RBCC Red Blood Cell Collection

C4B (CO4, CPAMD3) [Confidence: high (a blood group or CD marker)]
Complement C4-B (Basic complement C4; C3 and PZP-like alpha-2-macroglobulin domain-containing protein 3; Complement C4 beta chain; Complement C4-B alpha chain; C4a anaphylatoxin; C4b-B; C4d-B; Complement C4 gamma chain; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00418163
IPI00418163 C4B1 C4B1 membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a 2 extracellular n/a found at its expected molecular weight found at molecular weight

BGMUT chrg
139 chrg C4B C4B*1 3578G>A S1157N Ch1, 2, 4, 5; Rg1 6546707 Belt et al. the site of the first codon is not clear therefore nt substitutions are as shown in the reference sequence 2006-10-30 18:38:53.107 NA

UniProt P0C0L5
ID CO4B_HUMAN Reviewed; 1744 AA.
AC P0C0L5; A2BHY4; P01028; P78445; Q13160; Q13906; Q14033; Q14835;
read moreAC Q6U2E9; Q6U2G1; Q6U2I5; Q6U2L1; Q6U2L7; Q6U2L9; Q6U2M5; Q6VCV8;
AC Q96SA7; Q9NPK5; Q9UIP5;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 2.
DT 22-JAN-2014, entry version 92.
DE RecName: Full=Complement C4-B;
DE AltName: Full=Basic complement C4;
DE AltName: Full=C3 and PZP-like alpha-2-macroglobulin domain-containing protein 3;
DE Contains:
DE RecName: Full=Complement C4 beta chain;
DE Contains:
DE RecName: Full=Complement C4-B alpha chain;
DE Contains:
DE RecName: Full=C4a anaphylatoxin;
DE Contains:
DE RecName: Full=C4b-B;
DE Contains:
DE RecName: Full=C4d-B;
DE Contains:
DE RecName: Full=Complement C4 gamma chain;
DE Flags: Precursor;
GN Name=C4B; Synonyms=CO4, CPAMD3;
GN and
GN Name=C4B_2;
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 [GENOMIC DNA], AND VARIANT PHE-1317.
RC TISSUE=Blood;
RX PubMed=8575831; DOI=10.1007/s002510050059;
RA Ulgiati D., Townend D.C., Christiansen F.T., Dawkins R.L.,
RA Abraham L.J.;
RT "Complete sequence of the complement C4 gene from the HLA-A1, B8,
RT C4AQ0, C4B1, DR3 haplotype.";
RL Immunogenetics 43:250-252(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS TYR-347 AND ALA-907.
RA Rowen L., Dankers C., Baskin D., Faust J., Loretz C., Ahearn M.E.,
RA Banta A., Swartzell S., Smith T.M., Spies T., Hood L.;
RT "Sequence determination of 300 kilobases of the human class III MHC
RT locus.";
RL Submitted (OCT-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ALA-907 AND ASP-1073.
RA Sayer D., Puschendorf M., Wetherall J.;
RT "Molecular genetics of complement C4: implications for MHC evolution
RT and disease susceptibility gene mapping.";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS TYR-347
RP AND ALA-907.
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP PROTEIN SEQUENCE OF 680-756.
RX PubMed=6167582;
RA Moon K.E., Gorski J.P., Hugli T.E.;
RT "Complete primary structure of human C4a anaphylatoxin.";
RL J. Biol. Chem. 256:8685-8692(1981).
RN [6]
RP PROTEIN SEQUENCE OF 757-771 AND 980-990.
RX PubMed=1699796; DOI=10.1016/0014-5793(90)80389-Z;
RA Hessing M., van 't Veer C., Hackeng T.M., Bouma B.N., Iwanaga S.;
RT "Importance of the alpha 3-fragment of complement C4 for the binding
RT with C4b-binding protein.";
RL FEBS Lett. 271:131-136(1990).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 956-1336, AND VARIANT ASP-1073.
RC TISSUE=Liver;
RX PubMed=6546707; DOI=10.1016/0092-8674(84)90040-0;
RA Belt K.T., Carroll M.C., Porter R.R.;
RT "The structural basis of the multiple forms of human complement
RT component C4.";
RL Cell 36:907-914(1984).
RN [8]
RP PROTEIN SEQUENCE OF 957-1044.
RX PubMed=6978711;
RA Campbell R.D., Gagnon J., Porter R.R.;
RT "Amino acid sequence around the thiol and reactive acyl groups of
RT human complement component C4.";
RL Biochem. J. 199:359-370(1981).
RN [9]
RP PROTEIN SEQUENCE OF 957-1336.
RX PubMed=3696167; DOI=10.1016/0161-5890(87)90165-9;
RA Chakravarti D.N., Campbell R.D., Porter R.R.;
RT "The chemical structure of the C4d fragment of the human complement
RT component C4.";
RL Mol. Immunol. 24:1187-1197(1987).
RN [10]
RP PROTEIN SEQUENCE OF 990-1037.
RX PubMed=6950384; DOI=10.1073/pnas.78.12.7388;
RA Harrison R.A., Thomas M.L., Tack B.F.;
RT "Sequence determination of the thiolester site of the fourth component
RT of human complement.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:7388-7392(1981).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1055-1225 (ALLOTYPE C4B12).
RX PubMed=9759862;
RA Martinez-Quiles N., Paz-Artal E., Moreno-Pelayo M.A., Longas J.,
RA Ferre-Lopez S., Rosal M., Arnaiz-Villena A.;
RT "C4d DNA sequences of two infrequent human allotypes (C4A13 and C4B12)
RT and the presence of signal sequences enhancing recombination.";
RL J. Immunol. 161:3438-3443(1998).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1055-1225, AND VARIANTS ASN-1176;
RP VAL-1207 AND LEU-1210.
RX PubMed=14989716; DOI=10.1111/j.0001-2815.2004.00147.x;
RA Lopez-Goyanes A., Moreno M.A., Ferre S., Paz-Artal E.;
RT "C4d DNA sequence of complement C4B93 and recombination mechanisms for
RT its generation.";
RL Tissue Antigens 63:260-262(2004).
RN [13]
RP PROTEIN SEQUENCE OF 1199-1304.
RX PubMed=6832377; DOI=10.1016/0014-5793(83)80188-4;
RA Chakravarti D.N., Campbell R.D., Gagnon J.;
RT "Amino acid sequence of a polymorphic segment from fragment C4d of
RT human complement component C4.";
RL FEBS Lett. 154:387-390(1983).
RN [14]
RP PROTEIN SEQUENCE OF 1405-1431, AND SULFATION.
RX PubMed=3944109;
RA Hortin G., Sims H., Strauss A.W.;
RT "Identification of the site of sulfation of the fourth component of
RT human complement.";
RL J. Biol. Chem. 261:1786-1793(1986).
RN [15]
RP INVOLVEMENT IN C4BD AND SLE.
RX PubMed=3265961;
RA Wilson W.A., Perez M.C.;
RT "Complete C4B deficiency in black Americans with systemic lupus
RT erythematosus.";
RL J. Rheumatol. 15:1855-1858(1988).
RN [16]
RP FUNCTION, INVOLVEMENT OF HIS-1125 IN IMMUNOGLOBULIN-BINDING AND
RP HEMOLYSIS, AND MUTAGENESIS OF LEU-1120; SER-1121; ILE-1124 AND
RP HIS-1125.
RX PubMed=2395880; DOI=10.1073/pnas.87.17.6868;
RA Carroll M.C., Fathallah D.M., Bergamaschini L., Alicot E.M.,
RA Isenman D.E.;
RT "Substitution of a single amino acid (aspartic acid for histidine)
RT converts the functional activity of human complement C4B to C4A.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6868-6872(1990).
RN [17]
RP FUNCTION.
RX PubMed=8538770; DOI=10.1038/379177a0;
RA Dodds A.W., Ren X.D., Willis A.C., Law S.K.;
RT "The reaction mechanism of the internal thioester in the human
RT complement component C4.";
RL Nature 379:177-179(1996).
RN [18]
RP INVOLVEMENT IN SLE.
RX PubMed=10092831;
RA Lokki M.L., Circolo A., Ahokas P., Rupert K.L., Yu C.Y., Colten H.R.;
RT "Deficiency of human complement protein C4 due to identical frameshift
RT mutations in the C4A and C4B genes.";
RL J. Immunol. 162:3687-3693(1999).
RN [19]
RP REVIEW, DESCRIPTION OF ALLOTYPES, AND TISSUE SPECIFICITY.
RX PubMed=11367523; DOI=10.1016/S1567-5769(01)00019-4;
RA Blanchong C.A., Chung E.K., Rupert K.L., Yang Y., Yang Z., Zhou B.,
RA Moulds J.M., Yu C.Y.;
RT "Genetic, structural and functional diversities of human complement
RT components C4A and C4B and their mouse homologues, Slp and C4.";
RL Int. Immunopharmacol. 1:365-392(2001).
RN [20]
RP GLYCOSYLATION AT ASN-226.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1391, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1328, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [23]
RP STRUCTURAL BASIS OF POLYMORPHISM.
RX PubMed=2431902;
RA Yu C.Y., Belt K.T., Giles C.M., Campbell R.D., Porter R.R.;
RT "Structural basis of the polymorphism of human complement components
RT C4A and C4B: gene size, reactivity and antigenicity.";
RL EMBO J. 5:2873-2881(1986).
RN [24]
RP INVOLVEMENT IN SLE.
RX PubMed=17503323; DOI=10.1086/518257;
RA Yang Y., Chung E.K., Wu Y.L., Savelli S.L., Nagaraja H.N., Zhou B.,
RA Hebert M., Jones K.N., Shu Y., Kitzmiller K., Blanchong C.A.,
RA McBride K.L., Higgins G.C., Rennebohm R.M., Rice R.R., Hackshaw K.V.,
RA Roubey R.A., Grossman J.M., Tsao B.P., Birmingham D.J., Rovin B.H.,
RA Hebert L.A., Yu C.Y.;
RT "Gene copy-number variation and associated polymorphisms of complement
RT component C4 in human systemic lupus erythematosus (SLE): low copy
RT number is a risk factor for and high copy number is a protective
RT factor against SLE susceptibility in European Americans.";
RL Am. J. Hum. Genet. 80:1037-1054(2007).
CC -!- FUNCTION: Non-enzymatic component of the C3 and C5 convertases and
CC thus essential for the propagation of the classical complement
CC pathway. Covalently binds to immunoglobulins and immune complexes
CC and enhances the solubilization of immune aggregates and the
CC clearance of IC through CR1 on erythrocytes. C4A isotype is
CC responsible for effective binding to form amide bonds with immune
CC aggregates or protein antigens, while C4B isotype catalyzes the
CC transacylation of the thioester carbonyl group to form ester bonds
CC with carbohydrate antigens.
CC -!- FUNCTION: Derived from proteolytic degradation of complement C4,
CC C4a anaphylatoxin is a mediator of local inflammatory process. It
CC induces the contraction of smooth muscle, increases vascular
CC permeability and causes histamine release from mast cells and
CC basophilic leukocytes.
CC -!- SUBUNIT: Circulates in blood as a disulfide-linked trimer of
CC alpha, beta and gamma chains.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Complement component C4 is expressed at
CC highest levels in the liver, at moderate levels in the adrenal
CC cortex, adrenal medulla, thyroid gland,and the kidney, and at
CC lowest levels in the heart, ovary, small intestine, thymus,
CC pancreas and spleen. The extra-hepatic sites of expression may be
CC important for the local protection and inflammatory response.
CC -!- PTM: Prior to secretion, the single-chain precursor is
CC enzymatically cleaved to yield non-identical chains alpha, beta
CC and gamma. During activation, the alpha chain is cleaved by C1
CC into C4a and C4b, and C4b stays linked to the beta and gamma
CC chains. Further degradation of C4b by C1 into the inactive
CC fragments C4c and C4d blocks the generation of C3 convertase. The
CC proteolytic cleavages often are incomplete so that many structural
CC forms can be found in plasma.
CC -!- POLYMORPHISM: The complement component C4 is the most polymorphic
CC protein of the complement system. It is the product of 2 closely
CC linked and highly homologous genes, C4A and C4B. Once polymorphic
CC variation is discounted, the 2 isotypes differ by only 4 amino
CC acids at positions 1120-1125: PCPVLD for C4A and LSPVIH for C4B.
CC The 2 isotypes bear several antigenic determinants defining
CC Chido/Rodgers blood group system [MIM:614374]. Rodgers
CC determinants are generally associated with C4A allotypes, and
CC Chido with C4B. Variations at these loci involve not only
CC nucleotide polymorphisms, but also gene number and gene size. The
CC second copy of C4B gene present in some individuals has been
CC called C4B_2 by the HUGO Gene Nomenclature Committee (HGNC). Some
CC individuals may lack either C4A, or C4B gene. Partial deficiency
CC of C4A or C4B is the most commonly inherited immune deficiency
CC known in humans with a combined frequency over 31% in the normal
CC Caucasian population (PubMed:11367523).
CC -!- DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A
CC chronic, relapsing, inflammatory, and often febrile multisystemic
CC disorder of connective tissue, characterized principally by
CC involvement of the skin, joints, kidneys and serosal membranes. It
CC is of unknown etiology, but is thought to represent a failure of
CC the regulatory mechanisms of the autoimmune system. The disease is
CC marked by a wide range of system dysfunctions, an elevated
CC erythrocyte sedimentation rate, and the formation of LE cells in
CC the blood or bone marrow. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry. Interindividual copy-number variation (CNV) of complement
CC component C4 and associated polymorphisms result in different
CC susceptibilities to SLE. The risk of SLE susceptibility has been
CC shown to be significantly increased among subjects with only two
CC copies of total C4. A high copy number is a protective factor
CC against SLE.
CC -!- DISEASE: Complement component 4B deficiency (C4BD) [MIM:614379]: A
CC rare defect of the complement classical pathway associated with
CC the development of autoimmune disorders, mainly systemic lupus
CC with or without associated glomerulonephritis. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 anaphylatoxin-like domain.
CC -!- SIMILARITY: Contains 1 NTR domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA99717.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene
CC mutation database;
CC URL="http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system;=chrg";
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DR EMBL; U24578; AAA99717.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AF019413; AAB67980.1; -; Genomic_DNA.
DR EMBL; AY379860; AAR89087.1; -; Genomic_DNA.
DR EMBL; AY379862; AAR89089.1; -; Genomic_DNA.
DR EMBL; AY379864; AAR89091.1; -; Genomic_DNA.
DR EMBL; AY379866; AAR89093.1; -; Genomic_DNA.
DR EMBL; AY379868; AAR89095.1; -; Genomic_DNA.
DR EMBL; AY379870; AAR89097.1; -; Genomic_DNA.
DR EMBL; AY379872; AAR89099.1; -; Genomic_DNA.
DR EMBL; AY379874; AAR89101.1; -; Genomic_DNA.
DR EMBL; AY379876; AAR89103.1; -; Genomic_DNA.
DR EMBL; AY379878; AAR89105.1; -; Genomic_DNA.
DR EMBL; AY379880; AAR89107.1; -; Genomic_DNA.
DR EMBL; AY379882; AAR89109.1; -; Genomic_DNA.
DR EMBL; AY379884; AAR89111.1; -; Genomic_DNA.
DR EMBL; AY379886; AAR89113.1; -; Genomic_DNA.
DR EMBL; AY379888; AAR89115.1; -; Genomic_DNA.
DR EMBL; AY379890; AAR89117.1; -; Genomic_DNA.
DR EMBL; AY379892; AAR89119.1; -; Genomic_DNA.
DR EMBL; AY379894; AAR89121.1; -; Genomic_DNA.
DR EMBL; AY379896; AAR89123.1; -; Genomic_DNA.
DR EMBL; AY379898; AAR89125.1; -; Genomic_DNA.
DR EMBL; AY379900; AAR89127.1; -; Genomic_DNA.
DR EMBL; AY379902; AAR89130.1; -; Genomic_DNA.
DR EMBL; AY379904; AAR89132.1; -; Genomic_DNA.
DR EMBL; AY379906; AAR89134.1; -; Genomic_DNA.
DR EMBL; AY379908; AAR89136.1; -; Genomic_DNA.
DR EMBL; AY379910; AAR89138.1; -; Genomic_DNA.
DR EMBL; AY379912; AAR89139.1; -; Genomic_DNA.
DR EMBL; AY379914; AAR89142.1; -; Genomic_DNA.
DR EMBL; AY379916; AAR89144.1; -; Genomic_DNA.
DR EMBL; AY379918; AAR89145.1; -; Genomic_DNA.
DR EMBL; AY379920; AAR89148.1; -; Genomic_DNA.
DR EMBL; AY379922; AAR89150.1; -; Genomic_DNA.
DR EMBL; AY379924; AAR89151.1; -; Genomic_DNA.
DR EMBL; AY379959; AAR89163.1; -; Genomic_DNA.
DR EMBL; AY379936; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379937; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379938; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379939; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379940; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379941; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379942; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379943; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379944; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379945; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379946; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379947; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379948; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379949; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379950; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379951; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379952; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379953; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379954; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379955; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379956; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379957; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AY379958; AAR89163.1; JOINED; Genomic_DNA.
DR EMBL; AL049547; CAB89302.1; -; Genomic_DNA.
DR EMBL; BX679671; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; K02404; AAA59651.1; -; mRNA.
DR EMBL; U77887; AAK49811.1; -; Genomic_DNA.
DR EMBL; AY343497; AAQ99144.1; -; Genomic_DNA.
DR PIR; B20807; B20807.
DR RefSeq; NP_001002029.3; NM_001002029.3.
DR RefSeq; NP_001229752.1; NM_001242823.2.
DR UniGene; Hs.534847; -.
DR UniGene; Hs.720022; -.
DR ProteinModelPortal; P0C0L5; -.
DR SMR; P0C0L5; 20-670, 681-1420, 1455-1744.
DR DIP; DIP-47260N; -.
DR IntAct; P0C0L5; 1.
DR MEROPS; I39.951; -.
DR PhosphoSite; P0C0L5; -.
DR DMDM; 81175167; -.
DR SWISS-2DPAGE; P0C0L5; -.
DR PaxDb; P0C0L5; -.
DR PRIDE; P0C0L5; -.
DR DNASU; 721; -.
DR Ensembl; ENST00000375177; ENSP00000364321; ENSG00000228454.
DR Ensembl; ENST00000411583; ENSP00000407942; ENSG00000228267.
DR Ensembl; ENST00000435363; ENSP00000415941; ENSG00000224389.
DR Ensembl; ENST00000435500; ENSP00000412786; ENSG00000233312.
DR Ensembl; ENST00000449788; ENSP00000414200; ENSG00000236625.
DR GeneID; 100293534; -.
DR GeneID; 721; -.
DR KEGG; hsa:100293534; -.
DR KEGG; hsa:721; -.
DR UCSC; uc011doy.2; human.
DR CTD; 100293534; -.
DR CTD; 721; -.
DR GeneCards; GC06P031982; -.
DR GeneCards; GC06P031985; -.
DR H-InvDB; HIX0164690; -.
DR H-InvDB; HIX0164691; -.
DR H-InvDB; HIX0166073; -.
DR H-InvDB; HIX0166340; -.
DR H-InvDB; HIX0166869; -.
DR H-InvDB; HIX0167127; -.
DR H-InvDB; HIX0167359; -.
DR H-InvDB; HIX0167360; -.
DR HGNC; HGNC:1324; C4B.
DR HGNC; HGNC:42398; C4B_2.
DR MIM; 120820; gene.
DR MIM; 152700; phenotype.
DR MIM; 614374; phenotype.
DR MIM; 614379; phenotype.
DR neXtProt; NX_P0C0L5; -.
DR Orphanet; 169147; Immunodeficiency due to an early component of complement deficiency.
DR PharmGKB; PA25904; -.
DR eggNOG; COG2373; -.
DR HOVERGEN; HBG107123; -.
DR InParanoid; P0C0L5; -.
DR KO; K03989; -.
DR OMA; WISHYEL; -.
DR PhylomeDB; P0C0L5; -.
DR Reactome; REACT_6900; Immune System.
DR GeneWiki; Complement_component_4B; -.
DR NextBio; 20783275; -.
DR PRO; PR:P0C0L5; -.
DR ArrayExpress; P0C0L5; -.
DR Genevestigator; P0C0L5; -.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0006956; P:complement activation; TAS:Reactome.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IEA:GOC.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR Gene3D; 1.20.91.20; -; 1.
DR Gene3D; 2.60.40.690; -; 1.
DR InterPro; IPR009048; A-macroglobulin_rcpt-bd.
DR InterPro; IPR011626; A2M_comp.
DR InterPro; IPR002890; A2M_N.
DR InterPro; IPR011625; A2M_N_2.
DR InterPro; IPR000020; Anaphylatoxin/fibulin.
DR InterPro; IPR018081; Anaphylatoxin_comp_syst.
DR InterPro; IPR001840; Anaphylatoxn_comp_syst_dom.
DR InterPro; IPR001599; Macroglobln_a2.
DR InterPro; IPR019742; MacrogloblnA2_CS.
DR InterPro; IPR019565; MacrogloblnA2_thiol-ester-bond.
DR InterPro; IPR001134; Netrin_domain.
DR InterPro; IPR018933; Netrin_module_non-TIMP.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR InterPro; IPR008993; TIMP-like_OB-fold.
DR Pfam; PF00207; A2M; 1.
DR Pfam; PF07678; A2M_comp; 1.
DR Pfam; PF01835; A2M_N; 1.
DR Pfam; PF07703; A2M_N_2; 1.
DR Pfam; PF07677; A2M_recep; 1.
DR Pfam; PF01821; ANATO; 1.
DR Pfam; PF01759; NTR; 1.
DR Pfam; PF10569; Thiol-ester_cl; 1.
DR PRINTS; PR00004; ANAPHYLATOXN.
DR SMART; SM00104; ANATO; 1.
DR SMART; SM00643; C345C; 1.
DR SUPFAM; SSF47686; SSF47686; 1.
DR SUPFAM; SSF48239; SSF48239; 1.
DR SUPFAM; SSF49410; SSF49410; 1.
DR SUPFAM; SSF50242; SSF50242; 1.
DR PROSITE; PS00477; ALPHA_2_MACROGLOBULIN; 1.
DR PROSITE; PS01177; ANAPHYLATOXIN_1; 1.
DR PROSITE; PS01178; ANAPHYLATOXIN_2; 1.
DR PROSITE; PS50189; NTR; 1.
PE 1: Evidence at protein level;
KW Blood group antigen; Cleavage on pair of basic residues;
KW Complement pathway; Complete proteome; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Immunity; Inflammatory response;
KW Innate immunity; Polymorphism; Reference proteome; Secreted; Signal;
KW Sulfation; Systemic lupus erythematosus; Thioester bond.
FT SIGNAL 1 19
FT CHAIN 20 675 Complement C4 beta chain.
FT /FTId=PRO_0000042699.
FT PROPEP 676 679
FT /FTId=PRO_0000042700.
FT CHAIN 680 1446 Complement C4-B alpha chain.
FT /FTId=PRO_0000042701.
FT CHAIN 680 756 C4a anaphylatoxin.
FT /FTId=PRO_0000042702.
FT CHAIN 757 1446 C4b-B.
FT /FTId=PRO_0000042703.
FT CHAIN 957 1336 C4d-B.
FT /FTId=PRO_0000042704.
FT PROPEP 1447 1453
FT /FTId=PRO_0000042705.
FT CHAIN 1454 1744 Complement C4 gamma chain.
FT /FTId=PRO_0000042706.
FT DOMAIN 702 736 Anaphylatoxin-like.
FT DOMAIN 1595 1742 NTR.
FT MOD_RES 1417 1417 Sulfotyrosine.
FT MOD_RES 1420 1420 Sulfotyrosine.
FT MOD_RES 1422 1422 Sulfotyrosine.
FT CARBOHYD 226 226 N-linked (GlcNAc...).
FT CARBOHYD 862 862 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1328 1328 N-linked (GlcNAc...).
FT CARBOHYD 1391 1391 N-linked (GlcNAc...).
FT DISULFID 702 728 By similarity.
FT DISULFID 703 735 By similarity.
FT DISULFID 716 736 By similarity.
FT DISULFID 1595 1673 By similarity.
FT DISULFID 1618 1742 By similarity.
FT CROSSLNK 1010 1013 Isoglutamyl cysteine thioester (Cys-Gln).
FT VARIANT 347 347 S -> Y (in allotype C4B-long;
FT dbSNP:rs139889867).
FT /FTId=VAR_023729.
FT VARIANT 478 478 P -> L (in allotype C4B1-hi).
FT /FTId=VAR_069160.
FT VARIANT 907 907 T -> A (in allotype C4B-long and allotype
FT C4B2).
FT /FTId=VAR_023730.
FT VARIANT 1073 1073 G -> D (in allotype C4B2 and allotype
FT C4B5-Rg1).
FT /FTId=VAR_023731.
FT VARIANT 1176 1176 S -> N (in allotype C4B1a;
FT dbSNP:rs2746414).
FT /FTId=VAR_023732.
FT VARIANT 1207 1207 A -> V (in allotype C4B5-Rg1;
FT dbSNP:rs200888163).
FT /FTId=VAR_023734.
FT VARIANT 1210 1210 R -> L (in allotype C4B5-Rg1;
FT dbSNP:rs112683215).
FT /FTId=VAR_023735.
FT VARIANT 1317 1317 I -> F (in allotype C4B1-SC01).
FT /FTId=VAR_069161.
FT MUTAGEN 1120 1120 L->P: No effect on hemolytic activity,
FT nor on C1-dependent binding to IgG.
FT MUTAGEN 1121 1121 S->C: 30-40% decrease in hemolytic
FT activity and C1-dependent binding to IgG.
FT MUTAGEN 1124 1124 I->A: 50-60% decrease in hemolytic
FT activity and C1-dependent binding to IgG.
FT MUTAGEN 1125 1125 H->A: 20% decrease in hemolytic activity,
FT 2-fold increase in C1-dependent binding
FT to IgG.
FT MUTAGEN 1125 1125 H->D: 2.5-3 fold-decrease in hemolytic
FT activity, 3-fold increase in C1-dependent
FT binding to IgG.
FT CONFLICT 714 714 R -> S (in Ref. 3; AAR89101).
FT CONFLICT 729 729 R -> Q (in Ref. 3; AAR89127).
FT CONFLICT 980 981 VT -> LQ (in Ref. 1; AAA99717).
FT CONFLICT 1013 1013 Q -> E (in Ref. 8; AA sequence, 9; AA
FT sequence and 10; AA sequence).
FT CONFLICT 1109 1110 SQ -> IA (in Ref. 9; AA sequence).
FT CONFLICT 1271 1271 H -> V (in Ref. 9; AA sequence and 13; AA
FT sequence).
FT CONFLICT 1300 1300 R -> V (in Ref. 9; AA sequence and 13; AA
FT sequence).
FT CONFLICT 1654 1654 T -> RA (in Ref. 1; AAA99717).
FT CONFLICT 1698 1698 H -> Q (in Ref. 1; AAA99717).
SQ SEQUENCE 1744 AA; 192751 MW; E724B85F7FA673C5 CRC64;
MRLLWGLIWA SSFFTLSLQK PRLLLFSPSV VHLGVPLSVG VQLQDVPRGQ VVKGSVFLRN
PSRNNVPCSP KVDFTLSSER DFALLSLQVP LKDAKSCGLH QLLRGPEVQL VAHSPWLKDS
LSRTTNIQGI NLLFSSRRGH LFLQTDQPIY NPGQRVRYRV FALDQKMRPS TDTITVMVEN
SHGLRVRKKE VYMPSSIFQD DFVIPDISEP GTWKISARFS DGLESNSSTQ FEVKKYVLPN
FEVKITPGKP YILTVPGHLD EMQLDIQARY IYGKPVQGVA YVRFGLLDED GKKTFFRGLE
SQTKLVNGQS HISLSKAEFQ DALEKLNMGI TDLQGLRLYV AAAIIESPGG EMEEAELTSW
YFVSSPFSLD LSKTKRHLVP GAPFLLQALV REMSGSPASG IPVKVSATVS SPGSVPEVQD
IQQNTDGSGQ VSIPIIIPQT ISELQLSVSA GSPHPAIARL TVAAPPSGGP GFLSIERPDS
RPPRVGDTLN LNLRAVGSGA TFSHYYYMIL SRGQIVFMNR EPKRTLTSVS VFVDHHLAPS
FYFVAFYYHG DHPVANSLRV DVQAGACEGK LELSVDGAKQ YRNGESVKLH LETDSLALVA
LGALDTALYA AGSKSHKPLN MGKVFEAMNS YDLGCGPGGG DSALQVFQAA GLAFSDGDQW
TLSRKRLSCP KEKTTRKKRN VNFQKAINEK LGQYASPTAK RCCQDGVTRL PMMRSCEQRA
ARVQQPDCRE PFLSCCQFAE SLRKKSRDKG QAGLQRALEI LQEEDLIDED DIPVRSFFPE
NWLWRVETVD RFQILTLWLP DSLTTWEIHG LSLSKTKGLC VATPVQLRVF REFHLHLRLP
MSVRRFEQLE LRPVLYNYLD KNLTVSVHVS PVEGLCLAGG GGLAQQVLVP AGSARPVAFS
VVPTAATAVS LKVVARGSFE FPVGDAVSKV LQIEKEGAIH REELVYELNP LDHRGRTLEI
PGNSDPNMIP DGDFNSYVRV TASDPLDTLG SEGALSPGGV ASLLRLPRGC GEQTMIYLAP
TLAASRYLDK TEQWSTLPPE TKDHAVDLIQ KGYMRIQQFR KADGSYAAWL SRGSSTWLTA
FVLKVLSLAQ EQVGGSPEKL QETSNWLLSQ QQADGSFQDL SPVIHRSMQG GLVGNDETVA
LTAFVTIALH HGLAVFQDEG AEPLKQRVEA SISKASSFLG EKASAGLLGA HAAAITAYAL
TLTKAPADLR GVAHNNLMAM AQETGDNLYW GSVTGSQSNA VSPTPAPRNP SDPMPQAPAL
WIETTAYALL HLLLHEGKAE MADQAAAWLT RQGSFQGGFR STQDTVIALD ALSAYWIASH
TTEERGLNVT LSSTGRNGFK SHALQLNNRQ IRGLEEELQF SLGSKINVKV GGNSKGTLKV
LRTYNVLDMK NTTCQDLQIE VTVKGHVEYT MEANEDYEDY EYDELPAKDD PDAPLQPVTP
LQLFEGRRNR RRREAPKVVE EQESRVHYTV CIWRNGKVGL SGMAIADVTL LSGFHALRAD
LEKLTSLSDR YVSHFETEGP HVLLYFDSVP TSRECVGFEA VQEVPVGLVQ PASATLYDYY
NPERRCSVFY GAPSKSRLLA TLCSAEVCQC AEGKCPRQRR ALERGLQDED GYRMKFACYY
PRVEYGFQVK VLREDSRAAF RLFETKITQV LHFTKDVKAA ANQMRNFLVR ASCRLRLEPG
KEYLIMGLDG ATYDLEGHPQ YLLDSNSWIE EMPSERLCRS TRQRAACAQL NDFLQEYGTQ
GCQV
//

MIM 120820
*RECORD*
*FIELD* NO
120820
*FIELD* TI
*120820 COMPLEMENT COMPONENT 4B; C4B
;;COMPLEMENT COMPONENT 4F; C4F;;
BASIC C4;;
C4, CHIDO FORM
read more*FIELD* TX

CLONING

By the process of antigen-antibody crossed electrophoresis, Rosenfeld et
al. (1969) demonstrated heterogeneity in the fourth component of
complement, C4. Using immunofixation electrophoresis and family studies,
O'Neill et al. (1978) demonstrated that 2 different genetic loci control
the electrophoretic patterns of C4. Studies by Awdeh and Alper (1980)
provided direct evidence that 2 distinct but closely linked genes, C4A
and C4B, encode C4.

Both C3 (120700) and C4 are synthesized as single polypeptide chains
(Brade et al., 1977; Hall and Colten, 1977). In serum, however, C3
consists of 2 polypeptide chains and C4 consists of 3 (Porter and Reid,
1978).

Roos et al. (1982) showed that the alpha chains of C4A and C4B differ in
molecular weight, being 96,000 and 94,000, respectively. Each C4
molecule consists of beta-alpha-gamma subunits, in that sequence, in the
pro-C4. The secreted form of C4 is larger in molecular weight than the
major plasma form by about 5,000 (Chan et al., 1983). Presumably, the
extra piece is removed extracellularly by proteolytic cleavage.

Yu et al. (1986) demonstrated that C4A and C4B differ by only 4 amino
acids at position 1101 to 1106. Over this region C4A has the sequence
PCPVLD, while C4B has the sequence LSPVIH.

In a review of the molecular genetics of C4, Carroll and Alper (1987)
stated that C4A and C4B differ by 14 nucleotides. Allotypic and
serologic differences appear to result from single amino acid
substitutions.

GENE STRUCTURE

Palsdottir et al. (1987) showed that the 2 human C4 genes differ in
length because of the presence or absence of a 6.5-kb intron near the
5-prime end of the gene. The large intron was present in all C4A genes
but only in some C4B genes.

The C4A gene is usually approximately 22 kb long, whereas the C4B gene
is polymorphic in size, either 22 or 16 kb. This size variation is due
to the presence of a 7-kb intron located approximately 2.5 kb from the
5-prime end of the C4 genes (Prentice et al., 1986; Yu, 1991).

A 6.4-kb insertion present in intron 9 in 60% of human C4 genes contains
the complete human endogenous retrovirus-K(C4), or HERV-K(C4), in the
reverse orientation to the C4 coding sequence. By expressing open
reading frames from the HERV sequence in mouse cells transfected with
either C4A or C4B, Schneider et al. (2001) demonstrated that the
HERV-K(C4) antisense transcripts are present, that expression of the
HERV-like constructs is significantly downregulated in cells expressing
C4, and that gamma-interferon (147520)-induced upregulation of C4
enhances the downregulation of HERV in a dose-dependent manner.

MAPPING

The C4 locus in the guinea pig is linked to the major histocompatibility
complex (Shevach et al., 1976) and to Bf (Kronke et al., 1977). The
locus in man is in the major histocompatibility region on chromosome 6
(Teisberg et al., 1976; Ochs et al., 1977). The Ss protein of the mouse,
determined by a gene that is part of the MHC complex, is homologous to
C4 in man (Lachmann et al., 1975; Meo et al., 1975). Thus, linkage
homology is maintained in 3 species. Pollack et al. (1980) used the
linkage principle (and the tight linkage to HLA) for prenatal diagnosis
of C4 deficiency. On the basis of 4 overlapping cosmid clones, Carroll
et al. (1984) aligned 4 human complement genes known to map between
HLA-D and HLA-B. The C2 and BF genes, which are less than 2 kb apart,
are about 30 kb from the 2 C4 genes, which are separated from each other
by about 10 kb. Using a chromosome-specific C4 DNA pattern relative to
the loss or retention of other MHC genes on the same chromosome, in
subclones of a cell line with gamma-ray-induced lesions of the MHC
region, Whitehead et al. (1985) could document the location of C4
between HLA-B and HLA-DR.

Suto et al. (1996) demonstrated that the MHC class III region can be
examined directly and visually by multicolor fluorescence in situ
hybridization using stretched DNA preparations. By varying the time of
treatment with SDS solution, the extent of the DNA stretching could be
varied. The authors thus determined the organization of the human C4A,
C4B, 210HA (CYP21A), and 210HB (CYP21B) genes. The authors stated that
the method should be useful for rapid screening of gene deletions and
duplications and analysis of gene organization.

GENE FUNCTION

The C4B isotype of C4 displays 3- to 4-fold greater hemolytic activity
than does the C4A isotype. Carroll et al. (1990) demonstrated that a
conversion of residue 1106 from histidine to aspartic acid in C4B
changed the functional activity to that of C4A.

MOLECULAR GENETICS

'Half null' haplotypes, i.e., deletion on one or the other, but not
both, C4 loci on any given chromosome, are common in Caucasians (O'Neill
et al., 1978).

Awdeh and Alper (1980) introduced a typing system that allowed them to
detect 6 common structural variants and a deletion allele at the Rodgers
(C4A) locus and 2 structural variants and a deletion allele at the Chido
(C4B) locus in whites. See 614374 for information on the Chido/Rodgers
blood group system.

Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient
proband and provided evidence that C4 deficiency (see 614379) resulted
from homozygosity for a rare, double-null haplotype. The family
contained persons with 1, 2, 3, or 4 expressed C4 genes, and the mean
serum C4 levels roughly reflected the number of structural genes
present.

Wank et al. (1984) found a particular rare C4B allele in 25% of 59
unselected patients with primary glomerulonephritis but in only 2% of
the normal population--a relative risk of 22.1 for persons with the
variant C4B*2.9. The association with the membranoproliferative type was
especially strong. Welch and Beischel (1985) suggested that this
phenotype was an acquired variant in uremic patients homozygous for
C4B1. Studies by Lhotta et al. (1996) confirmed the presence of a uremic
variant of B1 in patients with chronic renal failure. The uremic variant
disappeared after renal transplantation resulting in normalization of
renal function.

Nerl et al. (1984) reported an increase in the frequency of the C4B
allele C4B2 in patients with Alzheimer disease (AD; 104300), but
Eikelenboom et al. (1988) failed to find a significant association
between C4B2 allelic frequency and AD.

By molecular studies at the DNA level, Schneider et al. (1986) found
that about half of the C4 genes typed as C4 null were deleted. Several
unrecognized homoduplication genes were detected. Null alleles at either
the C4A locus or the C4B locus, designated C4AQ0 and C4BQ0,
respectively, appeared to be relatively common, occurring at the C4A
locus in about 10% of normal persons and at the C4B locus in about 16%
of normal persons. The double-null haplotype was very rare.

To evaluate the molecular basis of the C4-null phenotypes, Partanen et
al. (1988) used Southern blotting techniques to analyze genomic DNA from
23 patients with systemic lupus erythematosus (SLE; 152700) and from
healthy controls. They confirmed the earlier findings of high
frequencies of C4-null phenotypes and of HLA-B8,DR3 antigens. In
addition, they found that among the patients most of both the C4A
(120810)- and C4B-null phenotypes resulted from gene deletions. Among
the controls, only the C4A-null phenotypes were predominantly the result
of gene deletions. In all SLE cases, the C4 gene deletions extended also
to a closely linked pseudogene, CYP21A (613815). Altogether, 52% of the
patients and 26% of the controls carried a C4/CYP21A deletion. Partanen
et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci
fell within the range of 30 to 38 kb, as determined by pulsed-field gel
electrophoresis. Because the deletion sizes in most other gene clusters
were more heterogeneous, the results suggested to Partanen et al. (1989)
the involvement of a specific mechanism in the generation of C4/CYP21
deletions.

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

In a 9-year-old girl with SLE and complete C4 deficiency, Welch et al.
(1990) found uniparental isodisomy 6. The girl had 2 identical
chromosome 6 haplotypes from the father and none from the mother.

In a study of the molecular basis of C4 null alleles, Braun et al.
(1990) found evidence for defective genes at the C4A locus and for gene
conversion at the C4B locus as demonstrated by the presence of
C4A-specific sequences. To characterize further the molecular basis of
these nonexpressed C4A genes, Barba et al. (1993) selected 9 pairs of
PCR primers from flanking genomic intron sequences to amplify all 41
exons from individuals with a defective C4A gene. The amplified products
were subjected to single-strand conformation polymorphism (SSCP)
analysis to detect possible mutations. PCR products exhibiting a
variation in the SSCP pattern were sequenced directly. In 10 of 12
individuals, a 2-bp insertion in exon 29 (120810.0001), leading to
nonexpression due to creation of a termination codon, was detected. The
insertion was linked to the haplotype HLA-B60-DR6 in 7 cases. In 1 of
the other 2 individuals without this mutation, evidence was obtained for
gene conversion to the C4B isotype. They suggested that the insertion
was due to slipped mispairing mediated by a direct repeat or run of
identical bases since the original sequence of the insertion site CTC
was changed to CTCTC by addition of a CT or a TC dinucleotide. Since the
reading frame was shifted, a complete change in the amino acid sequence
resulted, followed by a termination codon at the beginning of exon 30.

Kramer et al. (1991) demonstrated a marked drop in the frequency of the
C4-null allele (C4B*Q0) in elderly subjects: in 'young' and 'old' men
the frequency was 17.6% and 3.4%, respectively. This suggested that the
allele is a negative selection factor for survival. Whether this is a
direct effect of the gene or the result of linkage disequilibrium with
neighboring genes, such as HLA or CYP21, was discussed.

Fasano et al. (1992) studied a 7-year-old patient with recurrent
sinopulmonary infections in whom the rare C4A*Q0,B*Q0 double-null
haplotype was shown to be due to a recombination event within the C4B
locus in the mother, who possessed a C4A*Q0,B*1 haplotype and a
C4A*3,B*1 haplotype. By segregation analysis, they mapped the
recombination to a region 3-prime to the unique 6.4-kb TaqI restriction
fragment of the maternal C4B locus.

Szalai et al. (2002) found an increase in the frequency of the C4B*Q0
allele in patients with severe coronary artery disease (CAD) who
underwent bypass surgery compared to healthy controls (14.2% vs 9.9%).
Investigation of specific allelic combinations found that C4B*Q0 in
combination with TNF-alpha -308A (191160.0004) was significantly higher
in CAD patients, particularly those with preoperative myocardial
infarction.

Chung et al. (2002) stated that complement component C4 illustrates one
of the most unusual phenomena in genetic diversity. The frequent
germline variation in the number and size of C4 genes among different
individuals is extraordinary. The copy number of C4 genes in a diploid
human genome (i.e., the gene dosage) predominantly varies from 2 to 6 in
the white population. Each of these genes encodes a C4A or C4B protein.
C4 is a constituent of the 4-gene module termed the 'RCCX,' which takes
its designation from RP1 (see STK19; 604977), C4, CYP21, and TNXB
(600985). The 4-gene module duplicates as a discrete genetic unit in the
class III region of the major histocompatibility complex. Chung et al.
(2002) developed a comprehensive series of novel or improved techniques
to determine the total gene number of C4 and the relative dosages of C4A
and C4B in the diploid genome. Chung et al. (2002) applied these
techniques to elucidate the complement C4 polymorphisms in gene sizes,
gene numbers, and protein isotypes as well as their gene orders. In 4
informative families, a complex pattern of genetic diversity for RCCX
haplotypes in 1, 2, 3, and 4 C4 genes was demonstrated; each C4 gene may
be long or short, encoding a C4A or C4B protein. Chung et al. (2002)
suggested that this diversity may be related to different intrinsic
strengths among humans to defend against infections and susceptibilities
to autoimmune diseases.

Pursuing the role of copy number variation (CNV) of C4 genes in
susceptibility to autoimmune disease, Yang et al. (2007) investigated C4
gene CNV in 1,241 European Americans, including patients with systemic
lupus erythematosus (SLE; 152700), their first-degree relatives, and
unrelated healthy subjects. The gene copy number (GCN) varied from 2 to
6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four
copies of total C4, 2 copies of C4A, and 2 copies of C4B were the most
common GCN counts, but each constituted only between one half and three
quarters of the study population. Long C4 genes were strongly correlated
with C4A (P less than 0.0001). Short C4 genes were correlated with C4B
(P less than 0.0001). In comparison with healthy subjects, patients with
SLE clearly had the GCN of total C4 and C4A shifting to the lower side.
The risk of SLE disease susceptibility significantly increased among
subjects with only 2 copies of total C4 but decreased in those with 5
copies or more of C4. Both 0 copies and 1 copies were risk factors for
SLE, whereas 3 or more copies of C4A appeared to be protective.
Family-based association tests suggested that a specific haplotype with
a single short C4B in tight linkage disequilibrium with the -308A allele
of tumor necrosis factor-alpha (TNFA; 191160.0004) was more likely to be
transmitted to patients with SLE. The work demonstrated how gene CNV and
its related polymorphisms are associated with the susceptibility to a
human complex disease.

Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients
from the UK and 537 from Spain, and 1,179 controls for gene copy number
(GCN) of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0;
120810.0001) resulting in a null allele. The loss-of-function SNP in C4A
was not associated with SLE in either population. Boteva et al. (2012)
used multiple logistic regression to determine the independence of C4
CNV from known SNP and HLA-DRB1 associations. Overall, the findings
indicated that partial C4 deficiency states are not independent risk
factors for SLE in UK and Spanish populations. Although complete
homozygous deficiency of complement C4 is one of the strongest genetic
risk factors for SLE, partial C4 deficiency states do not independently
predispose to the disease.

EVOLUTION

Fontaine et al. (1980) found a common antigenic determinant on human C4b
and C3b (120700), supporting a common ancestral origin for C3 and C4.
However, C3 is located on chromosome 19.

ANIMAL MODEL

Ellman et al. (1970) found a deficiency of C4 in guinea pig, where total
deficiency was recessive. Hall and Colten (1978) showed that C4
deficiency in guinea pig was due to a defect in translation of specific
C4 mRNA on polysomes.

*FIELD* SA
Carroll and Porter (1983); Cream et al. (1979); Cunningham-Rundles
et al. (1977); Cunningham-Rundles et al. (1977); Curman et al. (1975);
Giles (1984); Hobart and Lachmann (1976); Mascart-Lemone et al. (1983);
O'Neill (1981); O'Neill et al. (1978); O'Neill et al. (1978); Olaisen
et al. (1979); Petersen et al. (1979); Rittner and Bertrams (1981);
Rittner et al. (1976); Schaller et al. (1977); Shreffler (1976)
*FIELD* RF
1. Awdeh, Z. L.; Alper, C. A.: Inherited structural polymorphism
of the fourth component of human complement. Proc. Nat. Acad. Sci. 77:
3576-3580, 1980.

2. Awdeh, Z. L.; Ochs, H. D.; Alper, C. A.: Genetic analysis of C4
deficiency. J. Clin. Invest. 67: 260-263, 1981.

3. Barba, G.; Rittner, C.; Schneider, P. M.: Genetic basis of human
complement C4A deficiency: detection of a point mutation leading to
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4. Boteva, L.; Morris, D. L.; Cortes-Hernandez, J.; Martin, J.; Vyse,
T. J.; Fernando, M. M. A.: Genetically determined partial complement
C4 deficiency states are not independent risk factors for SLE in UK
and Spanish populations. Am. J. Hum. Genet. 90: 445-456, 2012.

5. Brade, V.; Hall, R. E.; Colten, H. R.: Biosynthesis of pro-C3,
a precursor of the third component of complement. J. Exp. Med. 146:
759-765, 1977.

6. Braun, L.; Schneider, P. M.; Giles, C. M.; Bertrams, J.; Rittner,
C.: Null alleles of human complement C4: evidence for pseudogenes
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Med. 171: 129-140, 1990.

7. Carroll, M. C.; Alper, C. A.: Polymorphism and molecular genetics
of human C4. Brit. Med. Bull. 43: 50-65, 1987.

8. Carroll, M. C.; Campbell, R. D.; Bentley, D. R.; Porter, R. R.
: A molecular map of the human major histocompatibility complex class
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9. Carroll, M. C.; Fathallah, D. M.; Bergamaschini, L.; Alicot, E.
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acid for histidine) converts the functional activity of human complement
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10. Carroll, M. C.; Porter, R. R.: Cloning of a human complement
component C4 gene. Proc. Nat. Acad. Sci. 80: 264-267, 1983.

11. Chan, A. C.; Mitchell, K. R.; Munns, T. W.; Karp, D. R.; Atkinson,
J. P.: Identification and partial characterization of the secreted
form of the fourth component of human complement: evidence that it
is different from major plasma form. Proc. Nat. Acad. Sci. 80: 268-272,
1983.

12. Chung, E. K.; Yang, Y.; Rennebohm, R. M.; Lokki, M.-L.; Higgins,
G. C.; Jones, K. N.; Zhou, B.; Blanchong, C. A.; Yu, C. Y.: Genetic
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13. Chung, E. K.; Yang, Y.; Rupert, K. L.; Jones, K. N.; Rennebohm,
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14. Cream, J. J.; Olaisen, B.; Teisberg, P.; Soler, A. V.; Thompson,
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16. Cunningham-Rundles, C.; Tegoli, J.; Dupont, B.; Whitsett, C.;
Good, R. A.: Chemical studies on the Chido antigen. Transplant.
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17. Curman, B.; Ostberg, L.; Sandberg, L.; Malmheden-Erikkson, I.;
Stalenheim, G.; Rask, L.; Peterson, P. A.: H-2 linked Ss protein
is C-4 component of complement. Nature 258: 243-245, 1975.

18. Eikelenboom, P.; Goetz, J.; Pronk, J. C.; Hauptmann, G.: Complement
C4 phenotypes in dementia of the Alzheimer type. Hum. Hered. 38:
48-51, 1988.

19. Ellman, L.; Green, I.; Frank, M.: Genetically controlled total
deficiency of the fourth component of complement in the guinea pig. Science 170:
74-75, 1970.

20. Fasano, M. B.; Winkelstein, J. A.; LaRosa, T.; Bias, W. B.; McLean,
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21. Fontaine, M.; Daveau, M.; Lebreton, J. P.: A common antigenic
determinant on human C4b and C3b. Molec. Immun. 17: 1075-1078, 1980.

22. Giles, C. M.: A new genetic variant for Chido. Vox Sang. 46:
149-156, 1984.

23. Hall, R. E.; Colten, H. R.: Cell-free synthesis of the fourth
component of guinea pig complement (C4): identification of a precursor
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24. Hall, R. E.; Colten, H. R.: Genetic defect in biosynthesis of
the precursor form of the fourth component of complement. Science 199:
69-70, 1978.

25. Hobart, M. J.; Lachmann, P. J.: Allotypes of complement components
in man. Transplant. Rev. 32: 26-42, 1976.

26. Kramer, J.; Fulop, T.; Rajczy, K.; Ahn Tuan, N.; Fust, G.: A
marked drop in the incidence of the null allele of the B gene of the
fourth component of complement (C4B*Q0) in elderly subjects: C4B*Q0
as a probable negative selection factor for survival. Hum. Genet. 86:
595-598, 1991.

27. Kronke, M.; Hadding, U.; Geczy, A. F.; de Weck, A. L.; Bitter-Suermann,
D.: Linkage of guinea pig Bf and C4 to the GPLA. J. Immun 119:
2016-2018, 1977.

28. Lachmann, P. J.; Grennan, D.; Martin, A.; Demant, P.: Identification
of Ss protein as murine C4. Nature 258: 242-243, 1975.

29. Lhotta, K.; Schlogl, A.; Uring-Lambert, B.; Kronenberg, F.; Konig,
P.: Complement C4 phenotypes in patients with end-stage renal disease. Nephron 72:
442-446, 1996.

30. Mascart-Lemone, F.; Hauptmann, G.; Goetz, J.; Duchateau, J.; Delespesse,
G.; Vray, B.; Dab, I.: Genetic deficiency of C4 presenting with recurrent
infections and a SLE-like disease: genetic and immunologic studies. Am.
J. Med. 75: 295-304, 1983.

31. Meo, T.; Krasteff, T.; Shreffler, D. C.: Immunochemical characterization
of murine H-2 controlled Ss (serum substance) protein through identification
of its human homologue as the fourth component of complement. Proc.
Nat. Acad. Sci. 72: 4536-4540, 1975.

32. Nerl, C.; Mayeux, R.; O'Neill, G. J.: HLA-linked complement markers
in Alzheimer's and Parkinson's disease C4 variant (C4B2)--a possible
marker for senile dementia of the Alzheimer type. Neurology 34:
310-314, 1984.

33. O'Neill, G. J.: The genetic control of Chido and Rodgers blood
group substances. Seminars Hemat. 18: 32-38, 1981.

34. O'Neill, G. J.; Yang, S. Y.; Dupont, B.: Two HLA-linked loci
controlling the fourth component of human complement. Proc. Nat.
Acad. Sci. 75: 5165-5169, 1978.

35. O'Neill, G. J.; Yang, S. Y.; Dupont, B.: Chido and Rodgers blood
groups: relationships to C4 and HLA. Transplant. Proc. 10: 749-751,
1978.

36. O'Neill, G. J.; Yang, S. Y.; Tegoli, J.; Berger, R.; Dupont, B.
: Chido and Rodgers blood groups are distinct antigenic components
of human C4. Nature 273: 668-670, 1978.

37. Ochs, H. D.; Rosenfeld, S. I.; Thomas, E. D.; Giblett, E. R.;
Alper, C. A.; Dupont, B.; Schaller, J. G.; Gilliland, B. C.; Hansen,
J. A.; Wedgwood, R. J.: Linkage between the gene (or genes) controlling
synthesis of the fourth component of complement and the major histocompatibility
complex. New Eng. J. Med. 296: 470-475, 1977.

38. Olaisen, B.; Teisberg, P.; Nordhagen, R.; Michaelsen, T.; Gedde-Dahl,
T., Jr.: Human complement C4 locus is duplicated on some chromosomes. Nature 279:
736-737, 1979.

39. Palsdottir, A.; Fossdal, R.; Arnason, A.; Edwards, J. H.; Jensson,
O.: Heterogeneity of human C4 gene size: a large intron (6.5 kb)
is present in all C4A genes and some C4B genes. Immunogenetics 25:
299-304, 1987.

40. Partanen, J.; Kere, J.; Wessberg, S.; Koskimies, S.: Determination
of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase
genes by pulsed-field gel electrophoresis. Genomics 5: 345-349,
1989.

41. Partanen, J.; Koskimies, S.; Johansson, E.: C4 null phenotypes
among lupus erythematosus patients are predominantly the result of
deletions covering C4 and closely linked 21-hydroxylase A genes. J.
Med. Genet. 25: 387-391, 1988.

42. Petersen, G. B.; Sorensen, I. J.; Buskjaer, L.; Lamm, L. U.:
Genetic studies of complement C4 in man. Hum. Genet. 53: 31-36,
1979.

43. Pollack, M. S.; Ochs, H. D.; Dupont, B.: HLA typing of cultured
amniotic cells for the prenatal diagnosis of complement C4 deficiency. Clin.
Genet. 18: 197-200, 1980.

44. Porter, R. R.; Reid, K. B. M.: The biochemistry of complement. Nature 275:
699-704, 1978.

45. Prentice, H. L.; Schneider, P. M.; Strominger, J. L.: C4B gene
polymorphism detected in a human cosmid clone. Immunogenetics 23:
274-276, 1986.

46. Rittner, C.; Bertrams, J.: On the significance of C2, C4, and
factor B polymorphisms in disease. Hum. Genet. 56: 235-247, 1981.

47. Rittner, C.; Hauptmann, G.; Grosse-Wilde, H.; Grosshans, E.; Tongio,
M. M.; Mayer, S.: Linkage between HL-A (major histocompatibility
complex) and genes controlling the fourth component of complement.In:
Histocompatibility Testing 1975. Copenhagen: Munksgaard 1976.
Pp. 945-953.

48. Roos, M. H.; Mollenhauer, E.; Demant, P.; Rittner, C.: A molecular
basis for the two locus model of human complement component C4. Nature 298:
854-856, 1982.

49. Rosenfeld, S. I.; Ruddy, S.; Austen, K. F.: Structural polymorphism
of the fourth component of human complement. J. Clin. Invest. 48:
2283-2292, 1969.

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

51. Schaller, J. G.; Gilliland, B. G.; Ochs, H. D.; Leddy, J. P.;
Agodoa, L. C. Y.; Rosenfeld, S. I.: Severe systemic lupus erythematosus
with nephritis in a boy with deficiency of the fourth component of
complement. Arthritis Rheum. 20: 1519-1525, 1977.

52. Schneider, P. M.; Carroll, M. C.; Alper, C. A.; Rittner, C.; Whitehead,
A. S.; Yunis, E. J.; Colten, H. R.: Polymorphism of the human complement
C4 and steroid 21-hydroxylase genes: restriction fragment length polymorphisms
revealing structural deletions, homoduplications, and size variants. J.
Clin. Invest. 78: 650-657, 1986.

53. Schneider, P. M.; Witzel-Schlomp, K.; Rittner, C.; Zhang, L.:
The endogenous retroviral insertion in the human complement C4 gene
modulates the expression of homologous genes by antisense inhibition. Immunogenetics 53:
1-9, 2001.

54. Shevach, E. M.; Frank, M. M.; Green, I.: Linkage of gene controlling
the synthesis of the fourth component of complement to the major histocompatibility
complex of the guinea pig. Immunogenetics 3: 595-602, 1976.

55. Shreffler, D. C.: The S region of the mouse major histocompatibility
complex (H-2): genetic variation and functional role in complement
system. Transplant. Rev. 32: 140-167, 1976.

56. Suto, Y.; Tokunaga, K.; Watanabe, Y.; Hirai, M.: Visual demonstration
of the organization of the human complement C4 and 21-hydroxylase
genes by high-resolution fluorescence in situ hybridization. Genomics 33:
321-324, 1996.

57. Szalai, C.; Fust, G.; Duba, J.; Kramer, J.; Romics, L.; Prohaszka,
Z.; Csaszar, A.: Association of polymorphisms and allelic combinations
in the tumour necrosis factor-alpha-complement MHC region with coronary
artery disease. J. Med. Genet. 39: 46-51, 2002.

58. Teisberg, P.; Akesson, I.; Olaisen, B.; Gedde-Dahl, T., Jr.; Thorsby,
E.: Genetic polymorphism of C4 in man and localization of a structural
C4 locus to the HLA gene complex of chromosome 6. Nature 264: 253-254,
1976.

59. Wank, R.; Schendel, D. J.; O'Neill, G. J.; Riethmuller, G.; Held,
E.; Feucht, H. E.: Rare variant of complement C4 is seen in high
frequency in patients with primary glomerulonephritis. Lancet 323:
872-874, 1984. Note: Originally Volume I.

60. Welch, T. R.; Beischel, L.: C4 uremic variant: an acquired C4
allotype. Immunogenetics 22: 553-562, 1985.

61. Welch, T. R.; Beischel, L. S.; Choi, E.; Balakrishnan, K.; Bishof,
N. A.: Uniparental isodisomy 6 associated with deficiency of the
fourth component of complement. J. Clin. Invest. 86: 675-678, 1990.

62. Whitehead, A. S.; Colten, H. R.; Chang, C. C.; Demars, R.: Localization
of the human MHC-linked complement genes between HLA-B and HLA-DR
by using HLA mutant cell lines. J. Immun. 134: 641-643, 1985.

63. Yang, Y.; Chung, E. K.; Wu, Y. L.; Savelli, S. L.; Nagaraja, H.
N.; Zhou, B.; Hebert, M.; Jones, K. N.; Shu, Y.; Kitzmiller, K.; Blanchong,
C. A.; McBride, K. L.; and 11 others: Gene copy-number variation
and associated polymorphisms of complement component C4 in human systemic
lupus erythematosus (SLE): low copy number is a risk factor for and
high copy number is a protective factor against SLE susceptibility
in European Americans. Am. J. Hum. Genet. 80: 1037-1054, 2007.

64. Yu, C. Y.: The complete exon-intron structure of a human complement
component C4A gene: DNA sequences, polymorphism, and linkage to the
21-hydroxylase gene. J. Immun. 146: 1057-1066, 1991.

65. Yu, C. Y.; Belt, K. T.; Giles, C. M.; Campbell, R. D.; Porter,
R. R.: Structural basis of the polymorphism of human complement components
C4A and C4B: gene size, reactivity and antigenicity. EMBO J. 5:
2873-2881, 1986.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/29/2012
Cassandra L. Kniffin - updated: 10/17/2003
Anne M. Stumpf - updated: 12/5/2001
Paul J. Converse - updated: 4/30/2001

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

*FIELD* ED
carol: 04/13/2012
terry: 4/3/2012
ckniffin: 3/29/2012
mgross: 12/7/2011
mgross: 12/6/2011
mgross: 12/5/2011
carol: 11/28/2011
alopez: 3/23/2011
terry: 12/16/2009
terry: 2/3/2009
tkritzer: 1/9/2004
cwells: 11/7/2003
carol: 10/19/2003
ckniffin: 10/17/2003
alopez: 12/5/2001
mgross: 4/30/2001
terry: 4/30/1999
carol: 7/24/1998
terry: 8/6/1997
mark: 5/9/1996
terry: 5/7/1996
mark: 5/7/1996
mimadm: 4/29/1994
carol: 3/31/1992
supermim: 3/16/1992
carol: 8/7/1991
carol: 7/2/1991
carol: 1/11/1991

MIM 152700
*RECORD*
*FIELD* NO
152700
*FIELD* TI
#152700 SYSTEMIC LUPUS ERYTHEMATOSUS; SLE
EXCESS LYMPHOCYTE LOW MOLECULAR WEIGHT DNA, INCLUDED;;
read moreEXCESS LMW-DNA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
multiple genes are involved in the causation of systemic lupus
erythematosus.

DESCRIPTION

Systemic lupus erythematosus (SLE), a chronic, remitting, relapsing,
inflammatory, and often febrile multisystemic disorder of connective
tissue, acute or insidious at onset, is characterized principally by
involvement of the skin, joints, kidneys, and serosal membranes. Lupus
erythematosus is thought to represent a failure of the regulatory
mechanisms of the autoimmune system.

- Genetic Heterogeneity of Systemic Lupus Erythematosus

See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic
heterogeneity of susceptibility to SLE.

An autosomal recessive form of systemic lupus erythematosus (SLEB16;
614420) is caused by mutation in the DNASE1L3 gene (602244) on
chromosome 3p14.3.

CLINICAL FEATURES

Lappat and Cawein (1968) suggested that drug-induced, specifically
procainamide-induced, systemic lupus erythematosus is an expression of a
pharmacogenetic polymorphism. Among close relatives of a procainamide
SLE proband, they found antinuclear antibody in the serum in 3, and in
all 5, 'significant' history or laboratory findings suggesting an
immunologic disorder. Three had a coagulation abnormality. The finding
of complement deficiency (see 120900) in cases of lupus as well as
association with particular HLA types points to genetic factors
responsible for familial aggregation of this disease. On the other hand,
the evidence for viral etiology suggests nongenetic explanations.
Lupus-like illness occurs (Schaller, 1972) in carriers of chronic
granulomatous disease (306400).

Lessard et al. (1997) demonstrated that CYP2D6 (124030) is the major
isozyme involved in the formation of N-hydroxyprocainamide, a metabolite
potentially involved in the drug-induced lupus syndrome observed with
procainamide. Lessard et al. (1999) stated that further studies were
needed to demonstrate whether genetically-determined or
pharmacologically-modulated low CYP2D6 activity could prevent
drug-induced lupus during procainamide therapy.

Reed et al. (1972) described inflammatory vasculitis with persistent
nodules in members of 2 generations. Three females in the preceding
generation had rheumatoid arthritis. They noted aggravation on exposure
to sunlight and suppression of lesions with chloroquine therapy. They
considered this to be related to lupus erythematosus profunda
(Tuffanelli, 1971), which has a familial occurrence and is probably
related to SLE.

Brustein et al. (1977) described a woman with discoid lupus who had one
child in whom lesions of discoid lupus began at age 2 months and a
second child who developed a rash probably of lupus erythematosus at age
1 week. Sibley et al. (1993) described a family in which a brother and
sister and a niece of theirs had SLE complicated by ischemic
vasculopathy. Photographs of the hands and feet of 1 patient showing
gangrene of several fingers and all toes were presented. Extensive
osteonecrosis occurred in the niece.

Elcioglu and Hall (1998) reported 2 sibs with chondrodysplasia punctata
born to a mother with systemic lupus erythematosus. One child was
stillborn at 36 weeks' gestation and the other miscarried at 24 weeks'
gestation following the exacerbation of the mother's SLE. Austin-Ward et
al. (1998) also reported an infant with neonatal lupus and
chondrodysplasia punctata born to a mother with SLE. The infant also had
features similar to those seen in children exposed to oral
anticoagulants, although there was no history of this. Elcioglu and Hall
(1998) and Austin-Ward et al. (1998), along with Toriello (1998) in a
commentary on these 2 papers, suggested that there is evidence for an
association between maternal SLE and chondrodysplasia punctata in a
fetus. The pathogenesis of this association, however, remained unclear.
Kelly et al. (1999) reported a male infant with neonatal lupus
erythematosus manifested as a rash typical of the disorder, who also had
midface hypoplasia and multiple stippled epiphyses. It was the skin
abnormality in the infant that led to the diagnosis of SLE in his
mother. Over a 3-year follow-up, the child demonstrated strikingly short
stature, midface hypoplasia, anomalous digital development, slow
resolution of the stippled epiphyses, and near-normal cognitive
development. Kozlowski et al. (2004) described 2 brothers with
chondrodysplasia punctata, whose mother had longstanding lupus
erythematosus and epilepsy, for which she had been treated with
chloroquine and other therapeutic agents during both pregnancies.
Kozlowski et al. (2004) pointed to 7 reported instances of the
association between chondrodysplasia punctata and maternal SLE.

Kamat et al. (2003) described the first reported incidence of identical
triplets who developed SLE. The diagnosis of SLE was made at ages 8, 9,
and 11 years (in reverse birth order, the last born developing the
disorder at age 8). Photosensitivity and skin lesions were all early
manifestations. The 3 girls manifested different clinical signs and
symptoms; however, all 3 had skin rash, fatigue, and biopsy-proven
glomerulonephritis. The findings of laboratory studies were similar,
including positivity for antinuclear antibodies, anti-native DNA, and
anti-double-stranded DNA (dsDNA), as well as low levels of complement.

- SLE and Nephritis

Stein et al. (2002) analyzed 372 affected individuals from 160 multiplex
SLE families, of which 25 contained at least 1 affected male relative.
The presence of renal disease was significantly increased in female
family members with an affected male relative compared to those with no
affected male relative (p = 0.002); the trend remained after stratifying
by race and was most pronounced in European Americans. Stein et al.
(2002) concluded that the increased prevalence of renal disease
previously reported in men with SLE is, in large part, a familial rather
than sex-based difference, at least in multiplex SLE families.

Xing et al. (2005) added 392 individuals from 181 new multiplex SLE
families to the sample previously studied by Stein et al. (2002) and
replicated the finding that the prevalence of renal disease was
increased in families with affected male relatives compared to families
with no affected male relatives. Xing et al. (2005) concluded that
multiplex SLE families with at least 1 affected male relative constitute
a distinct subpopulation of multiplex SLE families.

OTHER FEATURES

DeHoratius et al. (1975) found anti-RNA antibodies in 82% of SLE cases
and 16% of their relatives, as compared with 5% of control cases. The
relatives who showed antibody were exclusively close household contacts
of SLE cases. Anti-RNA antibody was not found in unrelated household
contacts of SLE cases. The findings supported the hypothesis that both
an environmental agent, perhaps a virus, and genetic response are
involved in the pathogenesis of SLE. See 601821 for information about Ro
ribonucleoproteins.

Beaucher et al. (1977) found clinical and serologic abnormalities in the
household dogs of 2 families with multiple cases of clinical and
serologic SLE, as well as other autoimmune disorders. Since spontaneous
SLE occurs in dogs, a transmissible agent may be involved.

Horn et al. (1978) described mixed connective tissue disease (MCTD) in a
brother and sister from a sibship of 8. They were HLA-identical (A11B12;
A2B12). MCTD has characteristics overlapping SLE, scleroderma and
polymyositis. Sera give positive indirect immunofluorescence tests for
antinuclear antibodies with a characteristic coarse, speckled pattern.
The diagnosis is confirmed by finding antibodies against
ribonucleoprotein.

Batchelor et al. (1980) found an association of hydralazine-induced SLE
with HLA-DR4. Slow acetylators without SLE and cases of nondrug-induced
SLE did not show the association. Thus, spontaneous SLE may be a
fundamentally different entity. In an extensive kindred in which
elliptocytosis and lipomatosis (151900) were segregating as independent
dominants, Weinberg et al. (1980) found a high frequency of biologic
false-positive serologic tests for syphilis (BFP STS). The latter trait
appeared also to be a dominant, independent of the other two traits. Two
female pedigree members with BFP STS developed SLE.

Reidenberg et al. (1980) found an excess of slow acetylator phenotype in
SLE. On the other hand, Baer et al. (1986) could find no association
between acetylator phenotype and SLE and from a review of the literature
concluded that most workers have had similar results. See C3b receptor
(120620) for information on a polymorphism related to SLE.

Sakane et al. (1989) studied T- and B-cell function, using an IL-2
activity assay and spontaneous plaque-forming cell assay, respectively,
in 34 family members of 6 patients with SLE. Impaired IL2 activity was
found in 15 of 29 relatives but in none of 5 unrelated persons sharing
households with the probands. The B-cell assay was abnormal in 22 of 29
relatives but was also abnormal in 4 of 5 unrelated household members.
The authors concluded that there is a strong genetic component to the
impaired IL2 activity in relatives of patients with SLE; the evidence
suggests a genetic basis for the B-cell abnormalities, but environmental
influences may also play a role. Benke et al. (1989) observed increased
oxidative metabolism in PHA-stimulated lymphocytes from a subgroup of
patients with systemic lupus erythematosus. The authors suggested that
the increased oxidative activity may generate a chemical change in the
endogenous DNA in vivo and therefore may be a primary event in the
pathogenesis of autoimmunity in some patients with SLE.

Using EMSA analysis, Solomou et al. (2001) showed that whereas
stimulated T cells from normal individuals had increased binding of
phosphorylated CREB (123810) to the -180 site of the IL2 promoter,
nearly all stimulated T cells from SLE patients had increased binding
primarily of phosphorylated CREM (123812) at this site and to the
transcriptional coactivators CREBBP (600140) and EP300 (602700).
Increased expression of phosphorylated CREM correlated with decreased
production of IL2. Solomou et al. (2001) concluded that transcriptional
repression is responsible for the decreased production of IL2 and anergy
in SLE T cells.

Xu et al. (2004) demonstrated that activated T cells of lupus patients
resisted anergy and apoptosis by markedly upregulating and sustaining
cyclooxygenase-2 (COX2, or PTGS2; 600262) expression. Inhibition of COX2
caused apoptosis of the anergy-resistant lupus T cells by augmenting FAS
(134637) signaling and markedly decreasing the survival molecule FLIP
(603599), and this mechanism was found to involve anergy-resistant lupus
T cells selectively. Xu et al. (2004) noted that the gene encoding COX2
is located in a lupus susceptibility region on chromosome 1. They also
found that only some COX2 inhibitors were able to suppress the
production of pathogenic autoantibodies to DNA by causing autoimmune
T-cell apoptosis, an effect that was independent of PGE2. Xu et al.
(2004) suggested that these findings could be useful in the design of
lupus therapies.

Zhang et al. (2001) determined that SLE patients have increased serum
levels of B-lymphocyte stimulator (BLYS, or TNFSF13B; 603969) compared
with normal controls. Immunoprecipitation and Western blot analyses
revealed expression of a 17-kD soluble form of BLYS in patients but not
controls. Functional analysis demonstrated that most patient
serum-derived BLYS exhibited increased costimulatory activity for B-cell
proliferation in vitro. Patients with higher levels of BLYS also had
significantly higher levels of anti-dsDNA in IgG, IgM, and IgA classes
than did patients with low levels of BLYS. Although there was no
correlation between increased BLYS levels and clinical SLE activity,
there were slightly higher BLYS levels in patients with antinuclear
antibodies (ANA) and significantly increased BLYS levels in patients
with both ANA and a clinical impression of SLE, suggesting that elevated
BLYS precedes the formal fulfillment of the criteria for SLE. Zhang et
al. (2001) suggested that BLYS may play an antiapoptotic role in B-cell
tolerance loss and that anti-BLYS may be a potential therapy for SLE and
other autoimmune diseases.

Baechler et al. (2003) used global gene expression profiling of
peripheral blood mononuclear cells to identify distinct patterns of gene
expression that distinguished most SLE patients from healthy controls.
Strikingly, approximately half of the patients studied showed
dysregulated expression of genes in the interferon pathway. Furthermore,
this interferon gene expression 'signature' served as a marker for more
severe disease involving the kidneys, hematopoietic cells, and/or the
central nervous system. These results provided insight into the genetic
pathways underlying SLE, and identified a subgroup of patients who may
benefit from therapies targeted at the interferon pathway.

Using ELISA, Balada et al. (2008) determined that the DNA
deoxymethylcytosine content of purified CD4 (186940)-positive T cells
was lower in patients with SLE than in controls. RT-PCR analysis
detected no differences in DNMT1 (126375), DNMT3A (602769), or DNMT3B
(602900) transcript levels between SLE patients and controls. However,
simultaneous association of low complement counts with lymphopenia, high
titers of anti-dsDNA, or a high SLE disease activity index resulted in
an increase in at least 1 of the DNMTs. Balada et al. (2008) proposed
that patients with active SLE and DNA hypomethylation have increased
DNMT mRNA levels.

CLINICAL MANAGEMENT

Glucocorticoids are widely used to treat patients with autoimmune
diseases such as SLE. However, in the majority of SLE patients such
treatment regimens cannot maintain disease control, and more aggressive
approaches such as high-dose methylprednisolone pulse therapy are used
to provide transient reduction in disease activity. Guiducci et al.
(2010) demonstrated that, in vitro and in vivo, stimulation of
plasmacytoid dendritic cells (PDCs) through TLR7 (300365) and TLR9
(605474) can account for the reduced activity of glucocorticoids to
inhibit the interferon pathway in SLE patients and in 2 lupus-prone
mouse strains. The triggering of PDCs through TLR7 and TLR9 by nucleic
acid-containing immune complexes or by synthetic ligands activates the
NF-kappa-B (see 164011) pathway essential for PDC survival.
Glucocorticoids do not affect NF-kappa-B activation in PDCs, preventing
glucocorticoid induction of PDC death and the consequent reduction of
systemic IFN-alpha (147660) levels. Guiducci et al. (2010) concluded
that their findings unveiled a new role for self nucleic acid
recognition by TLRs and indicated that inhibitors of TLR7 and TLR9
signaling could prove to be effective corticosteroid-sparing drugs.

INHERITANCE

Block et al. (1975) comprehensively reviewed evidence from twin studies.
Higher concordance for clinical and serologic abnormality for
monozygotic twins supported a significant genetic factor.

Lahita et al. (1983) observed father-to-son transmission and noted
prepubertal onset of familial SLE in males.

Fielder et al. (1983) found an unexpectedly high frequency of null
(silent) alleles at the C4A (120810), C4B (120820) and C2 (613927) loci
in patients with SLE. HLA-DR3 showed a high frequency in these patients,
and a strong linkage disequilibrium between DR3 and the null alleles for
C4A and C4B was found. On the basis of the data reported by Fielder et
al. (1983), Green et al. (1986) concluded that association with null
alleles at the C4 loci is primary and the DR3 association secondary to
that. In addition to the association of SLE with MHC antigens DR2 and
DR3 and with homozygous deficiency of early complement components, the
fact that SLE occurs 3 to 4 times more frequently in blacks than in
whites (Siegel et al., 1970; Fessel, 1974) points to genetic factors.

GENOTYPE/PHENOTYPE CORRELATIONS

Sturfelt et al. (1990) found homozygous C4A deficiency in 13 of 80
patients (16%). Photosensitivity was a more impressive feature in these
homozygotes than in other lupus patients. The T4/Leu-3 molecule (186940)
is a T-cell differentiation antigen expressed on the surface of T
helper/inducer cells. Monoclonal antibodies that can recognize this
molecule include OKT4 and anti-Leu-3a, which bind to different
determinants (epitopes) on the T4/Leu-3 molecule. This molecule has an
important role in the recognition of class II MHC antigens by T cells.
Polymorphism of the T4 epitope had, by the time of the report of Stohl
et al. (1985), been identified only in blacks. Three phenotypes,
corresponding to 3 genotypes, were identified: the most common, the T4
epitope-intact phenotype, is manifest when fluorescence intensity upon
staining of T cells is as great with OKT4 as with anti-Leu-3a. The T4
epitope-deficient phenotype shows no staining with OKT4, and an
intermediate phenotype, representing heterozygosity for deficiency,
shows fluorescence intensity with OKT4 that is half that with
anti-Leu-3a.

MAPPING

- Genomewide Linkage Studies

Lee and Nath (2005) conducted a metaanalysis of 12 genome scans
generated from 9 independent studies involving 605 SLE families with
1,355 affected individuals. They identified 2 loci, 6p22.3-6p21.1 and
16p12.3-16q12.2, that met genomewide significance (p less than
0.000417). Lee and Nath (2005) noted that 6p22.3-6p21.1 contains the HLA
region.

Gaffney et al. (1998) reported the results of a genomewide
microsatellite marker screen in 105 SLE sib-pair families. Eighty of the
families were Caucasian; 5 were African American. By using multipoint
nonparametric methods, the strongest evidence for linkage was found near
the HLA locus; D6S257 gave a lod score of 3.90. D16S415 at 16q13 yielded
a lod score of 3.64; D14S276 at 14q21-q23 yielded a lod score of 2.81;
and D20S186 at 20p12 yielded a lod score of 2.62. Another 9 regions were
identified with lod scores equal to or greater than 1.00. The data
supported the hypothesis that multiple genes, including 1 in the HLA
region, influence susceptibility to human SLE.

Gaffney et al. (2000) performed a second genomewide screen in a 'new'
cohort of 82 SLE sib-pair families. Highest evidence of linkage was
found in 4 intervals: 10p13, 7p22, 7q21, and 7q36; all 4 had a lod score
greater than 2.0, and the locus on 7p22 had a lod score of 2.87. A
combined analysis of cohorts 1 and 2 (187 sib-pair families total)
showed that markers in 6p21-p11 (D6S426, lod score of 4.19) and 16q13
(D16S415, lod score of 3.85) met the criteria for significant linkage.

Using the ABI Prism linkage mapping set, which includes 350 polymorphic
markers with an average spacing of 12 cM, Shai et al. (1999) screened
the human genome in a sample of 188 lupus patients belonging to 80 lupus
families, each with 2 or more affected relatives per family, to localize
genetic intervals that may contain lupus susceptibility loci.
Nonparametric multipoint linkage analysis suggested evidence for
predisposing loci on chromosomes 1 and 18. However, no single locus with
overwhelming evidence for linkage was found, suggesting that there are
no 'major' susceptibility genes segregating in families with SLE, and
that the genetic etiology is more likely to result from the action of
several genes of moderate effect. Furthermore, support for a gene in the
1q44 region, as well as for a gene in the 1p36 region, was found clearly
only in Mexican American families with SLE, but not in families of
Caucasian ethnicity, suggesting that consideration of each ethnic group
separately is crucial.

Lindqvist et al. (2000) performed genome scans in families with multiple
SLE patients from Iceland and from Sweden. A number of regions gave lod
scores greater than 2: among Icelandic families, 4p15-p13, Z = 3.20;
9p22, Z = 2.27; and 19q13, Z = 2.06, which are homologous to the murine
regions containing the lmb2, sle2, and sle3 loci, respectively. The
fourth region among Icelandic families is located on 19p13 (D19S247, Z =
2.58) and a fifth on 2q37 (D2S125, Z = 2.06). Only 2 regions showed lod
scores above 2.0 in the Swedish families: 2q11 (D2S436, Z = 2.13) and
2q37 (D2S125, Z = 2.18). The combination of both family sets gave a
highly significant lod score at D2S125, with a Z of 4.24 in favor of
linkage for 2q37 (see 605218).

Gray-McGuire et al. (2000) presented the result of a genome scan of 126
pedigrees with 2 or more cases of SLE, including 469 sib pairs (affected
and unaffected) and 175 affected relative pairs. Using the revised
multipoint Haseman-Elston regression technique for concordant and
discordant sib pairs and a conditional logistic regression technique for
affected relative pairs, they identified linkage to chromosome
4p16-p15.2 (P = 0.0003, lod = 3.84) and presented evidence of an
epistatic interaction between 4p16-p15.2 and chromosome 5p15 in European
American families. Using data from an independent pedigree collection,
they confirmed the linkage to 4p16-p15.2 in European American families.
The most significant linkage that they found in the African American
subset was to the previously identified region on 1q (601744).

Johanneson et al. (2002) genotyped a set of 87 multicase families with
SLE from various European countries and recently admixed populations of
Mexico, Colombia, and the United States for 62 microsatellite markers on
chromosome 1. By parametric 2-point linkage analysis, 6 regions
previously described as being related to SLE (1p36, 1p21, 1q23, 1q25,
1q31, and 1q43) were identified that had lod scores greater than or
equal to 1.50. CD45 (151460) was considered a strong candidate gene
because of its position in 1q31-q32 and because of its involvement in
the regulation of the antigen-induced signaling of naive B and T cells.
Johanneson et al. (2002) found no association between the 77C-G
(151460.0001) mutation in the CD45 gene and SLE in the families they
studied. The locus at 1q31 showed a significant 3-point lod score of
3.79 and was contributed by families from all populations, with several
markers and under the same parametric model. They concluded that a locus
at 1q31 contains a major susceptibility gene, important to SLE in
'general populations.'

Scofield et al. (2003) selected 38 pedigrees that had an SLE patient
with thrombocytopenia from a collection of 184 pedigrees with multiple
cases of SLE. They established linkage at chromosome 1q22-q23 (maximum
lod = 3.71) in all 38 pedigrees and at 11p13 (maximum lod = 5.72) in the
13 African American pedigrees. Nephritis, serositis, neuropsychiatric
involvement, autoimmune hemolytic anemia, anti-double-stranded DNA, and
antiphospholipid antibody were associated with thrombocytopenia. The
results showed that SLE was more severe in the families with a
thrombocytopenic SLE patient, whether or not thrombocytopenia in an
individual patient was considered.

- Susceptibility Loci for SLE Mapped by Linkage Studies

See SLEB1 (601744) for discussion of an SLE susceptibility locus on
chromosome 1q41. Variations in the TLR5 gene (603031) have been
associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB2 (605218) for discussion of an SLE susceptibility locus on
chromosome 2q37. Variations in the PDCD1 gene (605218) have been
associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB3 (605480) for discussion of an SLE susceptibility locus on
chromosome 4p.

See SLEB4 (608437) for discussion of an SLE susceptibility locus on
chromosome 12q24.

See SLEB5 (609903) for discussion of an SLE susceptibility locus on
chromosome 13q32.

See SLEB6 (609939) for discussion of an SLE susceptibility locus on
chromosome 16q12-q13.

See SLEB7 (610065) for discussion of an SLE susceptibility locus on
chromosome 20p12.

See SLEB8 (610066) for discussion of an SLE susceptibility locus on
chromosome 20q13.1.

See SLEB9 (610927) for discussion of an SLE susceptibility locus on
chromosome 1q32.

See SLEB10 (612251) for discussion of an SLE susceptibility locus on
chromosome 7q32. Variations in the IRF5 gene (607218) have been
associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB11 (612253) for discussion of an SLE susceptibility locus on
chromosome 2q32.2-q32.3. Variations in the STAT4 gene (600558) have been
associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB12 (612254) for discussion of an SLE susceptibility locus on
chromosome 8p23.1.

See SLEB13 (612378) for discussion of an SLE susceptibility locus on
chromosome 6p23. Variations in the TNFAIP3 gene (191163) have been
associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB14 (613145) for discussion of an SLE susceptibility locus on
chromosome 1q21-q23. Variations in the CRP gene (123260) have been
associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB15 (300809) for a discussion of an SLE susceptibility locus on
chromosome Xq28.

- Susceptibility Loci for SLE with Nephritis

Renal disease occurs in 40 to 75% of SLE patients and contributes
significantly to morbidity and mortality (Garcia et al., 1996).
Quintero-Del-Rio et al. (2002) used 2 pedigree stratification strategies
to explore the impact of the American College of Rheumatology's renal
criterion for SLE classification upon genetic linkage with SLE. They
identified susceptibility loci for SLE associated with nephritis on
chromosomes 10q22.3 (SLEN1; 607965), 2q34-q35 (SLEN2; 607966), and
11p15.6 (SLEN3; 607967).

- Susceptibility Locus for SLE with Hemolytic Anemia

A locus for susceptibility to SLE with hemolytic anemia as an early or
prominent clinical manifestation shows linkage to 11q14 (SLEH1; 607279).

- Susceptibility Locus for SLE with Vitiligo

A locus for susceptibility to SLE associated with vitiligo has been
mapped to 17p13 (SLEV1; 606579).

- Association with the HLA-DRB1 Locus

Using a dense map of polymorphic microsatellites across the HLA region
in a large collection of families with SLE, Graham et al. (2002)
identified 3 distinct haplotypes that encompassed the class II region
and exhibited transmission distortion. By visualizing ancestral
recombinants, they narrowed the disease-associated haplotypes containing
DRB1*1501 and DRB1*0801 to a region of approximately 500 kb. They
concluded that HLA class II haplotypes containing DRB1 and DQB1 alleles
are strong risk factors for human SLE.

To identify risk loci for SLE susceptibility, Gateva et al. (2009)
selected SNPs from 2,466 regions that showed nominal evidence of
association to SLE (P less than 0.05) in a genomewide study and
genotyped them in an independent sample of 1,963 cases and 4,329
controls. This new cohort replicated the association with HLA-DRB1 at
dbSNP rs3135394 (odds ratio = 1.98, 95% confidence interval = 1.84-2.14;
combined P = 2.0 x 10(-60)).

- Association with the TNIP1 Gene on Chromosome 5q32

In a study of 1,963 patients from the United States and Sweden with SLE
compared with 4,329 controls, Gateva et al. (2009) identified
association with the TNIP1 gene (607714) at chromosome 5q32 (dbSNP
rs7708392, combined P value = 3.8 x 10(-13); odds ratio = 1.27, 95%
confidence interval = 1.10-1.35).

Han et al. (2009) performed a genomewide association study of SLE in a
Chinese Han population by genotyping 1,047 cases and 1,205 controls
using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2
additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009)
found association with a SNP in the TNIP1 gene, dbSNP rs10036748
(combined P = 1.67 x 10(-9); odds ratio = 0.81, 95% confidence interval
= 0.75-0.87).

MOLECULAR GENETICS

- Association with the PTPN22 Gene on Chromosome 1p13

In a study of 525 unrelated North American white individuals with SLE,
Kyogoku et al. (2004) found an association with the R620W polymorphism
in the PTPN22 gene (600716.0001), with estimated minor (T) allele
frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy
of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2
copies of the allele more than doubled this risk (odds ratio = 4.37).

Orru et al. (2009) reported a 788G-A variant, resulting in an
arg263-to-gln (R263Q; dbSNP rs33996649) substitution within the
catalytic domain of the PTPN22 gene, that leads to reduced phosphatase
activity. They genotyped 881 SLE patients and 1,133 healthy controls
from Spain and observed a significant protective effect (p = 0.006; OR,
0.58). Three replication cohorts of Italian, Argentinian, and Caucasian
North American populations failed to reach significance; however, the
combined analysis of 2,093 SLE patients and 2,348 controls confirmed the
protective effect (p = 0.0017; OR, 0.63).

To confirm additional risk loci for SLE susceptibility, Gateva et al.
(2009) selected SNPs from 2,466 regions that showed nominal evidence
association to SLE (P less than 0.05) in a genomewide study and
genotyped them in an independent sample of 1,963 cases and 4,329
controls. Gateva et al. (2009) showed an association with PTPN22 at
dbSNP rs2476601 (combined P value = 3.4 x 10(-12), odds ratio = 1.35,
95% confidence interval = 1.24-1.47).

- Association with the CRP Gene on Chromosome 1q21-q23

Relative deficiency of pentraxin proteins is implicated in the
pathogenesis of SLE. The C-reactive protein (CRP; 123260) response is
defective in patients with acute flares of disease, and mice with
targeted deletions of the APCS (104770) gene develop a lupus-like
illness. In humans, the CRP and APCS genes are both within the 1q23-q24
interval that has been linked to SLE. Among 586 simplex SLE families,
Russell et al. (2004) found that basal levels of CRP were influenced
independently by 2 CRP polymorphisms, which they designated CRP2 (dbSNP
rs1800947) and CRP4 (dbSNP rs1205), and the latter was associated with
SLE and antinuclear autoantibody production. Russell et al. (2004)
hypothesized that defective disposal of potentially immunogenic material
may be a contributory factor in lupus pathogenesis.

- Association with the FCGR2B Gene on Chromosome 1q22

In 193 Japanese patients with SLE and 303 healthy controls, Kyogoku et
al. (2002) found that homozygosity for an ile232-to-thr polymorphism in
the FCGR2B gene (I232T; 604590.0002) was significantly increased in SLE
patients compared with controls.

In membrane separation studies using a human monocytic cell line, Floto
et al. (2005) demonstrated that although wildtype FCGR2B readily
partitioned into the raft-enriched gradient fractions, FCGR2B-232T was
excluded from them. Floto et al. (2005) concluded that FCGR2B-232T is
unable to inhibit activating receptors because it is excluded from
sphingolipid rafts, resulting in the unopposed proinflammatory signaling
thought to promote SLE.

Su et al. (2004) identified 10 SNPs in the first FCGR2B promoter in 66
SLE patients and 66 controls. They determined that the proximal promoter
contains 2 functionally distinct haplotypes. Luciferase promoter
analysis showed that the less frequent haplotype, which had a frequency
of 9%, was associated with increased gene expression. A case-control
study of 243 SLE patients and 366 matched controls demonstrated that the
less frequent haplotype was significantly associated with the SLE
phenotype and was not in linkage disequilibrium with FCGR2A and FCGR3A
(146740) polymorphisms. Su et al. (2004) concluded that an expression
variant of FCGR2B is a risk factor for SLE.

In 190 European American patients with SLE and 130 European American
controls, Blank et al. (2005) found a significant association between
homozygosity for a -343C polymorphism in the promoter region of the
FCGR2B gene (604590.0001) and SLE. The surface expression of FCGR2B
receptors was significantly reduced in activated B cells from -343C/C
SLE patients. Blank et al. (2005) suggested that deregulated expression
of the mutant FCGR2B gene may play a role in the pathogenesis of human
SLE.

By comparing genotypes of patients with SLE from Hong Kong and the UK
with those of ethnically matched controls, followed by metaanalysis
using with other studies on southeast Asian and Caucasian SLE patients,
Willcocks et al. (2010) found that homozygosity for T232 of the I232T
FCGR2B polymorphism was strongly associated with SLE in both ethnic
groups. When studies in Caucasians and southeast Asians were combined,
T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P
= 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of
the SNP is more common in southeast Asians and Africans, populations
where malaria (see 611162) is endemic, than in Caucasians. Homozygosity
for T232 was significantly associated with protection from severe
malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no
association was found with susceptibility to bacterial infection.
Willcocks et al. (2010) proposed that malaria may have driven retention
of a polymorphism predisposing to a polygenic autoimmune disease and
thus may begin to explain the ethnic differences seen in the frequency
of SLE.

- Association with the FCGR3B Gene on Chromosome 1q23

Aitman et al. (2006) showed that copy number variation (CNV) of the
orthologous rat and human Fcgr3 genes is a determinant of susceptibility
to immunologically mediated glomerulonephritis. Positional cloning
identified loss of the rat-specific Fcgr3 paralog 'Fcgr3-related
sequence' (Fcgr3rs) as a determinant of macrophage overactivity and
glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of
FCGR3B (610665), an ortholog of rat Fcgr3, was associated with
glomerulonephritis in SLE.

Following up on the study of Aitman et al. (2006) in a larger sample,
Fanciulli et al. (2007) confirmed and strengthened their previous
finding of an association between low FCGR3B copy number and
susceptibility to glomerulonephritis in SLE patients. Low copy number
was also associated with risk of systemic SLE with no known renal
involvement as well as with microscopic polyangiitis and Wegener
granulomatosis (608710), but not with organ-specific Graves disease
(275000) or Addison disease (240200), in British and French cohorts.
Fanciulli et al. (2007) concluded that low FCGR3B copy number or
complete FCGR3B deficiency has a key role in the development of specific
autoimmunity.

Willcocks et al. (2008) confirmed that low copy number of FCGR3B was
associated with SLE in a Caucasian U.K. population, but they were unable
to find an association in a Chinese population. Investigations of the
functional effects of FCGR3B CNV revealed that FCGR3B CNV correlated
with cell surface expression, soluble FCGR3B production, and neutrophil
adherence to and uptake of immune complexes both in a patient family and
in the general population. Willcocks et al. (2008) found that
individuals from 3 U.K. cohorts with antineutrophil cytoplasmic
antibody-associated systemic vasculitis (AASV) were more likely to have
high FCGR3B CNV. They proposed that FCGR3B CNV is involved in immune
complex clearance, possibly explaining the association of low CNV with
SLE and high CNV with AASV.

Niederer et al. (2010) noted linkage disequilibrium (LD) between
multiallelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus.
Despite LD between FCGR3B CNV and a variant in FCGR2B (I232T;
604590.0002) that abolishes inhibitory function, both reduced CN of
FCGR3B and homozygosity of the FCGR2B-232T allele were individually
strongly associated with SLE risk. Thus copy number of FCGR3B, which
controls immune complex responses and uptake by neutrophils, and
variations in FCGR2B, which controls factors such as antibody production
and macrophage activation, are important in SLE pathogenesis.

Mueller et al. (2013) found that the increased risk of SLE associated
with reduced copy number of FCGR3B can be explained by the presence of a
chimeric gene, FCGR2B-prime, that occurs as a consequence of FCGR3B
deletion on FCGR3B zero-copy haplotypes. The FCGR2B-prime gene consists
of upstream elements and a 5-prime coding region that derive from
FCGR2C, and a 3-prime coding region that derives from FCGR2B (604590).
The coding sequence of FCGR2B-prime is identical to that of FCGR2B, but
FCGR2B-prime would be expected to be under the control of 5-prime
flanking sequences derived from FCGR2C. Mueller et al. (2013) found by
flow cytometry, immunoblotting, and cDNA sequencing that presence of the
chimeric FCGR2B-prime gene results in the ectopic presence of
Fc-gamma-RIIb on natural killer cells, providing an explanation for SLE
risk associated with reduced FCGR3B copy number. The 5 FCGR2/FCGR3 genes
are arranged across 2 highly paralogous genomic segments on chromosome
1q23. To pursue the underlying mechanism of SLE disease association with
FCGR3B copy number variation, Mueller et al. (2013) aligned the
reference sequence (GRCh37) of the proximal block of the FCGR locus
(chr1:161,480,906-161,564,008) to that of the distal block
(chr1:161,562,570-161,645,839). Identification of informative paralogous
sequence variants (PSVs) enabled Mueller et al. (2013) to narrow the
potential breakpoint region to a 24.5-kb region of paralogy between then
2 ancestral duplicated blocks. The complete absence of nonpolymorphic
PSVs in the 24.5-kb region prevented more precise localization of the
breakpoints in FCGR3B-deleted or FCGR3B-duplicated haplotypes.

- Association with the TNFSF6 Gene on Chromosome 1q23

The apoptosis genes FAS (TNFRSF6; 134637) and FASL (TNFSF6; 134638) are
candidate contributory genes in human SLE, as mutations in these genes
result in autoimmunity in several murine models of this disease. In
humans, FAS mutations result in a familial autoimmune
lymphoproliferative syndrome (e.g., 134637.0001). Wu et al. (1996)
studied DNA from 75 patients with SLE using SSCP analysis for potential
mutations of the extracellular domain of FASL. In 1 SLE patient who
exhibited lymphadenopathy, they found an 84-bp deletion within exon 4 of
the FASL gene, resulting in a predicted 28-amino acid in-frame deletion
(see 134638.0001).

- Association with the TNFSF4 Gene on Chromosome 1q25

By use of both a family-based study and a case-control study of SLE in
U.K. and Minnesota populations to screen the TNFRSF4 (600315) and TNFSF4
(603594) genes, Graham et al. (2008) found that an upstream region of
TNFSF4 contains a single risk haplotype (GCTAATCATTTGA) for SLE that
correlates with increased cell surface TNFSF4 expression and TNFSF4
transcript. The authors suggested that increased expression of TNFSF4
predisposes to SLE either by quantitatively augmenting
T-cell/antigen-presenting cell (APC) interaction or by influencing the
functional consequences of T-cell activation via TNFRSF4.

Han et al. (2009) performed a genomewide association study of SLE in a
Chinese Han population by genotyping 1,047 cases and 1,205 controls
using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2
additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009)
found association with the TNFSF4 gene at 2 SNPs, dbSNP rs1234315
(combined P value = 2.34 x 10(-26), odds ratio = 1.37, 95% confidence
interval 1.29-1.45) and dbSNP rs2205960 (combined P value = 2.53 x
10(-32), odds ratio = 1.46, 95% confidence interval 1.37-1.56).

- Association with the CR2 Gene on Chromosome 1q32

Wu et al. (2007) analyzed the CR2 gene, which lies in the SLEB9 (610927)
locus region, in 1,416 individuals from 258 Caucasian and 142 Chinese
SLE simplex families and demonstrated that a common 3-SNP haplotype
(120650.0001) was associated with SLE susceptibility (p = 0.00001) with
a 1.54-fold increased risk for development of disease. Wu et al. (2007)
concluded that the CR2 gene is likely a susceptibility gene for SLE.

- Association with the TLR5 Gene on Chromosome 1q41-q42

A polymorphism in the TLR5 gene (R392X; 603031.0001), which maps to the
SLEB1 (601744) locus, is associated with resistance to SLE development.

- Association with the STAT4 Gene on Chromosome 2q32

In 1,039 patients with SLE and 1,248 controls, Remmers et al. (2007)
identified an association between SLE (SLEB11; 612253) and the minor T
allele of dbSNP rs7574865 in intron 3 of the STAT4 gene (600558.0001).
The risk allele was present in 31% of chromosomes of patients with SLE
compared with 22% of those of controls (p = 1.87 x 10(-9)). Homozygosity
of the risk allele (TT) compared to absence of the allele was associated
with a more than doubled risk for lupus. The risk allele was also
associated with susceptibility to rheumatoid arthritis (RA; 180300).

- Association with the CTLA4 Gene on Chromosome 2q33

In a metaanalysis of 7 published studies and their own study, Barreto et
al. (2004) examined the association between an 49A-G polymorphism in the
CTLA4 gene (123890.0001) and SLE. The authors found that individuals
with the GG genotype were at significantly higher risk of developing
SLE; carriers of the A allele had a significantly lower risk of
developing the disease, and the AA genotype acted as a protective
genotype for SLE.

In a metaanalysis of 14 independent studies testing association between
CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G
polymorphism is significantly associated with SLE susceptibility,
particularly in Asians.

- Association with the PDCD1 Gene on Chromosome 2q37

Prokunina et al. (2002) analyzed 2,510 individuals, including members of
5 independent sets of families as well as unrelated individuals affected
with SLE, for SNPs that they had identified in the PDCD1 gene, which
maps within the SLEB2 locus (605218). They showed that one intronic SNP
(600244.0001) was associated with development of SLE in Europeans and
Mexicans. The associated allele of this SNP alters a binding site for
the RUNT-related transcription factor-1 (RUNX1; 151385) located in an
intronic enhancer, suggesting a mechanism through which it can
contribute to the development of SLE in humans.

- Association with the TREX1 Gene on Chromosome 3p21

Lee-Kirsch et al. (2007) analyzed the 3-prime repair exonuclease gene
TREX1 (606609) in 417 patients with SLE and 1,712 controls and
identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous
changes in 12 patients (see, e.g., 606609.0001). They identified only 2
nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk =
25.3). In vitro studies of 2 frameshift mutations revealed that both
caused altered subcellular distribution. The authors concluded that
TREX1 is implicated in the pathogenesis of SLE.

- Association with the BANK1 Gene on Chromosome 4q22-q24

Kozyrev et al. (2008) identified an association between SLE and a
nonsynonymous G-to-A transition in the BANK1 gene that results in a
substitution of his for arg at codon 61 (610292.0001), with the G allele
conferring risk.

- Association with the NKX2-5 Gene on Chromosome 5q34

Oishi et al. (2008) genotyped 3 SNPs in the NKX2-5 gene (600584) in 178
Japanese SLE patients and 1,425 controls and found association with
dbSNP rs3095870 in the 5-prime flanking region of NKX2-5 (p = 0.0037;
odds ratio, 1.74). Individuals having the risk genotype for both NKX2-5
and dbSNP 3748079 of the ITPR3 gene (147267) had a higher risk for SLE
(odds ratio, 5.77).

- Association with the ITPR3 Gene on Chromosome 6p21

Oishi et al. (2008) performed a case-control association study using
more than 50,000 genomewide gene-based SNPs in a total of 543 Japanese
SLE patients and 2,596 controls and identified significant association
with a -1009C-T transition (dbSNP rs3748079) located in a promoter
region of the ITPR3 gene (p = 1.78 x 10(-8); odds ratio, 1.88). Studies
in HEK293T cells showed that binding of NKX2-5 is specific to the
nonsusceptibility -1009T allele, and individuals with the risk genotype
of both ITPR3 and NKX2-5 (dbSNP rs3095870) had a higher risk for SLE
(odds ratio, 5.77). Oishi et al. (2008) concluded that genetic and
functional interactions of ITPR3 and NKX2-5 play a crucial role in the
pathogenesis of SLE.

- Association with the TNFA Gene on Chromosome 6p21.3

In a metaanalysis of 19 studies, Lee et al. (2006) found an association
between SLE and a -308A/G promoter polymorphism in the TNFA gene
(191160.0004). The findings were significant in European-derived
population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not
in Asian-derived populations.

- Association with the C4A and C4B Genes on Chromosome 6p21.3

Yang et al. (2007) investigated interindividual gene copy number
variation (CNV) of complement component C4 in relation to susceptibility
to SLE. They found that long C4 genes were strongly correlated with C4A
(120810); short C4 genes were correlated with C4B (120820). In
comparison with healthy subjects, patients with SLE clearly had the gene
copy number (GCN) of total C4 and C4A shifted to the lower side. The
risk of SLE disease susceptibility increased significantly among
subjects with only 2 copies of total C4 (patients 9.3%; unrelated
controls 1.5%) but decreased in those with 5 or more copies of C4
(patients 5.79%; controls 12%). Zero copies and 1 copy of C4A were risk
factors for SLE, whereas 3 or more copies of C4A appeared to be
protective. Family-based association tests suggested that a specific
haplotype with a single short C4B in tight linkage disequilibrium with
the -308A allele of TNFA (191160.0004) was more likely to be transmitted
to patients with SLE.

Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients
from the UK and 537 from Spain, and 1,179 controls for gene copy number
of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001)
resulting in a null allele. The loss-of-function SNP in C4A was not
associated with SLE in either population. Boteva et al. (2012) used
multiple logistic regression to determine the independence of C4 CNV
from known SNP and HLA-DRB1 associations. Overall, the findings
indicated that partial C4 deficiency states are not independent risk
factors for SLE in UK and Spanish populations. Although complete
homozygous deficiency of complement C4 is one of the strongest genetic
risk factors for SLE, partial C4 deficiency states do not independently
predispose to the disease.

- Association with the TNXB Gene on Chromosome 6p21.3

In a genomewide case-control association study of 178 Japanese SLE
patients and 899 controls, Kamatani et al. (2008) found significant
association between SLE and a SNP (dbSNP rs3130342) in the 5-prime
flanking region of the TNXB gene (600985) on chromosome 6p21.3 (p = 9.3
x 10(-7)); odds ratio, 3.11). The association was replicated
independently with 203 cases and 294 controls (p = 0.04; odds ratio,
1.52). Analysis in their Japanese SLE patients showed that the
association with dbSNP rs3130342 was independent of C4 copy number,
suggesting that the association previously reported between SLE and CNV
of the C4A gene (see Yang et al., 2007) likely reflected linkage
disequilibrium between C4A CNV and dbSNP rs3130342. Stratified analysis
also demonstrated that the association between dbSNP rs3130342 and SLE
was independent of the HLA-DRB1*1501 allele association with SLE.
Kamatani et al. (2008) concluded that TNXB is a candidate gene for SLE
susceptibility in the Japanese population.

- Association with the TNFAIP3 Gene on Chromosome 6q23

In separate genomewide association studies, Graham et al. (2008) and
Musone et al. (2008) found association between single-nucleotide
polymorphisms (SNPs) in the TNFAIP3 region (191163) and risk of SLE.
Graham et al. (2008) found association with SLE of a SNP that is also
associated with rheumatoid arthritis (RA; 180300).

- Association with the IRF5 Gene on Chromosome 7q32

Sigurdsson et al. (2005) and Graham et al. (2006) showed that a common
IRF5 (607218) haplotype, which drives elevated expression of multiple
unique forms of IRF5, is an important risk factor for SLE (SLEB10;
612251).

- Association with the DNASE1 Gene on Chromosome 16p13.3

In 2 unrelated females with SLE and no family history of the disorder,
Yasutomo et al. (2001) identified heterozygosity for a mutation in the
DNASE1 gene (125505.0001). The patients, aged 13 and 17 years, were
diagnosed as having SLE based on clinical features, high serum titers of
antibodies against double-stranded DNA, and Sjogren syndrome. Both
patients had substantially lower levels of DNASE1 activity in the sera
than in other SLE patients without a DNASE1 mutation. However, the
DNASE1 activity of SLE patients without DNASE1 mutations is lower than
that of healthy controls. The patient's B cells had 30 to 50% of the
DNASE1 activity of cells from controls, showing that heterozygous
mutation of DNASE1 reduces the total activity of this enzyme.

In 350 Korean patients with SLE and 330 Korean controls, Shin et al.
(2004) identified a nonsynonymous SNP in exon 8 of the DNASE1 gene,
2373A-G (Q244R; 125505.0002), that was significantly associated with an
increased risk of the production of anti-RNP and anti-dsDNA antibodies
among SLE patients. The frequency of the arg/arg minor allele was much
higher in patients who had the anti-RNP antibody (31%) than in patients
who did not have this antibody (14%) (P = 0.0006).

- Association with the ITGAM Gene on Chromosome 16p11.2

See SLEB6, 609939.

Nath et al. (2008) identified and replicated an association between
ITGAM (120980) at 16p11.2 and risk of SLE in 3,818 individuals of
European descent. The strongest association was at a nonsynonymous SNP,
dbSNP rs1143679 (120980.0001). Nath et al. (2008) further replicated
this association in 2 independent samples of individuals of African
descent. The International Consortium for Systemic Lupus Erythematosus
Genetics et al. (2008) likewise identified an association between SNPs
in ITGAM in 720 women of European ancestry with SLE and in 2 additional
independent sample sets. Several previously identified associations such
as the strong association between SLE and the HLA region on 6p21 and the
previously confirmed non-HLA locus IRF5 (607218) on 7q32 were found. The
International Consortium for Systemic Lupus Erythematosus Genetics et
al. (2008) also found association with replication for KIAA1542 (611780)
at 11p15.5, PXK (611450) in 3p14.3, and a SNP at 1q25.1.

Hom et al. (2008) identified SNPs near the ITGAM and ITGAX (151510)
genes that were associated with SLE; they believed variants of ITGAM to
be driving the association.

- Association with the IL6 Gene on chromosome 7p21

Linker-Israeli et al. (1999) used PCR and RFLP analysis to genotype the
AT-rich minisatellite in the 3-prime flanking region and the 5-prime
promoter-enhancer of IL6 (147620) in SLE patients and controls. In both
African-Americans and Caucasians, short allele sizes (less than 792 bp)
at the 3-prime minisatellite were found exclusively in SLE patients,
whereas the 828-bp allele was overrepresented in controls. No
association was found between SLE and alleles in the 5-prime region of
IL6. Patients homo- or heterozygous for the SLE-associated 3-prime
minisatellite alleles secreted higher levels of IL6, had higher
percentages of IL6-positive monocytes, and showed significantly enhanced
IL6 mRNA stability. Linker-Israeli et al. (1999) concluded that the
AT-rich minisatellite in the 3-prime region flanking of IL6 is
associated with SLE, possibly by increasing accessibility for
transcription factors.

- Association with the IL18 Gene on Chromosome 11q22

Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene (600953)
and genotyped an independent set of 752 Spanish systemic lupus
erythematosis patients and 595 Spanish controls. A -1297T-C SNP (dbSNP
rs360719) survived correction for multiple tests and was genotyped in 2
case-control replication cohorts from Italy and Argentina. Combined
analysis for the risk C allele remained significant (pooled odds ratio =
1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a
significant increase in the relative expression of IL18 mRNA in
individuals carrying the risk -1297C allele; in addition, -1297C allele
created a binding site for the transcriptional factor OCT1 (POU2F1;
164175). Sanchez et al. (2009) suggested that the dbSNP rs360719 variant
may play a role in susceptibility to SLE and in IL18 expression.

- Association with the CSK Gene on Chromosome 15q23-q25

The c-Src tyrosine kinase CSK (124095) physically interacts with the
intracellular phosphatase LYP (PTPN22; 600716) and can modify the
activation state of downstream Src kinases, such as LYN (165120), in
lymphocytes. Manjarrez-Orduno et al. (2012) identified an association of
CSK with SLE and refined its location to the intronic polymorphism dbSNP
rs34933034 (odds ratio = 1.32; p = 1.04 x 10(-9)). The risk allele at
this SNP is associated with increased CSK expression and augments
inhibitory phosphorylation of LYN. In carriers of the risk allele, there
is increased B-cell receptor-mediated activation of mature B cells, as
well as higher concentrations of plasma IgM, relative to individuals in
the nonrisk haplotype. Moreover, the fraction of transitional B cells is
doubled in the cord blood of carriers of the risk allele, due to an
expansion of late transitional cells in a stage targeted by selection
mechanisms. Manjarrez-Orduno et al. (2012) concluded that their results
suggested that the LYP-CSK complex increases susceptibility to lupus at
multiple maturation and activation points in B cells.

- Association with the EGR2 Gene on Chromosome 10q21

Based on phenotypic changes in knockout mice, Myouzen et al. (2010)
evaluated if polymorphisms in the EGR2 gene (129010) on chromosome 10q21
influence SLE susceptibility in humans. A significant positive
correlation with expression was identified in a SNP located at the
5-prime flanking region of EGR2. In a case-control association study
using 3 sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene
region, a peak of association with SLE susceptibility was observed for
dbSNP rs10761670. This SNP was also associated with susceptibility to
rheumatoid arthritis (RA; 180300), suggesting that EGR2 is a common risk
factor for SLE and RA. Among the SNPs in complete linkage disequilibrium
with dbSNP rs10761670, 2 SNPs (dbSNP rs1412554 and dbSNP rs1509957)
affected the binding of transcription factors and transcriptional
activity in vitro, suggesting that they may be candidates of causal
regulatory variants in this region. The authors proposed that EGR2 may
be a genetic risk factor for SLE, in which increased gene expression may
contribute to SLE pathogenesis.

PATHOGENESIS

The role of estrogen in determining female preponderance of lupus was
reviewed by Talal (1979). Patients with the XXY Klinefelter syndrome are
predisposed to lupus. Miller and Schwartz (1979) proposed 'that the
development of systemic lupus erythematosus requires the participation
of at least two functionally distinct classes of genes.'

Stohl et al. (1985) identified 3 unrelated Jamaican black patients with
SLE by American Rheumatism Association criteria (Tan et al., 1982) and
with homozygous T4 epitope deficiency. Lymphadenopathy was an impressive
feature and was present also in an asymptomatic and otherwise apparently
healthy T4-deficient brother of one of the SLE patients. In 1 family, 2
heterozygotes had Hb Constant Spring and 1 had idiopathic
thrombocytopenic purpura. The anti-DNA antibodies of unrelated SLE
patients share cross-reactive idiotypes. Thus, a restricted number of
germline genes may encode the autoantibodies involved in the
pathogenesis of SLE.

Solomon et al. (1983) described a monoclonal antibody, 3I, that
recognizes a cross-reactive idiotype on anti-DNA antibodies. Halpern et
al. (1985) used this monoclonal antibody to study the sera of 27 members
of 3 unrelated kindreds with SLE. Some healthy family members were found
to have high-titered reactivity with the antiidiotype. The antigenic
specificity of 3I-reactive antibodies in the serum of healthy persons is
unknown. Possibly 3I-reactive antibodies are made in response to some
unknown antigen and these antibodies subsequently mutate and acquire
reactivity with DNA. Diamond and Scharff (1984) showed that a monoclonal
antiphosphorylcholine antibody that has undergone a glutamic to alanine
substitution in a heavy chain hypervariable region loses affinity for
phosphorylcholine and acquires reactivity with DNA and other
phosphorylated macromolecules.

Schur (1995) reviewed the genetics of SLE, with particular reference to
the major histocompatibility complex. He showed that different but
related genes may be associated with lupus and autoantibodies in
different countries. He suggested that examination of homogeneous
(clinical, immunologic, ethnic, etc.) populations offers the best
possibility for unraveling the maze of multiple genes involved in the
disorder.

Kotzin (1996) reviewed the molecular mechanisms in the pathogenesis of
SLE. Vyse and Todd (1996) gave a general review of genetic analysis of
autoimmune diseases, including this one.

Sanghera et al. (1997) noted that beta-2-glycoprotein I (B2GPI, APOH;
138700) is a required cofactor for anionic phospholipid binding by the
antiphospholipid autoantibodies found in sera of many patients with SLE
and primary antiphospholipid syndrome (107320). These studies suggested
that the apoH-phospholipid complex forms the antigen to which the
autoantibodies are directed.

Yasutomo et al. (2001) identified an early termination mutation in
DNASE1 in 2 teenaged girls with SLE from Japan (125505.0001). The
nonsense mutations were associated with reduced DNASE activity and
extremely high immunoglobulin G titer against nucleosomal antigens.
Yasutomo et al. (2001) suggested that their data were consistent with
the hypothesis that a direct connection exists between low activity of
DNASE1 and progression of human SLE.

Blanco et al. (2001) hypothesized that SLE may be caused by alterations
in the functions of dendritic cells. Consistent with this, monocytes
from the blood of SLE patients were found to function as
antigen-presenting cells in vitro. Furthermore, serum from SLE patients
induced normal monocytes to differentiate into dendritic cells. These
dendritic cells could capture antigens from dying cells and present them
to CD4-positive T cells. The capacity of SLE patients' serum to induce
dendritic cell differentiation correlated with disease activity and
depended on the actions of interferon-alpha (147660). Thus, Blanco et
al. (2001) concluded that unabated induction of dendritic cells by
interferon-alpha may drive the autoimmune response in SLE.

Using a rheumatoid factor (RF+) transgenic B cell hybridoma line
originally isolated from an autoimmune MRL/lpr mouse used as a model for
SLE, Leadbetter et al. (2002) determined that these cells respond only
to IgG2a immune complexes containing DNA and not to haptens or proteins.
After ruling out complement receptors (i.e., CD21/CR2, 120650) as a
potential second receptor on B cells, screening of cells expressing the
adaptor protein Myd88 (602170), through which all toll-like receptors
signal, revealed that RF+ B cells lacking Myd88 are completely
unresponsive to IgG2a antinucleosome monoclonal antibodies (mAb). TLR9
(605474) responsiveness to CpG oligodeoxynucleotides (ODN) is presumed
to require endosome acidification. The response to stimulation of RF+ B
cells by IgG2a mAb or CpG-ODN, but not by TLR2 (603028) or TLR4 (603030)
agonists, was blocked by inhibitors of endosome acidification, notably
chloroquine, suggesting a mechanistic basis for its efficacy in the
treatment for both RA and SLE. Leadbetter et al. (2002) proposed that
other endogenous subcellular nucleic acid-protein autoantigens may
signal through other TLRs to abrogate peripheral B-cell tolerance. They
also suggested that infectious agent PAMP (patterns associated with
microbial pathogens) engaging TLRs may create a synergy with
autoantibody-autoantigen immune complexes, thus explaining the
association between infection and autoimmune disease flares.

Risk of SLE is higher in people of West African descent than in
Europeans. Molokhia et al. (2003) attempted to distinguish between
genetic and environmental explanations for this ethnic difference by
examining the relationship of disease risk to individual admixture
(defined as the proportion of the genome that is of West African
ancestry). They studied 124 cases of SLE and 219 matched controls
resident in Trinidad. Analysis of admixture was restricted to 52 cases
and 107 controls who reported no Indian or Chinese ancestry. These
individuals were typed with a panel of 26 SNPs and 5 insertion/deletion
polymorphisms chosen to have large allele frequency differentials
between West African, European, and Native American populations. Mean
West African admixture was 0.81 in cases and 0.74 in controls (P =
0.01). The risk ratio for SLE associated with unit change in this
admixture was estimated as 32.5. Adjustment for measures of
socioeconomic status (household amenities in childhood and years of
education) altered this risk ratio only slightly. These results
supported an additive genetic model for the ethnic difference in risk of
SLE between West Africans and Europeans, rather than an environmental
explanation or an 'overdominant' model in which risk is higher in
heterozygous than in homozygous individuals.

Kowal et al. (2006) demonstrated that human anti-NMDA receptor
antibodies isolated from patients with neuropsychiatric lupus caused
hippocampal neuron damage and memory deficits when administered to mice
with lipopolysaccharide to penetrate the blood-brain barrier. Postmortem
brain tissue from 5 patients with neuropsychiatric lupus showed
endogenous IgG that bound DNA and colocalized with NMDA receptor
antibodies for NR2A (GRIN2A; 138253) and NR2B (GRIN2B; 138252). The
findings suggested that some patients with neuropsychiatric lupus have
circulating anti-NMDAR antibodies capable of causing neuronal damage and
memory deficits if they breach the blood-brain barrier.

To examine the role of defensins in SLE pathogenesis, Sthoeger et al.
(2008) used ELISA and real-time PCR to measure the levels of the
alpha-defensin DEFA2 (125220) and the beta-defensin HBD2 (DEFB4; 602215)
in the blood of SLE patients. They found that HBD2 was undetectable in
sera from SLE patients, and that HBD2 mRNA was low in whole blood from
SLE patients, similar to controls. In contrast, DEFA2 levels were
significantly higher in all SLE patients compared with controls, and 60%
of patients had very high serum levels. High DEFA2 levels correlated
with disease activity, but not with neutrophil numbers, suggesting that
neutrophil degranulation may lead to alpha-defensin secretion in SLE
patients. Reduction of DEFA2 levels to the normal range correlated with
disease improvement.

- Excess Lymphocyte Low Molecular Weight DNA

Mackie et al. (1987) found circulating anticoagulants in multiple
members of SLE families, but also found coagulation abnormalities in
some spouses, suggesting that a transmissible agent or other
environmental factors may be involved. All patients with SLE show 2
classes of newly synthesized DNA in sucrose density gradients of
phytohemagglutinin-stimulated lymphocytes: a large-molecular-weight
fraction that comigrates with control DNA and an excess low molecular
weight DNA (LMW-DNA) fraction not found in control lymphocytes.

ANIMAL MODEL

Knight and Adams (1978) identified 2 genes in New Zealand white (NZW)
mice that determine development of nephritis in crosses with New Zealand
black (NZB) mice.

Theofilopoulos and Dixon (1985) provided a review of murine models of
SLE.

F1 hybrids of NZB and NZW mice are a model of human SLE. These mice
develop a severe immune complex-mediated nephritis, in which antinuclear
autoantibodies seem to play a major role. Vyse et al. (1996) used a
genetic analysis of a backcross between F1 hybrid mice and NZW mice to
provide insight into whether different autoantibodies are subject to
separate genetic influences and to determine which autoantibodies are
most important in the development of lupus-like nephritis. The results
showed one set of loci that coordinately regulated serum levels of IgG
antibodies to double-stranded DNA, single-stranded DNA, total histones,
and chromatin. These loci overlapped with loci that were linked to the
production of autoantibodies to the viral glycoprotein gp70. Loci linked
with anti-gp70 compared with antinuclear antibodies demonstrated the
strongest linkage with renal disease, suggesting that autoantibodies to
gp70 are the major pathogenic antibodies in this model of lupus
nephritis. Interestingly, a locus on the distal part of mouse chromosome
4, Nba1, was linked with nephritis but not with any of the
autoantibodies measured, suggesting that it contributes to renal disease
at a checkpoint distal to autoantibody production.

By linkage analysis, Morel et al. (1994) found that genomic intervals on
mouse chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3) and 17 (Sle4) are
strongly linked to lupus nephritis. Mohan et al. (1999) showed that on a
normal B6 background, the introduction of Sle1, as in the monocongenic
B6.NZMc1 mice, led to hyperglobulinemia, a breach in tolerance to
chromatin, and a modest expansion of activated lymphocytes. However,
serum autoantibodies did not target against double-stranded DNA or
basement membrane antigens. When Sle1 and Sle3 were combined, as in the
bicongenic B6.NZMc1/c7 mice, high titers of autoantibodies were
generated which had specificity not only for the different chromatin
epitopes (including dsDNA) but also for the intact glomeruli, leading to
fatal lupus glomerulonephritis. These findings lent strong support to a
2-step epistatic model for the formation of pathogenic nephrophilic
autoantibodies in lupus.

Gross et al. (2000) overexpressed BAFF (BLYS, or TNFSF13B; 603969) in
lymphoid cells of transgenic mice and found that the mice develop
symptoms characteristic of systemic lupus erythematosus and expand a
rare population of splenic B-1a lymphocytes. Circulating BAFF was more
abundant in New Zealand BWF1 and MRL lpr/lpr mice during the onset and
progression of SLE. Gross et al. (2000) identified 2 TNF receptor family
members, TACI (604907) and BCMA (109545), that bind BAFF. Treatment of
New Zealand BWF1 mice with soluble TACI-Ig fusion protein inhibited the
development of proteinuria and prolonged survival of the animals. These
findings demonstrated the involvement of BAFF and its receptors in the
develop of SLE and identified TACI/Ig as a promising treatment of
autoimmune disease in humans.

Systemic lupus erythematosus is characterized by the presence of
antinuclear antibodies (ANA) directed against naked DNA and entire
nucleosomes. It was thought that the resulting immune complexes
accumulate in vessel walls, glomeruli, and joints and cause a
hypersensitivity reaction type III that manifests as glomerulonephritis,
arthritis, and generalized vasculitis. Several studies had suggested
that increased liberation or disturbed clearance of nuclear DNA-protein
complexes after cell death may initiate and propagate the disease.
Consequently, DNASE1 (125505), which is a major nuclease present in
serum, urine, and secreta, may be responsible for the removal of DNA
from nuclear antigens at sites of high cell turnover and thus prevent
SLE. To test this hypothesis, Napirei et al. (2000) generated
Dnase1-deficient mice by gene targeting. They found that these animals
show the classic symptoms of SLE, namely the presence of ANA, the
deposition of immune complexes in glomeruli, and full-blown
glomerulonephritis in a Dnase1 dose-dependent manner. Moreover, in
agreement with earlier reports, they found Dnase1 activities in serum to
be lower in SLE patients than in normal subjects. The findings suggested
that lack or reduction of Dnase1 is a critical factor in the initiation
of human SLE.

Sun et al. (2002) reported that treatment with 2A, an agonistic
monoclonal antibody to CD137 (TNFRSF9; 602250), blocked lymphadenopathy
and spontaneous autoimmune disease in Fas-deficient mice (a model for
human SLE), ultimately leading to their prolonged survival.
Specifically, 2A treatment rapidly augmented interferon-gamma (IFNG;
147570) production and induced the depletion of autoreactive B cells and
abnormal double-negative T cells, possibly by increasing their apoptosis
through Fas- and TNF receptor-independent mechanisms. Sun et al. (2002)
concluded that agonistic monoclonal antibodies specific for
costimulatory molecules could be used as novel therapeutic agents to
deplete autoreactive lymphocytes and block autoimmune disease
progression.

To clarify mechanisms governing the anxiety seen in lupus, Nakamura et
al. (2003) carried out genomewide scans in mice and found that the
region including interferon-alpha (IFNA; 147660) on chromosome 4 in NZB
mice was significantly linked to the anxiety-like behavior seen in
SLE-prone BWF1 mice. This finding was confirmed by anxiety-like
performances of mice with heterozygous NZB/NZW alleles in the
susceptibility region bred onto the NZW background. In BWF1 mice,
neuronal IFN-alpha levels were elevated and blockade of the mu-1 opioid
receptor (OPRM1; 600018) or corticotropin-releasing hormone receptor-1
(CRHR1; 122561), possible downstream effectors for IFN-alpha in the
brain, partially overcame the anxiety-like behavior seen in these mice.
Neuronal corticotropin-releasing hormone levels were consistently higher
in BWF1 than NZW mice. Furthermore, pretreatment of mu-1 opioid receptor
antagonist abolished anxiety-like behavior seen in IFN-alpha-treated NZW
mice. Nakamura et al. (2003) concluded that a genetically determined
endogenous excess amount of IFN-alpha in the brain may form 1 aspect of
anxiety-like behavior seen in SLE-prone mice.

In SLE-prone NZB mice and their F1 cross with NZW mice, B cell
abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Li
et al. (2004) performed a genomewide scan for susceptibility genes for
aberrant activation of B1 cells in F1/NZB backcross mice and identified
the Ltk gene as a possible candidate. Sequence and functional analyses
of the gene revealed that NZB mice have a gain-of-function polymorphism
in the LTK kinase domain near YXXM, a binding motif of the p85 subunit
of phosphatidylinositol 3-kinase (PIK3R1; 171833). SLE patients had the
equivalent human LTK polymorphism at a significantly higher frequency
compared to healthy controls. Li et al. (2004) suggested that this LTK
SNP may cause upregulation of the PI3K pathway and possibly form a
genetic component of susceptibility to abnormal proliferation of
self-reactive B cells in SLE.

Tournoy et al. (2004) reported that in PS1 (104311) +/- PS2 (600759) -/-
mice, PS1 protein concentration was considerably lowered, functionally
reflected by reduced gamma-secretase activity and impaired beta-catenin
(CTNNB1; 116806) downregulation. Their phenotype was normal up to 6
months, when the majority of the mice developed an autoimmune disease
characterized by dermatitis, glomerulonephritis, keratitis, and
vasculitis, as seen in human systemic lupus erythematosus. Besides B
cell-dominated infiltrates, the authors observed a
hypergammaglobulinemia with immune complex deposits in several tissues,
high-titer nuclear autoantibodies, and an increased CD4+/CD8+ ratio. The
mice further developed a benign skin hyperplasia similar to human
seborrheic keratosis (182000) as opposed to malignant keratocarcinomata
observed in skin-specific PS1 'full' knockouts.

Despite the heterogeneity of factors influencing susceptibility to
lupus, McGaha et al. (2005) demonstrated that the partial restoration of
inhibitory Fc receptor (FC-gamma-RIIB; 604590) levels in B cells in
lupus-prone mouse strains is sufficient to restore tolerance and prevent
autoimmunity. Fc-gamma-RIIB regulates a common B-cell checkpoint in
genetically diverse lupus-prone mouse strains, and modest changes in its
expression can result in either tolerance or autoimmunity. McGaha et al.
(2005) suggested that increasing Fc-gamma-RIIB levels in B cells may be
an effective way to treat autoimmune diseases.

In the MRL-lpr mouse, Barber et al. (2005) found that pharmacologic
inhibition of phosphoinositide 3-kinase-gamma (PIK3CG; 601232), a kinase
that regulates inflammation, reduced CD4+ T-cell populations, reduced
glomerulonephritis, and prolonged life span.

In both mice and humans with SLE, DeGiorgio et al. (2001) found that a
subset of antibodies against dsDNA recognized portions of the
extracellular domain of the NMDA receptor subunits, NR2A (138253) and
NR2B (138252), which are present in the hippocampus, amygdala, and
hypothalamus. Murine and human anti-dsDNA/anti-NR2 antibodies mediated
apoptotic death of neurons in vitro and in vivo. Huerta et al. (2006)
showed that mice immunized to produce anti-dsDNA/anti-NR2 IgG antibodies
developed damage to neurons in the amygdala after being given
epinephrine to induce leaks in the blood-brain barrier. The resulting
neuronal insults were noninflammatory. Mice with antibody-mediated
damage in the amygdala developed behavioral changes characterized by a
deficient response to fear-conditioning paradigms. Huerta et al. (2006)
postulated that when the blood-brain barrier is compromised, neurotoxic
antibodies can penetrate the central nervous system and result in
cognitive, emotional, and behavioral changes, as seen in
neuropsychiatric lupus.

HISTORY

Fronek et al. (1986) found that the distribution of patterns of RFLPs at
the T-cell receptor beta chain locus (see 186930) was the same in SLE
patients as in their relatives and in controls. Thus, the authors
concluded that the TCRB 'genes are not coinherited with genes
responsible for' SLE. Wong et al. (1988) found no linkage to the alpha
(see 186880), beta, and gamma (see 186970) genes of the T-cell receptor.

Levcovitz et al. (1988) reported a family in which a
low-molecular-weight DNA marker for systemic autoimmune disease appeared
to be inherited as an autosomal dominant trait; however, the report was
later retracted.

Using flow cytometric analysis, Tao et al. (2005) found that NKT cells
from patients with active SLE were more susceptible to apoptosis induced
by anti-CD95 (TNFRSF6; 134637) than NKT cells from patients with
inactive SLE or normal controls. Further analysis suggested that
deficient expression of CD226 (605397) and survivin (BIRC5; 603352) in
NKT cells from patients with active SLE may explain the sensitivity of
these cells to apoptosis. However, in 2012, Tao et al. (2005) retracted
their paper.

*FIELD* SA
Arnett and Shulman (1976); Exner et al. (1980); First (1973); Hughes
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(1972); Larsen and Godal (1972); Leonhardt (1964); Lewis et al. (1974);
Pollak (1964); Raveche (1984); Reveille et al. (1983); Serdula and
Rhoads (1979); Siegel et al. (1965); Tsao et al. (1997); Yocum et
al. (1975)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Pericarditis

RESPIRATORY:
[Lung];
Pleuritis

GENITOURINARY:
[Kidneys];
Nephritis

SKELETAL:
[Limbs];
Arthritis

SKIN, NAILS, HAIR:
[Skin];
Erythematous malar rash;
Photosensitivity;
Discoid rash

NEUROLOGIC:
[Central nervous system];
Seizures;
Psychosis

HEMATOLOGY:
Leukopenia;
Thrombocytopenia;
Hemolytic anemia

IMMUNOLOGY:
Systemic lupus erythematosus

LABORATORY ABNORMALITIES:
Antiphospholipid antibody;
Anti dsDNA antibody;
Serum antinuclear antibody

MISCELLANEOUS:
Complement deficiency (e.g. C2 and C4 null alleles) are susceptible
to developing SLE;
Association between HLA class II alleles and presence of autoantibodies;
Onset between ages 16-55;
Female to male ratio 8-13:1

MOLECULAR BASIS:
Susceptibility to SLE caused by mutation in the tumor necrosis factor
ligand superfamily, member 6 gene (TNFSF6, 134638.0001);
Susceptibility to SLE caused by mutation in the receptor for Fc fragment
of IgG, low affinity IIa gene (FCGR2A, 146790.0001)

*FIELD* CN
Ada Hamosh - reviewed: 1/5/2001
Kelly A. Przylepa - revised: 3/16/2000

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

*FIELD* ED
joanna: 07/23/2013
joanna: 4/1/2001
joanna: 1/5/2001
kayiaros: 3/16/2000

*FIELD* CN
George E. Tiller - updated: 9/17/2013
George E. Tiller - updated: 8/26/2013
Paul J. Converse - updated: 5/1/2013
Ada Hamosh - updated: 2/25/2013
Ada Hamosh - updated: 1/15/2013
Paul J. Converse - updated: 9/24/2012
Paul J. Converse - updated: 8/3/2012
Cassandra L. Kniffin - updated: 3/29/2012
Marla J. F. O'Neill - updated: 1/9/2012
Paul J. Converse - updated: 4/29/2011
Cassandra L. Kniffin - updated: 1/14/2011
George E. Tiller - updated: 7/8/2010
Ada Hamosh - updated: 7/1/2010
Ada Hamosh - updated: 2/17/2010
Paul J. Converse - updated: 11/25/2009
Marla J. F. O'Neill - updated: 11/12/2009
George E. Tiller - updated: 7/31/2009
Marla J. F. O'Neill - updated: 11/18/2008
Ada Hamosh - updated: 10/22/2008
Paul J. Converse - updated: 7/31/2008
Paul J. Converse - updated: 5/27/2008
Marla J. F. O'Neill - updated: 9/24/2007
Marla J. F. O'Neill - updated: 9/20/2007
George E. Tiller - updated: 6/21/2007
Victor A. McKusick - updated: 5/23/2007
Cassandra L. Kniffin - updated: 4/12/2007
Paul J. Converse - updated: 10/27/2006
Cassandra L. Kniffin - updated: 9/29/2006
George E. Tiller - updated: 9/11/2006
Victor A. McKusick - updated: 4/26/2006
Cassandra L. Kniffin - updated: 4/5/2006
George E. Tiller - updated: 3/21/2006
George E. Tiller - updated: 3/20/2006
Cassandra L. Kniffin - updated: 3/2/2006
Marla J. F. O'Neill - updated: 2/15/2006
Paul J. Converse - updated: 11/11/2005
Marla J. F. O'Neill - updated: 10/26/2005
Cassandra L. Kniffin - updated: 10/4/2005
Marla J. F. O'Neill - updated: 7/21/2005
Marla J. F. O'Neill - updated: 6/21/2005
Victor A. McKusick - updated: 3/31/2005
Ada Hamosh - updated: 3/7/2005
George E. Tiller - updated: 2/23/2005
Marla J. F. O'Neill - updated: 10/18/2004
Marla J. F. O'Neill - updated: 9/30/2004
Victor A. McKusick - updated: 9/8/2004
Marla J. F. O'Neill - updated: 4/27/2004
Marla J. F. O'Neill - updated: 3/15/2004
Victor A. McKusick - updated: 1/16/2004
Victor A. McKusick - updated: 7/21/2003
Victor A. McKusick - updated: 5/19/2003
Victor A. McKusick - updated: 4/28/2003
Victor A. McKusick - updated: 3/25/2003
Victor A. McKusick - updated: 12/23/2002
Victor A. McKusick - updated: 10/8/2002
Paul J. Converse - updated: 4/10/2002
Ada Hamosh - updated: 11/26/2001
Paul J. Converse - updated: 4/27/2001
Ada Hamosh - updated: 4/12/2001
Paul J. Converse - updated: 2/21/2001
Victor A. McKusick - updated: 12/13/2000
Victor A. McKusick - updated: 11/16/2000
Ada Hamosh - updated: 8/14/2000
Wilson H. Y. Lo - updated: 9/1/1999
Victor A. McKusick - updated: 5/19/1999
Victor A. McKusick - updated: 5/6/1999
Victor A. McKusick - updated: 2/4/1999
Victor A. McKusick - updated: 12/18/1998
Michael J. Wright - updated: 11/16/1998
Mark H. Paalman - updated: 4/10/1997

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

*FIELD* ED
mgross: 10/04/2013
alopez: 9/17/2013
alopez: 8/26/2013
mgross: 5/1/2013
alopez: 2/27/2013
terry: 2/25/2013
alopez: 1/15/2013
carol: 11/8/2012
mgross: 9/25/2012
terry: 9/24/2012
mgross: 8/3/2012
terry: 8/3/2012
mgross: 6/25/2012
terry: 5/3/2012
carol: 4/13/2012
terry: 4/3/2012
ckniffin: 3/29/2012
carol: 1/10/2012
terry: 1/9/2012
mgross: 5/3/2011
terry: 4/29/2011
carol: 4/25/2011
carol: 1/24/2011
ckniffin: 1/14/2011
terry: 9/8/2010
carol: 8/5/2010
wwang: 8/5/2010
wwang: 7/23/2010
terry: 7/8/2010
alopez: 7/2/2010
terry: 7/1/2010
alopez: 3/1/2010
terry: 2/17/2010
wwang: 1/5/2010
ckniffin: 12/29/2009
terry: 12/16/2009
mgross: 12/4/2009
terry: 11/25/2009
wwang: 11/25/2009
terry: 11/12/2009
ckniffin: 8/18/2009
wwang: 8/17/2009
terry: 7/31/2009
terry: 6/3/2009
terry: 1/30/2009
wwang: 11/24/2008
terry: 11/18/2008
alopez: 10/29/2008
terry: 10/22/2008
alopez: 8/26/2008
mgross: 8/14/2008
terry: 7/31/2008
carol: 6/16/2008
carol: 6/2/2008
carol: 5/30/2008
carol: 5/27/2008
terry: 5/27/2008
alopez: 3/11/2008
wwang: 10/1/2007
terry: 9/24/2007
alopez: 9/20/2007
wwang: 6/22/2007
terry: 6/21/2007
alopez: 5/29/2007
terry: 5/23/2007
wwang: 4/19/2007
ckniffin: 4/12/2007
wwang: 4/12/2007
mgross: 1/18/2007
mgross: 10/27/2006
wwang: 10/2/2006
ckniffin: 9/29/2006
alopez: 9/11/2006
wwang: 5/4/2006
wwang: 5/1/2006
terry: 4/26/2006
wwang: 4/7/2006
ckniffin: 4/5/2006
wwang: 3/21/2006
wwang: 3/20/2006
ckniffin: 3/2/2006
wwang: 2/28/2006
wwang: 2/21/2006
terry: 2/15/2006
mgross: 11/14/2005
terry: 11/11/2005
wwang: 10/31/2005
wwang: 10/28/2005
terry: 10/26/2005
carol: 10/11/2005
ckniffin: 10/4/2005
wwang: 7/22/2005
terry: 7/21/2005
carol: 7/19/2005
wwang: 6/29/2005
terry: 6/21/2005
wwang: 4/6/2005
wwang: 3/31/2005
terry: 3/31/2005
wwang: 3/9/2005
wwang: 3/7/2005
tkritzer: 3/3/2005
terry: 3/1/2005
terry: 2/23/2005
carol: 1/25/2005
carol: 10/18/2004
tkritzer: 9/30/2004
terry: 9/8/2004
carol: 4/27/2004
alopez: 4/2/2004
carol: 3/15/2004
cwells: 1/16/2004
terry: 1/16/2004
alopez: 12/3/2003
tkritzer: 8/21/2003
carol: 7/23/2003
terry: 7/21/2003
tkritzer: 5/29/2003
terry: 5/20/2003
tkritzer: 5/19/2003
alopez: 5/7/2003
tkritzer: 5/2/2003
terry: 4/28/2003
tkritzer: 4/8/2003
tkritzer: 4/2/2003
terry: 3/25/2003
tkritzer: 1/3/2003
tkritzer: 12/26/2002
terry: 12/23/2002
mgross: 10/8/2002
carol: 10/8/2002
alopez: 4/10/2002
alopez: 11/26/2001
terry: 11/26/2001
terry: 7/26/2001
mgross: 4/27/2001
alopez: 4/12/2001
carol: 3/28/2001
mgross: 2/21/2001
terry: 2/21/2001
carol: 2/16/2001
carol: 12/19/2000
terry: 12/13/2000
mgross: 11/16/2000
alopez: 8/18/2000
terry: 8/14/2000
mcapotos: 3/3/2000
alopez: 11/22/1999
carol: 9/1/1999
kayiaros: 7/13/1999
mgross: 5/19/1999
mgross: 5/17/1999
mgross: 5/12/1999
terry: 5/6/1999
carol: 2/6/1999
terry: 2/4/1999
carol: 12/29/1998
terry: 12/18/1998
dkim: 12/15/1998
alopez: 12/8/1998
terry: 11/16/1998
carol: 6/9/1998
terry: 6/1/1998
terry: 11/5/1997
alopez: 7/29/1997
alopez: 5/21/1997
mark: 4/10/1997
jenny: 12/9/1996
terry: 11/25/1996
mark: 10/17/1996
mark: 10/9/1996
terry: 8/19/1996
marlene: 8/6/1996
terry: 8/2/1996
terry: 6/28/1996
terry: 6/26/1996
pfoster: 11/10/1995
mark: 5/5/1995
carol: 10/19/1994
jason: 7/18/1994
terry: 5/11/1994
warfield: 3/28/1994

MIM 614374
*RECORD*
*FIELD* NO
614374
*FIELD* TI
#614374 BLOOD GROUP, CHIDO/RODGERS SYSTEM
;;CHIDO/RODGERS BLOOD GROUP SYSTEM
*FIELD* TX
read moreA number sign (#) is used with this entry because the Chido/Rodgers
blood group system is based on variation in 2 closely linked genes, C4A
(120810) and C4B (120820).

DESCRIPTION

The blood groups Chido (Ch) and Rodgers (Rg) are epitopes on the C4
protein, and polymorphisms associated with these epitopes may lead to
the formation of antibodies to the Ch or Rg antigens in transfused
patients. Identification of anti-Ch or anti-Rg is based on antibody
neutralization with plasma from Ch-positive or Rg-positive individuals
and lack of reactivity with qualified Ch-negative or Rg-negative red
blood cells. The C4 protein occurs in 2 forms, C4A and C4B, which are
encoded by 2 closely linked genes. C4A and C4B are expressed as
single-chain precursors of 1,744 amino acids that are nearly identical,
with amino acids differences at residues 1101 to 1106 distinguishing C4A
from C4B. C4A and C4B are also distinguished by their expression of
either the Ch antigen or the Rg antigen at residues 1188 to 1191, where
the Ch1 epitope has ADLR and the Rg1 epitope has VDLL. C4A proteins
usually carry the Rg antigens, and C4B proteins usually carry the Ch
antigens, although in some haplotypes these associations are switched.
Nine antigens have been described for the Ch/Rg system: 6 of high
prevalence for Ch, 2 of high prevalence for Rg, and 1 of low prevalence,
WH. Eight phenotypes of the Ch/Rg system have been established, with
88.2% of individuals having the Ch(1,2,3) Chido phenotype and 95.0% of
individuals having the Rg(1,2) Rodgers phenotype (review by Mougey
(2010)).

MOLECULAR GENETICS

Awdeh and Alper (1980) introduced a typing system that allowed them to
detect 6 common structural alleles at the Rodgers (C4A) locus or 2 or 3
at the Chido (C4B) locus in whites.

HISTORY

The Chido blood group, which was discovered by Harris et al. (1967), is
an antigenic characteristic of C4B. Chido has a low frequency of
negatives (2%) and is tightly linked to HLA (Middleton and Crookston,
1972), closer to HLA-B (142830) than to HLA-A (14280). The Chido antigen
resembles the HLA antigens in molecular structure.

Like Chido, Rodgers has a low frequency of negatives (about 3%) and is
closely linked to HLA (Giles et al., 1976).

*FIELD* SA
Middleton et al. (1974)
*FIELD* RF
1. Awdeh, Z. L.; Alper, C. A.: Inherited structural polymorphism
of the fourth component of human complement. Proc. Nat. Acad. Sci. 77:
3576-3580, 1980.

2. Giles, C. M.; Gedde-Dahl, T., Jr.; Robson, E. B.; Thorsby, E.;
Olaisen, B.; Arnason, A.; Kissmeyer-Nielsen, F.; Schreuder, I.: Rg(a)
(Rodgers) and the HLA region: linkage and associations. Tissue Antigens 8:
143-149, 1976.

3. Harris, J. P.; Tegoli, J.; Swanson, J.; Fisher, N.; Gavin, J.;
Noades, J.: A nebulous antibody responsible for cross-matching difficulties
(Chido). Vox Sang. 12: 140-142, 1967.

4. Middleton, J.; Crookston, M. C.: Chido-substance in plasma. Vox
Sang. 23: 256-261, 1972.

5. Middleton, J.; Crookston, M. C.; Falk, J. A.; Robson, E. B.; Cook,
P. J. L.; Batchelor, J. R.; Bodmer, J.; Ferrara, G. B.; Festenstein,
J.; Harris, H.; Kissmeyer-Nielsen, F.; Lawler, S. D.; Sachs, J. A.;
Wolf, E.: Linkage of Chido and HL-A. Tissue Antigens 4: 366-373,
1974.

6. Mougey, R.: A review of the Chido/Rodgers blood group. Immunohematology 26:
30-38, 2010.

*FIELD* CD
Matthew B. Gross: 12/5/2011

*FIELD* ED
terry: 12/09/2011
mgross: 12/5/2011

MIM 614379
*RECORD*
*FIELD* NO
614379
*FIELD* TI
#614379 COMPLEMENT COMPONENT 4B DEFICIENCY; C4BD
;;C4B DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because C4B deficiency is
read morecaused by mutation in the C4B gene (120820).

CLINICAL FEATURES

Partial deficiency of C4 was found in 3 persons during a screening of
42,000 healthy Japanese (Torisu et al., 1970).

Of 26 patients with autoimmune chronic active hepatitis beginning in
childhood, Vergani et al. (1985) found low C4 in 18 (69%) and low C3
serum levels in 5 (19%). Associated characteristics indicated a defect
in synthesis of C4 and a genetic basis thereof was indicated by the fact
that C4 phenotyping in 20 patients and in 26 parents showed that 90% and
81%, respectively, had null allotypes at either the C4A or C4B locus
compared with 59% in controls.

Homozygous deficiency of C4A (614380) is associated with systemic lupus
erythematosus (152700) and with type I diabetes mellitus; homozygous
deficiency of C4B is associated with susceptibility to bacterial
meningitis (Winkelstein, 1987).

In 3 African-American patients with systemic lupus erythematosus (SLE;
152700), Wilson and Perez (1988) found complete deficiency of plasma
C4B.

Lhotta et al. (1990) stated that only 17 cases of complete deficiency of
C4 had been described. They described a patient with complete deficiency
and renal disease, first presenting as severe Henoch-Schonlein purpura
with renal involvement at the age of 17. Six years later, he developed
hypertension and nephrotic syndrome, requiring hemodialysis followed by
cadaveric kidney graft. After 2 years of uncomplicated course, the
patient suffered a recurrence of his primary disease in the grafted
kidney.

MOLECULAR GENETICS

Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient
proband and provided evidence that the deficiency results from
homozygosity for a rare, double-null haplotype. The family contained
persons with 1, 2, 3, or 4 expressed C4 genes, and the mean serum C4
levels roughly reflected the number of structural genes present.

To evaluate the molecular basis of the C4-null phenotypes, Partanen et
al. (1988) used Southern blotting techniques to analyze genomic DNA from
23 patients with systemic lupus erythematosus (SLE; 152700) and from
healthy controls. They confirmed the earlier findings of high
frequencies of C4-null phenotypes and of HLA-B8,DR3 antigens. In
addition, they found that among the patients most of both the C4A
(120810)- and C4B-null phenotypes resulted from gene deletions. Among
the controls, only the C4A-null phenotypes were predominantly the result
of gene deletions. In all SLE cases, the C4 gene deletions extended also
to a closely linked pseudogene, CYP21A (613815). Altogether, 52% of the
patients and 26% of the controls carried a C4/CYP21A deletion. Partanen
et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci
fell within the range of 30 to 38 kb, as determined by pulsed-field gel
electrophoresis. Because the deletion sizes in most other gene clusters
were more heterogeneous, the results suggested to Partanen et al. (1989)
the involvement of a specific mechanism in the generation of C4/CYP21
deletions.

In a 9-year-old girl with SLE and complete C4 deficiency, Welch et al.
(1990) found uniparental isodisomy 6. The girl had 2 identical
chromosome 6 haplotypes from the father and none from the mother.

Fasano et al. (1992) studied a 7-year-old patient with recurrent
sinopulmonary infections in whom the rare C4A*Q0,B*Q0 double-null
haplotype was shown to be due to a recombination event within the C4B
locus in the mother, who possessed a C4A*Q0,B*1 haplotype and a
C4A*3,B*1 haplotype. By segregation analysis, they mapped the
recombination to a region 3-prime to the unique 6.4-kb TaqI restriction
fragment of the maternal C4B locus.

Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients
from the UK and 537 from Spain, and 1,179 controls for gene copy number
(GCN) of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0;
120810.0001) resulting in a null allele. The loss-of-function SNP in C4A
was not associated with SLE in either population. Boteva et al. (2012)
used multiple logistic regression to determine the independence of C4
CNV from known SNP and HLA-DRB1 associations. Overall, the findings
indicated that partial C4 deficiency states are not independent risk
factors for SLE in UK and Spanish populations. Although complete
homozygous deficiency of complement C4 is one of the strongest genetic
risk factors for SLE, partial C4 deficiency states do not independently
predispose to the disease.

POPULATION GENETICS

Ranford et al. (1987) found an extraordinarily high frequency of C4
deficiency in the Australian aboriginal population of Darwin: 29% as
compared with 12% in aborigines in Alice Springs and 17% in Canberra
blood donors. Partial C4B deficiency was also higher in Darwin
aborigines than in the other populations.

*FIELD* RF
1. Awdeh, Z. L.; Ochs, H. D.; Alper, C. A.: Genetic analysis of C4
deficiency. J. Clin. Invest. 67: 260-263, 1981.

2. Boteva, L.; Morris, D. L.; Cortes-Hernandez, J.; Martin, J.; Vyse,
T. J.; Fernando, M. M. A.: Genetically determined partial complement
C4 deficiency states are not independent risk factors for SLE in UK
and Spanish populations. Am. J. Hum. Genet. 90: 445-456, 2012.

3. Fasano, M. B.; Winkelstein, J. A.; LaRosa, T.; Bias, W. B.; McLean,
R. H.: A unique recombination event resulting in a C4A*Q0,C4B*Q0
double null haplotype. J. Clin. Invest. 90: 1180-1184, 1992.

4. Lhotta, K.; Konig, P.; Hintner, H.; Spielberger, M.; Dittrich,
P.: Renal disease in a patient with hereditary complete deficiency
of the fourth component of complement. Nephron 56: 206-211, 1990.

5. Partanen, J.; Kere, J.; Wessberg, S.; Koskimies, S.: Determination
of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase
genes by pulsed-field gel electrophoresis. Genomics 5: 345-349,
1989.

6. Partanen, J.; Koskimies, S.; Johansson, E.: C4 null phenotypes
among lupus erythematosus patients are predominantly the result of
deletions covering C4 and closely linked 21-hydroxylase A genes. J.
Med. Genet. 25: 387-391, 1988.

7. Ranford, P.; Serjeantson, S. W.; Hay, J.; Dunckley, H.: A high
frequency of inherited deficiency of complement component C4 in Darwin
aborigines. Aust. New Zeal. J. Med. 17: 420-423, 1987.

8. Torisu, M.; Sonozaki, H.; Inai, S.; Arata, M.: Deficiency of the
fourth component of complement in man. J. Immunogenet. 104: 728-737,
1970.

9. Vergani, D.; Wells, L.; Larcher, V. F.; Nasaruddin, B. A.; Davies,
E. T.; Mieli-Vergani, G.; Mowat, A. P.: Genetically determined low
C4: a predisposing factor to autoimmune chronic active hepatitis. Lancet 325:
294-298, 1985. Note: Originally Volume II.

10. Welch, T. R.; Beischel, L. S.; Choi, E.; Balakrishnan, K.; Bishof,
N. A.: Uniparental isodisomy 6 associated with deficiency of the
fourth component of complement. J. Clin. Invest. 86: 675-678, 1990.

11. Wilson, W. A.; Perez, M. C.: Complete C4B deficiency in black
Americans with systemic lupus erythematosus. J. Rheum. 15: 1855-1858,
1988.

12. Winkelstein, J. A.: Personal Communication. Baltimore, Md.
9/15/1987.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/29/2012

*FIELD* CD
Matthew B. Gross: 12/6/2011

*FIELD* ED
carol: 04/13/2012
terry: 4/3/2012
ckniffin: 3/29/2012
mgross: 12/7/2011
mgross: 12/6/2011