred by HLA-A3 or HLA-DR2 is halved in individuals
bearing HLA-A*0201, encoding HLA-A2. To study mechanisms of MS
susceptibility, Friese et al. (2008) generated a humanized mouse model
with mice expressing HLA-A3 or HLA-A2 and a myelin-specific autoreactive
T-cell receptor, termed 2D1-TCR, derived from an MS patient. Only 4% of
mice doubly transgenic for HLA-A3 and 2D1-TCR developed MS-like disease
spontaneously, but they developed disease more frequently and severely
after immunization with myelin proteolipid protein (PLP; 300401), which
is presented by HLA-A3. CNS infiltration by Cd4- and Cd8-positive T
cells showed that the latter were involved in disease induction and the
former in disease progression. Mice expressing HLA-A2 had diminished
T-cell responsiveness to PLP, and flow cytometry revealed modulated
2D1-TCR expression. Friese et al. (2008) concluded that MHC class I
alleles and CD8-positive T cells are directly implicated in the
pathogenesis of MS, and that a network of MHC interactions shapes the
risk of MS in each individual.

Tan et al. (2009) found that Pacap (ADCYAP1; 102980)-deficient mice
developed heightened clinical and pathologic manifestations in response
to induced experimental autoimmune encephalitis compared to wildtype
mice. The increased sensitivity of the mutant mice was accompanied by
enhanced mRNA expression of proinflammatory cytokines, chemokines and
chemotactic factor receptors, and downregulation of antiinflammatory
cytokines in the spinal cord. There was also a decrease in regulatory T
cells associated with increased lymphocyte proliferation and decreased
TGFB1 secretion in lymph nodes. The results demonstrated that endogenous
Pacap provides protection in a mouse model of autoimmune encephalitis,
and also identified PACAP as an intrinsic regulator of regulatory T cell
abundance after inflammation.

Using intravital 2-photon imaging and flow cytometric analysis in a
Lewis rat model of EAE, Bartholomaus et al. (2009) demonstrated the
interactive processes between effector T cells and cerebral structures
from their first arrival to the manifestation of autoimmune disease.
Initially, T cells were arrested at leptomeningeal vessels and crawled
preferentially against the blood flow along the luminal surface. After
diapedesis, the cells continued their scan on the abluminal vascular
surface and the underlying pial membrane. There, T cells encountered
phagocytes that presented antigens, both foreign as well as myelin
proteins. Over time, there was an increase in the number and duration of
T cell-antigen presenting cell contacts, with increased expression of
Ifng and Il17 in the meninges and brain parenchyma and intensified
invasion of non-specific T cells in the CNS mediating further
inflammation. Bartholomaus et al. (2009) concluded that autoimmune
lesions are initiated around pial veins, with incoming T cells
systematically scanning first the inner, then the outer vascular
surfaces on at least 3 distinct levels.

- Therapeutic Strategies

Chabas et al. (2001) used microarray analysis of spinal cords from rats
paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of
multiple sclerosis, and identified increased osteopontin (OPN)
transcripts. Osteopontin-deficient mice were resistant to progressive
EAE and had frequent remissions, and myelin-reactive T cells in Opn -/-
mice produced more interleukin-10 (124092) and less interferon-gamma
(147570) than in Opn +/+ mice. Chabas et al. (2001) concluded that
osteopontin appears to regulate T helper cell-1 (TH1)-mediated
demyelinating disease, and may offer a potential target in blocking
development of progressive MS.

Butzkueven et al. (2002) showed that the neurotrophic cytokine leukemia
inhibitory factor (LIF; 159540) directly prevents oligodendrocyte death
in animal models of MS, oligodendrocytes being the cells responsible for
myelination in the CNS. They also demonstrated that this therapeutic
effect complements endogenous LIF receptor (LIFR; 151443) signaling,
which already serves to limit oligodendrocyte loss during immune attack.
The results provided a novel approach for the treatment of MS.

Youssef et al. (2002) tested atorvastatin (Lipitor) in chronic and
relapsing EAE, a CD4+ Th1-mediated CNS demyelinating disease model of
multiple sclerosis. Youssef et al. (2002) showed that oral atorvastatin
prevented or reversed chronic and relapsing paralysis. Atorvastatin
induced STAT6 (601512) phosphorylation and secretion of Th2 cytokines
IL4 (147780), IL5 (147850), and IL10, and of TGF-beta (190180).
Conversely, STAT4 (600558) phosphorylation was inhibited and secretion
of Th1 cytokines, including IL2 (147680), IL12 (see IL12B; 161561),
IFN-gamma, and TNF-alpha, was suppressed. Atorvastatin promoted
differentiation of Th0 cells into Th2 cells. In adoptive transfer, these
Th2 cells protected recipient mice from EAE induction. Atorvastatin
reduced CNS infiltration and MHC class II (see 142857) expression.
Treatment of microglia inhibited IFNG-inducible transcription at
multiple MHC class II transactivator promoters and suppressed class II
upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of
CD40 (109535), CD80 (112203), and CD86 (601020) costimulatory molecules.
L-mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's
effects on antigen-presenting cells (APC) and T cells. Atorvastatin
treatment of either APC or T cells suppressed antigen-specific T-cell
activation. Youssef et al. (2002) concluded that atorvastatin has
pleiotropic immunomodulatory effects involving both APC and T cell
compartments.

Chen et al. (2006) found that treating mice with anti-Il23 p19, like
anti-Il23 p40, effectively blocked both acute EAE and EAE relapse.
Anti-Il23 treatment blocked invasion of the CNS by T cells and
inflammatory macrophages, and it reduced serum Il17 (603149) levels and
CNS expression of Ifng, Ip10 (CXCL10; 147310), Il17, Il6 (147620), and
Tnf mRNA. Anti-Il23 prevented EAE relapse, at least in part, by
inhibiting epitope spreading. Although anti-Il17 blocked EAE relapse, it
did not significantly reduce the number of infiltration foci, suggesting
no effect on inflammatory cell migration but a possible downregulation
of inflammatory effector cell function.

Beraud et al. (2006) demonstrated that intracerebroventricular infusion
of BgK-F6A, a selective blocker of the potassium channel Kcna1 (176260),
greatly reduced neurologic deficits in EAE rats. BgK-F6A increased the
frequency of miniature excitatory postsynaptic currents in cultured rat
hippocampal cells without affecting T-cell activation. Treated rats
showed decreased ventriculomegaly, decreased cerebral injury, and
preservation of brain bioenergetics compared to control rats.

In mice with EAE, Yang et al. (2010) found that inhibition of Nogoa (see
604475) using small interfering RNA (siRNA) resulted in suppression of
Nogoa expression and functional neurologic recovery. Myelin-specific
T-cell proliferation and cytokine production were unchanged, and the
response was determined to result from increased axonal repair, as
demonstrated by enhanced GAP43 (162060)-positive axons in the lesions.
Of note, mice given the treatment at the time of disease onset showed a
better response than those given treatment at the time of disease
induction, indicating that a compromised blood-brain barrier was
necessary for the siRNA to gain access to the central nervous system.
The findings indicated that inhibition of NogoA can promote neuronal
repair and functional recovery in a mouse model of MS.

Using the relapsing-remitting mouse model of spontaneously developing
experimental autoimmune encephalomyelitis, Berer et al. (2011) showed
that the commensal gut flora, in the absence of pathogenic agents, is
essential in triggering immune processes, leading to a
relapsing-remitting autoimmune disease driven by myelin-specific CD4+ T
cells. Berer et al. (2011) showed further that recruitment and
activation of autoantibody-producing B cells from the endogenous immune
repertoire depends on availability of the target autoantigen, myelin
oligodendrocyte glycoprotein (MOG; 159465), and commensal microbiota.
Berer et al. (2011) concluded that their observations identified a
sequence of events triggering organ-specific autoimmune disease and that
these processes may offer novel therapeutic targets.

*FIELD* SA
Bird (1975); Ebers et al. (1981); Rife (1954); Sadovnick and Macleod
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*FIELD* CS
INHERITANCE:
Multifactorial

HEAD AND NECK:
[Eyes];
Vision loss, monocular;
Diplopia

GENITOURINARY:
[Bladder];
Incomplete bladder emptying;
Incontinence;
Hesitancy

NEUROLOGIC:
[Central nervous system];
Spasticity;
High intensity area in white matter on head MRI;
Depression;
Emotional lability;
Cognitive dysfunction;
Scattered CNS demyelination;
[Peripheral nervous system];
Weakness;
Paresthesias;
Sensory loss;
Incoordination

LABORATORY ABNORMALITIES:
Increased CSF immunoglobulin levels;
Oligoclonal bands in CSF;
Myelin basic protein in CSF

MISCELLANEOUS:
Onset 20-55 years of age;
Women affected more than men (3:2);
Association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly
demonstrated in high-risk (northern European) populations.

MOLECULAR BASIS:
Susceptibility conferred by mutations in the protein tyrosine phosphatase,
receptor type, c polypeptide gene (PTPRC, 151460.0001);
Susceptibility conferred by mutations in the MHC class II transactivator
gene (MHC2TA, 600005.0007)

*FIELD* CN
Joanna S. Amberger - updated: 6/29/2005
Ada Hamosh - reviewed: 5/15/2000
Kelly A. Przylepa - revised: 2/21/2000

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

*FIELD* ED
joanna: 12/29/2011
joanna: 6/29/2005
joanna: 5/15/2000
kayiaros: 2/21/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
George E. Tiller - updated: 8/21/2013
Cassandra L. Kniffin - updated: 3/12/2013
Ada Hamosh - updated: 9/4/2012
Ada Hamosh - updated: 8/10/2012
Cassandra L. Kniffin - updated: 6/19/2012
Cassandra L. Kniffin - updated: 4/4/2012
Paul J. Converse - updated: 2/23/2012
Ada Hamosh - updated: 2/8/2012
Ada Hamosh - updated: 12/20/2011
George E. Tiller - updated: 11/15/2011
Ada Hamosh - updated: 8/24/2011
Cassandra L. Kniffin - updated: 8/2/2011
Cassandra L. Kniffin - updated: 4/18/2011
Cassandra L. Kniffin - updated: 6/25/2010
Ada Hamosh - updated: 6/11/2010
Cassandra L. Kniffin - updated: 4/15/2010
Cassandra L. Kniffin - updated: 3/24/2010
Cassandra L. Kniffin - updated: 12/29/2009
Cassandra L. Kniffin - updated: 12/22/2009
Paul J. Converse - updated: 11/30/2009
Cassandra L. Kniffin - updated: 11/13/2009
Cassandra L. Kniffin - updated: 10/15/2009
George E. Tiller - updated: 8/24/2009
Cassandra L. Kniffin - updated: 8/6/2009
Cassandra L. Kniffin - updated: 6/23/2009
Cassandra L. Kniffin - updated: 6/8/2009
Cassandra L. Kniffin - updated: 5/18/2009
George E. Tiller - updated: 5/14/2009
Cassandra L. Kniffin - updated: 4/14/2009
Marla J. F. O'Neill - updated: 12/10/2008
Paul J. Converse - updated: 12/3/2008
Ada Hamosh - updated: 9/8/2008
Cassandra L. Kniffin - updated: 2/7/2008
Cassandra L. Kniffin - updated: 1/7/2008
Cassandra L. Kniffin - updated: 11/13/2007
Cassandra L. Kniffin - updated: 10/16/2007
Cassandra L. Kniffin - updated: 9/13/2007
Ada Hamosh - updated: 8/20/2007
Ada Hamosh - updated: 10/24/2006
George E. Tiller - updated: 9/5/2006
Paul J. Converse - updated: 6/20/2006
Cassandra L. Kniffin - updated: 4/12/2006
Paul J. Converse - updated: 2/9/2006
Marla J. F. O'Neill - updated: 2/2/2006
Cassandra L. Kniffin - updated: 11/29/2005
Victor A. McKusick - updated: 10/13/2005
George E. Tiller - updated: 9/9/2005
Cassandra L. Kniffin - updated: 3/4/2005
Ada Hamosh - updated: 2/7/2005
Cassandra L. Kniffin - updated: 12/21/2004
Victor A. McKusick - updated: 11/12/2004
Cassandra L. Kniffin - updated: 9/17/2004
Cassandra L. Kniffin - updated: 8/27/2004
Jane Kelly - updated: 7/30/2004
Victor A. McKusick - updated: 1/8/2004
George E. Tiller - updated: 10/13/2003
Cassandra L. Kniffin - updated: 3/13/2003
Victor A. McKusick - updated: 2/28/2003
Ada Hamosh - updated: 2/21/2003
Victor A. McKusick - updated: 2/12/2003
Cassandra L. Kniffin - updated: 1/3/2003
Ada Hamosh - updated: 11/20/2002
Michael B. Petersen - updated: 11/7/2002
Cassandra L. Kniffin - updated: 10/15/2002
George E. Tiller - updated: 9/19/2002
Paul J. Converse - updated: 9/4/2002
Victor A. McKusick - updated: 8/23/2002
George E. Tiller - updated: 8/14/2002
Victor A. McKusick - updated: 6/4/2002
Cassandra L. Kniffin - updated: 5/24/2002
Victor A. McKusick - updated: 3/21/2002
Victor A. McKusick - updated: 2/26/2002
Victor A. McKusick - updated: 1/9/2002
Ada Hamosh - updated: 1/4/2002
Michael B. Petersen - updated: 11/28/2001
Michael B. Petersen - updated: 11/21/2001
Victor A. McKusick - updated: 10/23/2001
Victor A. McKusick - updated: 9/12/2001
Victor A. McKusick - updated: 11/27/2000
Victor A. McKusick - updated: 10/23/2000
Orest Hurko - updated: 12/2/1999
Ada Hamosh - updated: 11/1/1999
Wilson H. Y. Lo - updated: 10/26/1999
Orest Hurko - updated: 9/22/1999
Orest Hurko - reorganized: 9/22/1999
Orest Hurko - updated: 7/2/1999
Orest Hurko - updated: 3/5/1999
Victor A. McKusick - updated: 2/20/1999
Orest Hurko - updated: 11/25/1998
Victor A. McKusick - updated: 11/3/1998
Victor A. McKusick - updated: 2/11/1998
Orest Hurko - updated: 11/6/1996
Moyra Smith - updated: 8/9/1996
Orest Hurko - updated: 2/22/1996

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

*FIELD* ED
carol: 01/06/2014
ckniffin: 1/6/2014
mgross: 10/7/2013
mgross: 10/4/2013
alopez: 8/21/2013
alopez: 3/15/2013
ckniffin: 3/12/2013
terry: 12/19/2012
terry: 9/24/2012
alopez: 9/6/2012
terry: 9/4/2012
carol: 8/13/2012
terry: 8/10/2012
carol: 6/20/2012
ckniffin: 6/19/2012
carol: 4/5/2012
terry: 4/4/2012
ckniffin: 4/4/2012
terry: 2/23/2012
alopez: 2/13/2012
terry: 2/8/2012
alopez: 1/11/2012
terry: 12/22/2011
terry: 12/20/2011
alopez: 11/15/2011
terry: 11/8/2011
alopez: 8/25/2011
terry: 8/24/2011
wwang: 8/9/2011
ckniffin: 8/2/2011
terry: 4/25/2011
wwang: 4/22/2011
ckniffin: 4/18/2011
wwang: 3/25/2011
ckniffin: 3/22/2011
alopez: 11/10/2010
wwang: 9/24/2010
ckniffin: 8/2/2010
wwang: 7/6/2010
ckniffin: 6/25/2010
ckniffin: 6/24/2010
alopez: 6/16/2010
terry: 6/11/2010
wwang: 5/5/2010
ckniffin: 4/15/2010
carol: 3/25/2010
ckniffin: 3/24/2010
wwang: 1/14/2010
wwang: 1/13/2010
ckniffin: 12/29/2009
ckniffin: 12/22/2009
mgross: 11/30/2009
wwang: 11/30/2009
ckniffin: 11/13/2009
wwang: 11/13/2009
ckniffin: 10/15/2009
alopez: 9/14/2009
wwang: 8/24/2009
wwang: 8/17/2009
ckniffin: 8/6/2009
wwang: 7/20/2009
ckniffin: 6/23/2009
wwang: 6/22/2009
ckniffin: 6/8/2009
wwang: 5/21/2009
ckniffin: 5/18/2009
alopez: 5/14/2009
wwang: 4/28/2009
ckniffin: 4/14/2009
terry: 3/3/2009
carol: 2/16/2009
wwang: 2/13/2009
ckniffin: 2/9/2009
terry: 1/12/2009
carol: 12/10/2008
mgross: 12/3/2008
carol: 10/24/2008
alopez: 9/17/2008
terry: 9/8/2008
wwang: 2/25/2008
ckniffin: 2/7/2008
wwang: 1/22/2008
ckniffin: 1/7/2008
wwang: 11/20/2007
ckniffin: 11/13/2007
wwang: 10/19/2007
ckniffin: 10/16/2007
alopez: 9/24/2007
ckniffin: 9/13/2007
alopez: 8/31/2007
terry: 8/20/2007
alopez: 11/6/2006
terry: 10/24/2006
alopez: 9/5/2006
mgross: 6/20/2006
wwang: 4/19/2006
ckniffin: 4/12/2006
mgross: 2/9/2006
wwang: 2/3/2006
terry: 2/2/2006
wwang: 12/6/2005
ckniffin: 11/29/2005
joanna: 10/17/2005
alopez: 10/14/2005
terry: 10/13/2005
alopez: 9/30/2005
terry: 9/9/2005
terry: 6/24/2005
tkritzer: 3/8/2005
ckniffin: 3/4/2005
alopez: 2/9/2005
wwang: 2/7/2005
tkritzer: 12/29/2004
ckniffin: 12/21/2004
alopez: 11/16/2004
terry: 11/12/2004
tkritzer: 10/4/2004
ckniffin: 9/17/2004
tkritzer: 9/7/2004
ckniffin: 8/27/2004
tkritzer: 8/6/2004
terry: 7/30/2004
carol: 5/24/2004
cwells: 1/12/2004
terry: 1/8/2004
cwells: 10/13/2003
carol: 6/11/2003
tkritzer: 6/9/2003
ckniffin: 5/29/2003
carol: 4/21/2003
tkritzer: 4/8/2003
tkritzer: 4/7/2003
ckniffin: 3/13/2003
tkritzer: 3/7/2003
tkritzer: 3/5/2003
terry: 2/28/2003
alopez: 2/24/2003
terry: 2/21/2003
cwells: 2/13/2003
cwells: 2/12/2003
cwells: 1/3/2003
cwells: 11/20/2002
terry: 11/18/2002
cwells: 11/7/2002
alopez: 11/4/2002
carol: 10/18/2002
ckniffin: 10/15/2002
cwells: 9/19/2002
mgross: 9/4/2002
tkritzer: 8/28/2002
tkritzer: 8/26/2002
terry: 8/23/2002
cwells: 8/14/2002
terry: 6/4/2002
carol: 5/24/2002
ckniffin: 5/23/2002
alopez: 3/27/2002
terry: 3/21/2002
mgross: 3/7/2002
terry: 2/26/2002
alopez: 1/16/2002
mcapotos: 1/9/2002
terry: 1/4/2002
cwells: 12/5/2001
cwells: 11/29/2001
cwells: 11/28/2001
cwells: 11/21/2001
carol: 11/5/2001
mcapotos: 10/30/2001
terry: 10/23/2001
carol: 9/17/2001
mcapotos: 9/13/2001
mcapotos: 9/12/2001
carol: 9/10/2001
mgross: 11/28/2000
terry: 11/27/2000
mcapotos: 11/6/2000
mcapotos: 11/2/2000
terry: 10/23/2000
terry: 2/8/2000
carol: 12/3/1999
terry: 12/2/1999
alopez: 11/3/1999
terry: 11/1/1999
carol: 10/26/1999
carol: 9/22/1999
mgross: 7/2/1999
carol: 3/5/1999
carol: 2/23/1999
terry: 2/20/1999
carol: 11/25/1998
carol: 11/9/1998
terry: 11/3/1998
alopez: 2/11/1998
dholmes: 2/6/1998
mark: 11/11/1997
terry: 8/6/1997
mark: 7/16/1997
alopez: 7/7/1997
joanna: 6/23/1997
jamie: 11/22/1996
mark: 11/6/1996
terry: 10/23/1996
terry: 8/9/1996
marlene: 8/8/1996
mark: 8/7/1996
terry: 8/5/1996
terry: 4/15/1996
mark: 2/22/1996
terry: 2/9/1996
terry: 10/30/1995
mark: 9/13/1995
carol: 3/1/1995
mimadm: 6/25/1994
warfield: 4/8/1994
carol: 10/19/1993

MIM 151460
*RECORD*
*FIELD* NO
151460
*FIELD* TI
*151460 PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, C; PTPRC
;;LEUKOCYTE-COMMON ANTIGEN; LCA;;
read moreT200 GLYCOPROTEIN;;
CD45;;
CD45R;;
Ly5, HOMOLOG OF;;
B220
*FIELD* TX

CLONING

T200 glycoprotein, also known as leukocyte-common antigen (LCA) or CD45,
is a major high molecular mass leukocyte cell surface molecule. It is an
integral membrane protein tyrosine phosphatase (Charbonneau et al.,
1988; Tonks et al., 1988, 1990). T200 is expressed on all hematopoietic
cells except mature red cells and their immediate progenitors. It is not
found, however, on other differentiated tissues; thus, it can be used as
an antigenic marker with which to identify undifferentiated
hematopoietic tumors. Ralph et al. (1987) isolated cDNA clones of T200
glycoprotein from a variety of human lymphoid cells, deduced the
complete primary structure of the molecule from the cDNA sequence of
these clones, and identified 3 structural variants which probably arise
by cell-type-specific alternative splicing.

Thomas et al. (1987) presented evidence that variants of T200
glycoprotein are generated in the mouse by alternative mRNA splicing.

Jacobsen et al. (2000) stated that the CD45 glycoprotein exists in
multiple isoforms, depending on alternative splicing of exons 4, 5, and
6. The corresponding protein domains are characterized by the binding of
monoclonal antibodies specific for CD45RA (exon 4), CD45RB (exon 5),
CD45RC (exon 6), and CD45RO (exons 4 to 6 spliced out). In T cells,
alternative splicing of CD45 is regulated so that naive or unprimed T
cells predominantly express CD45RA-positive isoforms and switch to
expression of CD45RO upon activation. CD45RO expression is correlated
with the memory T-cell phenotype (Akbar et al., 1988).

GENE FUNCTION

Trowbridge (1991) reviewed the information on CD45 indicating that it is
a prototype for transmembrane protein-tyrosine phosphatase (PTP).
Fischer et al. (1991) reviewed protein-tyrosine phosphatases in general
and CD45 specifically. CD45 is found only in hematopoietic cells where
it comprises up to 10% of the cell surface. It is a prime example of a
receptor-linked PTP of type I.

Irie-Sasaki et al. (2001) showed that CD45 suppresses JAK kinases (see
147795) and negatively regulates cytokine receptor signaling. Targeted
disruption of the CD45 gene leads to enhanced cytokine and interferon
receptor-mediated activation of JAKs and STAT proteins. In vitro, CD45
directly dephosphorylates and binds to JAKs. Functionally, CD45
negatively regulates interleukin-3-mediated cellular proliferation,
erythropoietin-dependent hematopoiesis, and antiviral responses in vitro
and in vivo. Irie-Sasaki et al. (2001) concluded that their data
identified an unexpected and novel function for CD45 as a hematopoietic
JAK phosphatase that negatively regulates cytokine receptor signaling.

Jacobsen et al. (2000) stated that CD45 is essential for activation of T
and B cells by mediating cell-to-cell contacts and regulating
protein-tyrosine kinases involved in signal transduction. CD45 is also
involved in integrin-mediated adhesion and migration of immune cells.
Mice and humans lacking CD45 expression are characterized by a block of
T-cell maturation (Kishihara et al., 1993; Kung et al., 2000).

Xu and Weiss (2002) noted that a negatively regulating ligand inducing
CD45 dimerization had not been identified to that time. They
hypothesized that spontaneous and isoform-differential homodimerization
could offer an alternative mechanism for regulating CD45. Immunoblot
analysis showed that RO isoform-enriched chemically crosslinked primary
T cells or transfected cells expressing RO homodimerize more efficiently
and rapidly than RAB and RABC isoforms. This homodimerization occurs in
existing cell surface monomers independently of the inhibitory wedge
domain and the transmembrane and intracellular domains. The dimerization
efficiency of RABC increased substantially after removal of the abundant
sialic acids on this isoform, but sialidase treatment did not further
enhance RO homodimerization. Expression of the isoforms in
O-glycosylation-defective cell lines showed that the dimerization
efficiency of RABC could approach that of RO. TCR stimulation results in
lower calcium mobilization and lower soluble inositol phosphate
increases in RO isoform-expressing cells compared to RABC-expressing
cells. Xu and Weiss (2002) concluded that the smallest CD45 isoform, RO,
homodimerizes with the highest efficiency, resulting in decreased
signaling via the T cell receptor. Preferential homodimerization may
account for its expression at the termination of the primary T cell
response, whereas expression of RABC (RA) is required for activation of
naive T cells. They proposed that these results demonstrate the biologic
significance of alternative splicing and suggest a model for the
regulation of receptor-like protein tyrosine phosphatase (RPTP)
dimerization and function.

Using a short hairpin RNA interference screen, Oberdoerffer et al.
(2008) identified HNRNPLL (611208) as a critical inducible regulator of
CD45 alternative splicing. HNRNPLL showed upregulated expression in
stimulated T lymphocytes, bound CD45 transcripts, and was necessary and
sufficient for CD45 alternative splicing. Depletion or overexpression of
HNRNPLL in B- and T-cell lines and in primary T cells resulted in
reciprocal alteration of CD45RA and CD45RO expression. Exon array
analysis showed that HNRNPLL knockdown led to significant alternative
exon usage in 132 genes, including CD45. Analysis of cord blood (i.e.,
naive) T cells after activation showed significant alternative exon
usage in 36 of these genes, including elevated expression of exons 4 and
6 of CD45. Oberdoerffer et al. (2008) proposed that HNRNPLL induction
during hematopoietic cell activation and differentiation may allow cells
to rapidly shift their transcriptomes to favor proliferation and inhibit
cell death.

Shukla et al. (2011) provided evidence that CTCF (604167) can promote
inclusion of weak upstream exons by mediating local RNA polymerase II
pausing both in a mammalian model system for alternative splicing, CD45,
and genomewide. They further showed that CTCF binding to CD45 exon 5 is
inhibited by DNA methylation, leading to reciprocal effects on exon 5
inclusion. Shukla et al. (2011) concluded that their results provided a
mechanistic basis for developmental regulation of splicing outcome
through heritable epigenetic marks.

GENE STRUCTURE

Fernandez-Luna et al. (1991) isolated the CD45 gene in a single YAC
clone and estimated its size to be approximately 120 +/- 10 kb.

Jacobsen et al. (2000) stated that the CD45 gene contains 35 exons.

Timon and Beverley (2001) sequenced 2.7 kb of the 5-prime-flanking
region of the CD45 gene. By CAT and EMSA analysis, they determined that
the only region with promoter activity is localized within the highly
conserved first intron of the gene and is not tissue restricted.
Promoter activity is strongest in the 3-prime end of intron 1, and the
sequence lacks similarity with known promoters and initiators.
Five-prime RACE analysis identified an alternative exon 1, designated
1a, which, like exon 1b, can be spliced to exon 2, a structure also
observed in mouse.

MAPPING

By in situ hybridization, Ralph et al. (1987) demonstrated that the gene
encoding human T200 is located on chromosome 1q31-q32. By somatic cell
hybridization, Akao et al. (1987) confirmed the chromosomal assignment.
By physical mapping on a 610-kb YAC, Goff et al. (1999) determined that
the PTPRC gene colocalizes with marker D1S413 on chromosome 1q31-q32.

The smallest human T200 variant is homologous to Ly5 in the mouse (Saga
et al., 1986). Chromosome 1 of the mouse was found to be the site of the
gene or genes for at least 2 isoforms of Ly5 (Shen et al., 1985). Seldin
et al. (1987) studied variants of Ly5 in inbred and natural populations
of mice. Summarizing the data, Seldin et al. (1987) stated that 'genetic
and biochemical data favor the interpretation that a single gene on
distal chromosome 1 (of the mouse) encodes these Ly-5 isoforms.' The
gene is located in a region of the distal part of mouse chromosome 1
that carries many genes homologous to genes in human 1q21.3-q32 (Seldin
et al., 1988). Seldin et al. (1988) stated that CD45, the human
equivalent of Ly5, is located in band 1q31. They commented on the large
number of genes of immunologic interest clustered in this region. The
list includes the Ly17 gene, which encodes the Fc IgG1/IgG2A receptor
(Ravetch et al., 1986); the IGFR2 gene (146790) has been mapped to human
chromosome 1.

MOLECULAR GENETICS

In 3 of 4 independent case-control studies, Jacobsen et al. (2000)
demonstrated an association of a 77C-G SNP in the PTPRC gene
(151460.0001) with multiple sclerosis (MS; 126200). Furthermore, they
found that the PTPRC mutation was linked to and associated with the
disease in 3 MS nuclear families. However, studies by Vorechovsky et al.
(2001) Barcellos et al. (2001), Cocco et al. (2004), and Szvetko et al.
(2009) found no association between the PTPRC SNP and multiple
sclerosis.

Lynch and Weiss (2001) identified 4 distinct splice regulatory elements
within CD45 exon 4, with the strongest being exonic splicing silencer-1
(ESS1), which is disrupted by the 77C-G polymorphism. Functional
analysis showed that ESS1 normally functions to repress the weak 5-prime
splice site of exon 4. Lynch and Weiss (2001) concluded that proper
functioning of the immune system depends on a complex interplay of
regulatory activities that mediate appropriate splicing of CD45 exon 4.

Kung et al. (2000) studied a male child who presented at 2 months of age
with T-, B+, NK+ severe combined immunodeficiency (SCID; 608971) and
eventually succumbed to a B-cell lymphoma at 2 years of age. Lymph node
biopsies from the patient showed a lack of histologic organization and
germinal center formation, and stained thin sections from the lymph node
showed no expression of CD45. Indeed, CD45 expression was lacking on all
leukocytes. Kung et al. (2000) identified a large deletion in one allele
of the CD45 gene and a point mutation (151460.0002) in the other. A
population of peripheral blood T lymphocytes was greatly diminished and
unresponsive to mitogen stimulation. Despite normal B-lymphocyte
numbers, serum immunoglobulin levels decreased with age.

Tchilian et al. (2001) characterized a deletion mutation in the CD45
gene of a Kurdish infant with SCID, originally reported by Cale et al.
(1997), born to heterozygous, consanguineous parents. Despite successful
bone marrow transplantation at age 8 months, the patient died with
reactivated cytomegalovirus at age 10 months. RT-PCR and sequence
analysis identified a 6-bp deletion in exon 11 of the CD45 gene
(151460.0003) that resulted in the loss of glu339 and tyr340 in the
first fibronectin type III module of the extracellular domain. Flow
cytometric analysis demonstrated a lack of surface CD45 expression in
the patient and in CHO cells transfected with the mutant cDNA but not in
her parents or a healthy homozygous sib. Western blot analysis showed
that deletion of the 2 amino acids results in a markedly reduced
expression of the 220-kD protein. Genetic analysis of over 500
individuals from related and unrelated ethnic groups failed to detect
the mutation, suggesting it is not a common polymorphism. Computational
analysis of the structure of the mutant protein suggested that the lack
of tyr340 destabilizes the fibronectin module, leading to unfolding and
intracellular degradation. Tchilian et al. (2001) concluded that CD45
screening should be included in patients with otherwise unexplained
immunodeficiency.

In a patient with familial hemophagocytic lymphohistiocytosis (603553),
McCormick et al. (2003) identified a 77C-G polymorphism in exon A of the
CD45 gene which caused a defect in its splicing and cosegregated with a
thr435-to-met mutation in the PRF1 gene (T435M; 170280.0010). The
authors postulated that both mutations were involved in the disorder.

Stanton et al. (2003) described a polymorphism in exon 6 of the PTPRC
gene, 138A-G, with a very high prevalence in Japanese and Korean
populations. The polymorphism results in a thr47-to-ala (T47A) amino
acid change at a potential O- and N-linked glycosylation site. The
138A-G variant was present at a frequency of 23.7% in the Japanese
population but absent in Caucasoids. Peripheral blood T cells from
individuals carrying the variant showed a significant decrease in the
proportion of cells expressing the A, B, and C isoforms of CD45 and a
high frequency of CD45R0+ cells. These phenotypic alterations in the
138A-G carriers may lead to changes in ligand binding, homodimerization
of CD45, and altered immune responses, suggesting the involvement of
natural selection in controlling the 138A-G carrier frequency. Analysis
of exon 6 138A-C and exon 4 77C-G (151460.0001) variants in different
populations showed striking differences in the frequency and
distribution of these mutations, suggesting effects of natural
selection. Boxall et al. (2004) reported that the 138A-G polymorphism
caused altered CD45 isoform expression, promoting splicing towards low
molecular weight CD45 isoforms. The frequency of A/G heterozygotes was
significantly reduced among patients with autoimmune Graves disease
(275000) or hepatitis B infection, whereas G/G homozygotes were absent
from a cohort of Hashimoto thyroiditis (140300) patients. Individuals
carrying a G allele exhibited altered cytokine production in vitro and
an increased proportion of memory T cells. Boxall et al. (2004)
suggested that the 138G variant allele may strongly influence these
diseases by modulation of immune mechanisms and that it may have
achieved its high frequency as a result of a natural selection probably
related to pathogen resistance.

Motta-Mena et al. (2011) noted that a conserved sequence motif, the
activation-responsive sequence (ARS), is common to CD45 variable exons
4, 5, and 6 and drives repression of these exons in both resting and
activated T cells. The ARS consists of imperfect tandem repeats of the
sequence MCYYGCA, where M is C or A and Y is C or T. The ARS core motif
is embedded in distinct sequence contexts in each of the CD45 variable
exons, with the context of exon 4, termed ESS1, being most complex.
Using a systematic mutational analysis of sequences within ESS1,
Motta-Mena et al. (2011) demonstrated that mutations in the ESS1 element
could be grouped into distinct functional classes that could be
explained, in part, by disruption of binding by distinct proteins. The
77C-G polymorphism, which occurs in the ARS motif of exon 4, weakly
altered binding of the primary CD45 regulatory protein, HNRNPL (603083),
but greatly abrogated binding of HNRNPK (600712) and HNRNPE2 (PCBP2;
601210). Although neither HNRNPK and HNRNPE2 played a prominent role in
CD45 splicing under wildtype conditions, both proteins had a
compensatory role when the activity of HNRNPL was compromised.
Motta-Mena et al. (2011) proposed that the loss of redundant control by
HNRNPK and HNRNPE2 provides a molecular mechanism for the effect of the
77C-G polymorphism.

ANIMAL MODEL

Majeti et al. (2000) reported the phenotype of mice with a single point
mutation, glu613 to arg (E613R), that inactivated the inhibitory wedge
of Cd45. The E613R mutation caused polyclonal lymphocyte activation
leading to lymphoproliferation and severe autoimmune nephritis with
autoantibody production, resulting in death. Both homozygotes and
heterozygotes developed pathology, indicating genetic dominance of
E613R. The dramatic phenotype of mice with the E613R mutation
demonstrated the in vivo importance of negative regulation of CD45 by
dimerization, supporting the model for regulation of CD45, and
receptor-like transmembrane protein tyrosine phosphatases (RPTPs) in
general.

Hesslein et al. (2006) observed normal NK cell function, including
cytolytic activity mediated by immunoreceptor tyrosine-based activation
motif (ITAM)-dependent receptors (e.g., TYROBP; 604142), in Cd45 -/-
mice. However, cytokine and chemokine secretion mediated by these
receptors was severely diminished. RT-PCR analysis showed deficient
cytokine and chemokine expression at the mRNA level, and Western blot
analysis showed deficient MAP kinase (e.g., MAP2K1; 176872) activation.
Hesslein et al. (2006) concluded that CD45-dependent regulation of
ITAM-dependent signaling pathways is essential for NK cell-mediated
cytokine production, but not for cytolytic activity.

*FIELD* AV
.0001
HEPATITIS C VIRUS, SUSCEPTIBILITY TO
PTPRC, 77C-G

In a patient with multiple sclerosis (MS; 126200), Jacobsen et al.
(2000) identified a heterozygous C-to-G transversion at nucleotide 77 of
exon 4 of the PTPRC gene (Thude et al., 1995). Although the variation
did not change the encoded amino acids, it prohibited splicing of exon 4
pre-mRNA. The SNP was associated with MS in 3 of 4 independent
case-control studies, yielding p values ranging from 1.5 x 10(-4) to
0.034. Jacobsen et al. (2000) found that the mutation was linked to and
associated with the disease in 3 MS nuclear families. However, studies
by Vorechovsky et al. (2001), Barcellos et al. (2001), Cocco et al.
(2004), and Szvetko et al. (2009) found no association between the PTPRC
SNP and multiple sclerosis.

Vorechovsky et al. (2001) also found no association between the 77C-G
SNP and patients with common variable immunodeficiency (CVID) or IgA
deficiency (IgAD) and over 1,000 controls. They found no difference in
the frequency of the 77G allele in patients and controls in these
disorders with a strong autoimmune component in etiology.

Wood et al. (2002) found no evidence of association between this
mutation and susceptibility to type I diabetes mellitus (222100) or
Graves disease (275000). Johanneson et al. (2002) found no evidence of
association between this mutation and susceptibility to systemic lupus
erythematosus (152700).

Dawes et al. (2006) found that there were twice as many 77C-G
heterozygotes among hepatitis C virus (HCV; see 609532)-infected
patients than in a healthy UK control population; no 77C-G homozygotes
were observed in either group. In addition, there were twice as many
77C-G heterozygotes among chronic HCV carriers than in individuals who
resolved HCV infection. FACs and immunoblot analyses showed that
lymphocytes, particularly CD8 (see 186910)-positive T cells, from 77C-G
heterozygotes had a significantly increased proportion of
CD45RA-positive cells compared with controls. Individuals heterozygous
for 77C-G also showed more rapid dephosphorylation of tyr505 of LCK
(153390) after in vitro stimulation. Transgenic mice with Cd45
expression mimicking that in human 77C-G heterozygotes had an altered
Cd8 cell phenotype and more rapid proliferative responses and Lck
activation, as in humans. Dawes et al. (2006) concluded that 77C-G
heterozygotes have an altered T-cell phenotype and greater
susceptibility to HCV infection and severe HCV-induced fibrosis.

Motta-Mena et al. (2011) found that the 77C-G polymorphism, which occurs
in the ARS motif of exon 4, weakly altered binding of the primary CD45
regulatory protein, HNRNPL (603083), but greatly abrogated binding of
HNRNPK (600712) and HNRNPE2 (PCBP2; 601210). Although neither HNRNPK and
HNRNPE2 played a prominent role in CD45 splicing under wildtype
conditions, both proteins had a compensatory role when the activity of
HNRNPL was compromised. Motta-Mena et al. (2011) proposed that the loss
of redundant control by HNRNPK and HNRNPE2 provides a molecular
mechanism for the effect of the 77C-G polymorphism.

.0002
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
PTPRC, IVS13DS, G-A, +1

In a child with T-, B+, NK+ SCID (608971), Kung et al. (2000) identified
compound heterozygosity at the PTPRC gene: the allele inherited from the
mother carried a large deletion, while the other allele had a G-to-A
transition at position +1 of the donor splice site of intron 13. Since
the father did not carry the mutation, the allele had presumably
undergone spontaneous mutation (although, for the privacy of the family,
paternity was not proven genetically).

.0003
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
PTPRC, 6-BP DEL, NT1168

In a Kurdish infant with T-, B+, NK+ SCID (608971), Tchilian et al.
(2001) identified a 6-bp deletion at nucleotide 1168 in exon 11 of the
PTPRC gene, leading to the deletion of 2 amino acids in the
extracellular domain fibronectin type III module. The mutation resulted
in a lack of surface PTPRC expression.

.0004
SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
PTPRC, LYS540TER

Roberts et al. (2012) identified a boy with T cell-negative, B
cell-positive, NK cell-positive SCID (608971) who was born to
nonconsanguineous parents. The patient lacked CD45 expression and was
successfully treated by maternal bone marrow transplantation at age 10
months. At age 5 years, the patient appeared to be phenotypically
normal. SNP array and whole exome sequencing analysis revealed that the
patient's mother was heterozygous for an A-to-T transversion at
nucleotide 1618 of the CD45 gene, resulting in a lys540-to-ter (K540X)
substitution. The paternal alleles exhibited no detectable mutation. The
patient had no change in copy number, but loss of heterozygosity, for
the entire length of chromosome 1, indicating that SCID was caused by
uniparental disomy (UPD) with isodisomy of the entire maternal
chromosome 1 bearing the mutant allele. Nonlymphoid cells retained UPD
of the entire maternal chromosome 1. The faulty chromosome also carried
mutations in 7 other genes predicted to have deleterious effects on
protein function. The authors noted that in the year preceding the birth
of the patient, the parents had experienced miscarriage of a 7-week-old
embryo with trisomy of all chromosomes, suggesting potentially defective
meiosis in 1 or both parents. However, the patient did have a healthy
older sister and younger brother. Roberts et al. (2012) proposed that
UPD should be considered in SCID and other recessive disorders,
particularly when only 1 patient appears to be homozygous for an
abnormal gene found in only 1 parent.

*FIELD* RF
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17. Kung, C.; Pingel, J. T.; Heikinheimo, M.; Klemola, T.; Varkila,
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hemophagocytic lymphohistiocytosis and CD45 abnormal splicing. Am.
J. Med. Genet. 117A: 255-260, 2003.

21. Motta-Mena, L. B.; Smith, S. A.; Mallory, M. J.; Jackson, J.;
Wang, J.; Lynch, K. W.: A disease-associated polymorphism alters
splicing of the human CD45 phosphatase gene by disrupting combinatorial
repression by heterogeneous nuclear ribonucleoproteins (hnRNPs). J.
Biol. Chem. 286: 20043-20053, 2011.

22. Oberdoerffer, S.; Moita, L. F.; Neems, D.; Freitas, R. P.; Hacohen,
N.; Rao, A.: Regulation of CD45 alternative splicing by heterogeneous
ribonucleoprotein, hnRNPLL. Science 321: 686-691, 2008.

23. Ralph, S. J.; Thomas, M. L.; Morton, C. C.; Trowbridge, I. S.
: Structural variants of human T200 glycoprotein (leukocyte-common
antigen). EMBO J. 6: 1251-1257, 1987.

24. Ravetch, J. V.; Luster, A. D.; Weinshank, R.; Kochan, J.; Pavlovec,
A.; Portnoy, D. A.; Hulmes, J.; Pan, T.-C. E.; Unkeless, J. C.: Structural
heterogeneity and functional domains of murine immunoglobulin G Fc
receptors. Science 234: 718-725, 1986.

25. Roberts, J. L.; Buckley, R. H.; Luo, B.; Pei, J.; Lapidus, A.;
Peri, S.; Wei, Q.; Shin, J.; Parrott, R. E.; Dunbrack, R. L., Jr.;
Testa, J. R.; Zhong, X.-P.; Wiest, D. L.: CD45-deficient severe combined
immunodeficiency caused by uniparental disomy. Proc. Nat. Acad. Sci. 109:
10456-10461, 2012.

26. Saga, Y.; Tung, J.-S.; Shen, F.-W.; Boyse, E. A.: Sequences of
Ly-5 cDNA: isoform-related diversity of Ly-5 mRNA. Proc. Nat. Acad.
Sci. 83: 6940-6944, 1986. Note: Erratum: Proc. Nat. Acad. Sci. 84:
1991 only, 1987.

27. Seldin, M. F.; D'Hoostelaere, L. A.; Steinberg, A. D.; Saga, Y.;
Morse, H. C., III: Allelic variants of Ly-5 in inbred and natural
populations of mice. Immunogenetics 26: 74-78, 1987.

28. Seldin, M. F.; Morse, H. C.; LeBoeuf, R. C.; Steinberg, A. D.
: Establishment of a molecular genetic map of distal mouse chromosome
1: further definition of a conserved linkage group syntenic with human
chromosome 1q. Genomics 2: 48-56, 1988.

29. Shen, F.-W.; Saga, Y.; Litman, G.; Freeman, G.; Tung, J.-S.; Cantor,
H.; Boyse, E. A.: Cloning of Ly-5 cDNA. Proc. Nat. Acad. Sci. 82:
7360-7363, 1985.

30. Shukla, S.; Kavak, E.; Gregory, M.; Imashimizu, M.; Shutinoski,
B.; Kashlev, M.; Oberdoerffer, P.; Sandberg, R.; Oberdoerffer, S.
: CTCF-promoted RNA polymerase II pausing links DNA methylation to
splicing. Nature 479: 74-79, 2011.

31. Stanton, T.; Boxall, S.; Hirai, K.; Dawes, R.; Tonks, S.; Yasui,
T.; Kanaoka, Y.; Yuldasheva, N.; Ishiko, O.; Bodmer, W.; Beverley,
P. C. L.; Tchilian, E. Z.: A high-frequency polymorphism in exon
6 of the CD45 tyrosine phosphatase gene (PTPRC) resulting in altered
isoform expression. Proc. Nat. Acad. Sci. 100: 5997-6002, 2003.

32. Szvetko, A. L.; Jones, A.; Mackenzie, J.; Tajouri, L.; Csurhes,
P. A.; Greer, J. M.; Pender, M. P.; Griffiths, L. R.: An investigation
of the C77G and C772T variations within the human protein tyrosine
phosphatase receptor type C gene for association with multiple sclerosis
in an Australian population. Brain Res. 1255: 148-152, 2009.

33. Tchilian, E. Z.; Wallace, D. L.; Wells, R. S.; Flower, D. R.;
Morgan, G.; Beverley, P. C. L.: A deletion in the gene encoding the
CD45 antigen in a patient with SCID. J. Immun. 166: 1308-1313, 2001.

34. Thomas, M. L.; Reynolds, P. J.; Chain, A.; Ben-Neriah, Y.; Trowbridge,
I. S.: B-cell variant of mouse T200 (Ly-5): evidence for alternative
mRNA splicing. Proc. Nat. Acad. Sci. 84: 5360-5363, 1987.

35. Thude, H.; Hundrieser, J.; Wonigeit, K.; Schwinzer, R.: A point
mutation in the human CD45 gene associated with defective splicing
of exon A. Europ. J. Immun. 25: 2101-2106, 1995.

36. Timon, M.; Beverley, P. C. L.: Structural and functional analysis
of the human CD45 gene (PTPRC) upstream region: evidence for a functional
promoter within the first intron of the gene. Immunology 102: 180-189,
2001.

37. Tonks, N. K.; Charbonneau, H.; Diltz, C. D.; Fischer, E. H.; Walsh,
K. A.: Demonstration that the leukocyte common antigen CD45 is a
protein tyrosine phosphatase. Biochemistry 27: 8695-8701, 1988.

38. Tonks, N. K.; Diltz, C. D.; Fischer, E. H.: CD45, an integral
membrane protein tyrosine phosphatase: characterization of enzyme
activity. J. Biol. Chem. 265: 10674-10680, 1990.

39. Trowbridge, I. S.: CD45: a prototype for transmembrane protein
tyrosine phosphatases. J. Biol. Chem. 266: 23517-23520, 1991.

40. Vorechovsky, I.; Kralovicova, J.; Tchilian, E.; Masterman, T.;
Zhang, Z.; Ferry, B.; Misbah, S.; Chapel, H.; Webster, D.; Hellgren,
D.; Anvret, M.; Hillert, J.; Hammarstrom, L.; Beverley, P. C.: Does
77C-G in PTPRC modify autoimmune disorders linked to the major histocompatibility
locus? Nature Genet. 29: 22-23, 2001.

41. Wood, J. P.; Bieda, K.; Segni, M.; Herwig, J.; Krause, M.; Usadel,
K. H.; Badenhoop, K.: CD45 exon 4 point mutation does not confer
susceptibility to type 1 diabetes mellitus or Graves' disease. Europ.
J. Immunogenet. 29: 73-74, 2002.

42. Xu, Z.; Weiss, A.: Negative regulation of CD45 by differential
homodimerization of the alternatively spliced isoforms. Nature Immun. 3:
764-771, 2002.

*FIELD* CN
Paul J. Converse - updated: 8/20/2013
Paul J. Converse - updated: 3/12/2013
Ada Hamosh - updated: 11/29/2011
Paul J. Converse - updated: 11/11/2011
Cassandra L. Kniffin - updated: 2/9/2009
Paul J. Converse - updated: 8/28/2008
George E. Tiller - updated: 6/21/2007
Paul J. Converse - updated: 9/21/2006
Paul J. Converse - updated: 6/14/2006
Cassandra L. Kniffin - updated: 10/28/2004
Victor A. McKusick - updated: 6/19/2003
Victor A. McKusick - updated: 4/7/2003
Victor A. McKusick - updated: 12/23/2002
Paul J. Converse - updated: 7/23/2002
Victor A. McKusick - updated: 8/24/2001
Paul J. Converse - updated: 5/14/2001
Carol A. Bocchini - updated: 3/6/2001
Paul J. Converse - updated: 2/16/2001
Ada Hamosh - updated: 1/19/2001
Stylianos E. Antonarakis - updated: 1/3/2001
Victor A. McKusick - updated: 11/27/2000

*FIELD* CD
Victor A. McKusick: 6/15/1987

*FIELD* ED
carol: 10/01/2013
mgross: 8/20/2013
mgross: 3/19/2013
terry: 3/12/2013
terry: 12/20/2012
alopez: 12/1/2011
terry: 11/29/2011
mgross: 11/18/2011
terry: 11/11/2011
wwang: 2/13/2009
ckniffin: 2/9/2009
mgross: 8/28/2008
terry: 8/28/2008
wwang: 6/22/2007
terry: 6/21/2007
mgross: 9/21/2006
mgross: 6/19/2006
terry: 6/14/2006
mgross: 10/3/2005
carol: 10/28/2004
ckniffin: 10/18/2004
joanna: 3/17/2004
alopez: 6/26/2003
terry: 6/19/2003
alopez: 6/10/2003
tkritzer: 4/7/2003
tkritzer: 12/26/2002
terry: 12/23/2002
alopez: 8/6/2002
alopez: 7/23/2002
alopez: 4/24/2002
terry: 8/24/2001
mgross: 5/14/2001
terry: 3/6/2001
carol: 3/6/2001
mgross: 2/21/2001
terry: 2/16/2001
mcapotos: 1/30/2001
carol: 1/22/2001
terry: 1/19/2001
mgross: 1/3/2001
mgross: 11/29/2000
mgross: 11/28/2000
terry: 11/27/2000
dkim: 7/23/1998
psherman: 4/10/1998
mark: 12/4/1995
carol: 3/12/1994
supermim: 3/16/1992
carol: 2/21/1992
carol: 2/12/1992
carol: 6/6/1991
supermim: 6/4/1991

MIM 608971
*RECORD*
*FIELD* NO
608971
*FIELD* TI
#608971 SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE,
B CELL-POSITIVE, NK CELL-POSITIVE
read more;;SCID, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-POSITIVE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that T
cell-negative (T-), B cell-positive (B+), natural killer cell-positive
(NK+) severe combined immunodeficiency (SCID) can be caused by
homozygous or compound heterozygous mutation in the interleukin-7
receptor gene (IL7R; 146661) on chromosome 5p13 or the CD45 gene
(151460) on chromosome 1q31. CD45-deficient T-, B+, NK+ SCID can also be
caused by uniparental disomy (see 151460.0004).

For a general phenotypic description and a discussion of genetic
heterogeneity of autosomal recessive SCID, see 601457.

CLINICAL FEATURES

Cale et al. (1997) reported a child, born of consanguineous Turkish
parents, who presented at age 2 months with a fever, rash,
hepatosplenomegaly, lymphadenopathy, pneumonitis, and pancytopenia.
Cytomegalovirus was detected in buffy coats, a liver biopsy,
nasopharyngeal aspirates, and urine. Laboratory investigation showed low
T-cell numbers and decreased immunoglobulins with normal B-cell numbers.
All nucleated hematopoietic cells had abnormal expression of CD45.

Puel et al. (1998) reported a patient who presented at age 2 months with
gastroesophageal reflux. Despite a Nissen fundoplication and pylorotomy,
he continued to cough and had poor weight gain. He also had recurrent
otitis, thrush, and a monilial diaper dermatitis. Immunologic evaluation
showed elevated IgG and IgA, both of which contained paraproteins. A
second unrelated patient presented at age 1 month with recurrent otitis
media resistant to treatment, persistent oral moniliasis, diarrhea,
fevers, and poor growth. At the age of 13 months, he developed
parainfluenza type 3. Both patients had normal or elevated numbers of
CD20+ B cells, greatly diminished CD3+ T cells, and normal or elevated
CD16+ NK cells. Proliferation to mitogen and allogeneic cells was
defective, but NK-cell killing of K562 target cells was normal. The
second patient received a haploidentical bone marrow transplant, with
which full immunologic reconstitution was achieved, and was clinically
well more than 4 years posttransplantation.

Roifman et al. (2000) reported 3 patients from a consanguineous Sicilian
family with markedly reduced circulating T cells, an absence of serum Ig
in spite of normal B-cell numbers, and preserved NK cell numbers and
function. Although the Ig levels and NK phenotype were distinct from
X-linked SCID (300400), the patients were indistinguishable clinically,
with severe and persistent viral and protozoal infections.

MOLECULAR GENETICS

- IL7R Gene

In 2 unrelated patients with T-, B+, NK+ SCID, Puel et al. (1998)
identified mutations in the IL7R gene (146661.0001-146661.0004).

In 3 affected patients from a consanguineous Sicilian family with T-,
B+, NK+ SCID, Roifman et al. (2000) identified a homozygous mutation in
the IL7R gene (146661.0005).

- CD45 Gene

In a patient with T-, B+, NK+ SCID previously reported by Cale et al.
(1997), Tchilian et al. (2001) identified a homozygous deletion in the
CD45 gene (151460.0003).

Roberts et al. (2012) identified a boy with CD45-deficient T-, B+, NK-
SCID who was born to nonconsanguineous parents. The patient was
successfully treated by maternal bone marrow transplantation at age 10
months and appeared to be phenotypically normal at age 5 years. The
patient's mother was heterozygous for a lys540-to-ter (K540X;
151460.0004) mutation in the CD45 gene, but the paternal alleles
exhibited no detectable mutation. The patient had no change in copy
number, but loss of heterozygosity, for the entire length of chromosome
1, indicating that SCID was caused by uniparental disomy (UPD) with
isodisomy of the entire maternal chromosome 1 bearing the mutant allele.
Nonlymphoid cells retained UPD of the entire maternal chromosome 1. The
faulty chromosome also carried mutations in 7 other genes predicted to
have deleterious effects on protein function. Roberts et al. (2012)
proposed that UPD should be considered in SCID and other recessive
disorders, particularly when only 1 patient appears to be homozygous for
an abnormal gene found in only 1 parent.

*FIELD* RF
1. Cale, C. M.; Klein, N. J.; Novelli, V.; Veys, P.; Jones, A. M.;
Morgan, G.: Severe combined immunodeficiency with abnormalities in
expression of the common leucocyte antigen, CD45. Arch. Dis. Child. 76:
163-164, 1997.

2. Puel, A.; Ziegler, S. F.; Buckley, R. H.; Leonard, W. J.: Defective
IL7R expression in T-B+NK+ severe combined immunodeficiency. Nature
Genet. 20: 394-397, 1998.

3. Roberts, J. L.; Buckley, R. H.; Luo, B.; Pei, J.; Lapidus, A.;
Peri, S.; Wei, Q.; Shin, J.; Parrott, R. E.; Dunbrack, R. L., Jr.;
Testa, J. R.; Zhong, X.-P.; Wiest, D. L.: CD45-deficient severe combined
immunodeficiency caused by uniparental disomy. Proc. Nat. Acad. Sci. 109:
10456-10461, 2012.

4. Roifman, C. M.; Zhang, J.; Chitayat, D.; Sharfe, N.: A partial
deficiency of interleukin-7R-alpha is sufficient to abrogate T-cell
development and cause severe combined immunodeficiency. Blood 96:
2803-2807, 2000.

5. Tchilian, E. Z.; Wallace, D. L.; Wells, R. S.; Flower, D. R.; Morgan,
G.; Beverley, P. C. L.: A deletion in the gene encoding the CD45
antigen in a patient with SCID. J. Immun. 166: 1308-1313, 2001.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive secondary to recurrent infections

HEAD AND NECK:
[Ears];
Otitis media;
[Mouth];
Candida albicans infection;
Thrush

RESPIRATORY:
[Lung];
Recurrent acute pneumonia

ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea

SKIN, NAILS, HAIR:
[Skin];
Dermatitis

IMMUNOLOGY:
Frequent opportunistic infections;
Lymphadenopathy;
Normal or elevated numbers of functional natural killer cells (NK);
Normal or elevated number of peripheral blood B cells;
Absent peripheral blood T cells;
Serum immunoglobulins may be absent, normal, or increased

MISCELLANEOUS:
Presents at 2 to 3 months of age;
Death within several months if untreated

MOLECULAR BASIS:
Caused by mutation in the interleukin 7 receptor gene (IL7R, 146661.0001);
Caused by mutation in the protein tyrosine phosphatase, receptor type,
c polypeptide gene (PTPRC, 151460.0002);
Caused by mutation in the CD3 antigen, delta subunit gene (CD3D,
186790.0001);
Caused by mutation in the CD3 antigen, epsilon subunit gene (CD3E,
186830.0003)

*FIELD* CD
Cassandra L. Kniffin: 10/20/2004

*FIELD* ED
joanna: 10/08/2010
ckniffin: 10/20/2004

*FIELD* CN
Paul J. Converse - updated: 8/20/2013
Marla J. F. O'Neill - updated: 1/19/2005

*FIELD* CD
Cassandra L. Kniffin: 10/15/2004

*FIELD* ED
ckniffin: 01/29/2014
mgross: 8/20/2013
terry: 3/15/2013
carol: 4/30/2012
terry: 3/21/2012
carol: 2/1/2005
terry: 1/19/2005
carol: 10/28/2004
ckniffin: 10/20/2004