RBCC Red Blood Cell Collection

IGHG1 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ig gamma-1 chain C region
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01857
ID IGHG1_HUMAN Reviewed; 330 AA.
AC P01857;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Ig gamma-1 chain C region;
GN Name=IGHG1;
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].
RX PubMed=6287432; DOI=10.1093/nar/10.13.4071;
RA Ellison J.W., Berson B.J., Hood L.E.;
RT "The nucleotide sequence of a human immunoglobulin C gamma1 gene.";
RL Nucleic Acids Res. 10:4071-4079(1982).
RN [2]
RP PROTEIN SEQUENCE OF 1-135 (MYELOMA PROTEIN EU).
RX PubMed=5489771; DOI=10.1021/bi00818a008;
RA Cunningham B.A., Rutishauser U., Gall W.E., Gottlieb P.D.,
RA Waxdal M.J., Edelman G.M.;
RT "The covalent structure of a human gamma G-immunoglobulin. VII. Amino
RT acid sequence of heavy-chain cyanogen bromide fragments H1-H4.";
RL Biochemistry 9:3161-3170(1970).
RN [3]
RP PROTEIN SEQUENCE OF 136-329 (EU).
RX PubMed=5530842; DOI=10.1021/bi00818a009;
RA Rutishauser U., Cunningham B.A., Bennett C., Konigsberg W.H.,
RA Edelman G.M.;
RT "The covalent structure of a human gamma G-immunoglobulin. 8. Amino
RT acid sequence of heavy-chain cyanogen bromide fragments H5-H7.";
RL Biochemistry 9:3171-3181(1970).
RN [4]
RP PROTEIN SEQUENCE (MYELOMA PROTEIN NIE).
RX PubMed=826475;
RA Ponstingl H., Hilschmann N.;
RT "The rule of antibody structure. The primary structure of a monoclonal
RT IgG1 immunoglobulin (myeloma protein Nie). III. The chymotryptic
RT peptides of the H-chain, alignment of the tryptic peptides and
RT discussion of the complete structure.";
RL Hoppe-Seyler's Z. Physiol. Chem. 357:1571-1604(1976).
RN [5]
RP PROTEIN SEQUENCE (MYELOMA PROTEIN KOL), AND DISULFIDE BONDS.
RX PubMed=6884994;
RA Schmidt W.E., Jung H.-D., Palm W., Hilschmann N.;
RT "Three-dimensional structure determination of antibodies. Primary
RT structure of crystallized monoclonal immunoglobulin IgG1 KOL, I.";
RL Hoppe-Seyler's Z. Physiol. Chem. 364:713-747(1983).
RN [6]
RP DISULFIDE BONDS.
RX PubMed=4923144; DOI=10.1021/bi00818a011;
RA Gall W.E., Edelman G.M.;
RT "The covalent structure of a human gamma G-immunoglobulin. X.
RT Intrachain disulfide bonds.";
RL Biochemistry 9:3188-3196(1970).
RN [7]
RP DISULFIDE BONDS.
RX PubMed=1002129;
RA Dreker L., Schwarz J., Reichel W., Hilschmann N.;
RT "Rule of antibody structure. The primary structure of a monoclonal
RT IgG1 immunoglobulin (myeloma protein Nie), I: purification and
RT characterization of the protein, the L- and H-chains, the cyanogen
RT bromide cleavage products, and the disulfide bridges.";
RL Hoppe-Seyler's Z. Physiol. Chem. 357:1515-1540(1976).
RN [8]
RP GLYCOSYLATION AT ASN-180.
RX PubMed=19358553; DOI=10.1021/ac900231w;
RA Thaysen-Andersen M., Mysling S., Hojrup P.;
RT "Site-specific glycoprofiling of N-linked glycopeptides using MALDI-
RT TOF MS: strong correlation between signal strength and glycoform
RT quantities.";
RL Anal. Chem. 81:3933-3943(2009).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-180, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [10]
RP GLYCOSYLATION AT ASN-180.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=7236608; DOI=10.1021/bi00512a001;
RA Deisenhofer J.;
RT "Crystallographic refinement and atomic models of a human Fc fragment
RT and its complex with fragment B of protein A from Staphylococcus
RT aureus at 2.9- and 2.8-A resolution.";
RL Biochemistry 20:2361-2370(1981).
RN [13]
RP INVOLVEMENT IN MULTIPLE MYELOMA.
RX PubMed=8943038; DOI=10.1073/pnas.93.24.13931;
RA Bergsagel P.L., Chesi M., Nardini E., Brents L.A., Kirby S.L.,
RA Kuehl W.M.;
RT "Promiscuous translocations into immunoglobulin heavy chain switch
RT regions in multiple myeloma.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:13931-13936(1996).
RN [14]
RP INVOLVEMENT IN MULTIPLE MYELOMA.
RX PubMed=11972529; DOI=10.1046/j.1365-2141.2002.03438.x;
RA Harrison C.J., Mazzullo H., Ross F.M., Cheung K.L., Gerrard G.,
RA Harewood L., Mehta A., Lachmann H.J., Hawkins P.N., Orchard K.H.;
RT "Translocations of 14q32 and deletions of 13q14 are common chromosomal
RT abnormalities in systemic amyloidosis.";
RL Br. J. Haematol. 117:427-435(2002).
CC -!- INTERACTION:
CC P31994:FCGR2B; NbExp=31; IntAct=EBI-356114, EBI-724784;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- DISEASE: Multiple myeloma (MM) [MIM:254500]: A malignant tumor of
CC plasma cells usually arising in the bone marrow and characterized
CC by diffuse involvement of the skeletal system, hyperglobulinemia,
CC Bence-Jones proteinuria and anemia. Complications of multiple
CC myeloma are bone pain, hypercalcemia, renal failure and spinal
CC cord compression. The aberrant antibodies that are produced lead
CC to impaired humoral immunity and patients have a high prevalence
CC of infection. Amyloidosis may develop in some patients. Multiple
CC myeloma is part of a spectrum of diseases ranging from monoclonal
CC gammopathy of unknown significance (MGUS) to plasma cell leukemia.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry. A chromosomal aberration involving
CC IGHG1 is found in multiple myeloma. Translocation
CC t(11;14)(q13;q32) with the IgH locus. Translocation
CC t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3)
CC with FGFR3; translocation t(6;14)(p25;q32) with IRF4.
CC -!- MISCELLANEOUS: Nie has the G1M(17) allotypic marker, 97-K, and the
CC G1M(1) markers, 239-D and 241-L. KOL and EU sequences have the
CC G1M(3) marker and the G1M (non-1) markers.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC82527.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=IMGT/GENE-DB;
CC URL="http://www.imgt.org/IMGT_GENE-DB/GENElect?query=2+IGHG1&species;=Homo+sapiens";
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DR EMBL; J00228; AAC82527.1; ALT_INIT; Genomic_DNA.
DR PIR; A93433; GHHU.
DR UniGene; Hs.510635; -.
DR PDB; 1AJ7; X-ray; 2.10 A; H=1-103.
DR PDB; 1AQK; X-ray; 1.84 A; H=1-103.
DR PDB; 1BEY; X-ray; 3.25 A; H=1-98.
DR PDB; 1D5B; X-ray; 2.80 A; B/H=1-101.
DR PDB; 1D5I; X-ray; 2.00 A; H=1-101.
DR PDB; 1D6V; X-ray; 2.00 A; H=1-101.
DR PDB; 1DFB; X-ray; 2.70 A; H=1-103.
DR PDB; 1DN2; X-ray; 2.70 A; A/B=120-326.
DR PDB; 1E4K; X-ray; 3.20 A; A/B=106-330.
DR PDB; 1FC1; X-ray; 2.90 A; A/B=106-329.
DR PDB; 1FC2; X-ray; 2.80 A; D=106-329.
DR PDB; 1FCC; X-ray; 3.20 A; A/B=121-326.
DR PDB; 1GAF; X-ray; 1.95 A; H=1-103.
DR PDB; 1H3T; X-ray; 2.40 A; A/B=108-330.
DR PDB; 1H3U; X-ray; 2.40 A; A/B=108-330.
DR PDB; 1H3V; X-ray; 3.10 A; A/B=108-330.
DR PDB; 1H3W; X-ray; 2.85 A; M=108-330.
DR PDB; 1H3Y; X-ray; 4.10 A; A/B=108-330.
DR PDB; 1HKL; X-ray; 2.68 A; H=1-103.
DR PDB; 1HZH; X-ray; 2.70 A; H/K=1-330.
DR PDB; 1I7Z; X-ray; 2.30 A; B/D=1-103.
DR PDB; 1L6X; X-ray; 1.65 A; A=120-326.
DR PDB; 1N7M; X-ray; 1.80 A; L=2-102.
DR PDB; 1OP3; X-ray; 1.75 A; H/M=1-102.
DR PDB; 1OQO; X-ray; 2.30 A; A/B=119-330.
DR PDB; 1OQX; X-ray; 2.60 A; A/B=119-330.
DR PDB; 1T83; X-ray; 3.00 A; A/B=107-330.
DR PDB; 1T89; X-ray; 3.50 A; A/B=107-330.
DR PDB; 1VGE; X-ray; 2.00 A; H=1-103.
DR PDB; 2DTS; X-ray; 2.20 A; A/B=108-330.
DR PDB; 2GJ7; X-ray; 5.00 A; A/B=106-330.
DR PDB; 2I5Y; X-ray; 2.20 A; H=1-101.
DR PDB; 2IWG; X-ray; 2.35 A; A/D=120-326.
DR PDB; 2J6E; X-ray; 3.00 A; A/B=99-330.
DR PDB; 2JB5; X-ray; 2.80 A; H=1-102.
DR PDB; 2JB6; X-ray; 2.85 A; B/H=1-102.
DR PDB; 2O5X; X-ray; 2.05 A; H=1-108.
DR PDB; 2O5Y; X-ray; 2.85 A; H=1-108.
DR PDB; 2O5Z; X-ray; 2.40 A; H=1-108.
DR PDB; 2OSL; X-ray; 2.60 A; A/H=1-103.
DR PDB; 2QAD; X-ray; 3.30 A; D/H=1-101.
DR PDB; 2QL1; X-ray; 2.53 A; A=106-330.
DR PDB; 2QQK; X-ray; 2.75 A; H=1-107.
DR PDB; 2QQL; X-ray; 3.10 A; H=1-107.
DR PDB; 2QQN; X-ray; 2.20 A; H=1-107.
DR PDB; 2QR0; X-ray; 3.50 A; B/F/H/L/N/R/T/X=1-103.
DR PDB; 2R56; X-ray; 2.80 A; H/I=1-100.
DR PDB; 2RCJ; X-ray; -; C/D/G/H/K/L/O/P/S/T=1-326.
DR PDB; 2RCS; X-ray; 2.10 A; H=1-103.
DR PDB; 2VXQ; X-ray; 1.90 A; H=1-100.
DR PDB; 2WAH; X-ray; 2.51 A; A/B=120-328.
DR PDB; 3AGV; X-ray; 2.15 A; A/B=120-330.
DR PDB; 3AVE; X-ray; 2.00 A; A/B=108-330.
DR PDB; 3AY4; X-ray; 2.20 A; A/B=108-330.
DR PDB; 3B2U; X-ray; 2.58 A; C/F/H/J/N/Q/T/W=1-102.
DR PDB; 3B2V; X-ray; 3.30 A; H=1-102.
DR PDB; 3BDY; X-ray; 2.60 A; H=1-107.
DR PDB; 3BE1; X-ray; 2.90 A; H=1-107.
DR PDB; 3BKY; X-ray; 2.61 A; H=1-104.
DR PDB; 3BN9; X-ray; 2.17 A; D/F=1-107.
DR PDB; 3BQU; X-ray; 3.00 A; B=2-103.
DR PDB; 3C08; X-ray; 2.15 A; H=1-102.
DR PDB; 3C09; X-ray; 3.20 A; C/H=1-102.
DR PDB; 3C2S; X-ray; 2.30 A; A=106-330.
DR PDB; 3CFJ; X-ray; 2.60 A; B/D/F/H=1-104.
DR PDB; 3CFK; X-ray; 2.60 A; B/D/F/H/I/K/N/P=1-104.
DR PDB; 3CSY; X-ray; 3.40 A; A/C/E/G=1-101.
DR PDB; 3D0L; X-ray; 2.35 A; B=2-105.
DR PDB; 3D0V; X-ray; 2.05 A; B=2-105.
DR PDB; 3D6G; X-ray; 2.30 A; A/B=119-328.
DR PDB; 3D85; X-ray; 1.90 A; B=1-108.
DR PDB; 3DJ9; X-ray; 1.75 A; A=119-225.
DR PDB; 3DNK; X-ray; 2.84 A; A/B=119-330.
DR PDB; 3DO3; X-ray; 2.50 A; A/B=119-330.
DR PDB; 3DRO; X-ray; 3.90 A; B=2-103.
DR PDB; 3DRQ; X-ray; 2.00 A; B=2-103.
DR PDB; 3DVG; X-ray; 2.60 A; B=1-107.
DR PDB; 3DVN; X-ray; 2.70 A; B/H=1-107.
DR PDB; 3EYF; X-ray; 2.30 A; B/D=1-108.
DR PDB; 3EYO; X-ray; 2.50 A; B/D=1-108.
DR PDB; 3EYQ; X-ray; 2.40 A; D=1-108.
DR PDB; 3FJT; X-ray; 2.50 A; A/B=119-327.
DR PDB; 3O11; X-ray; 2.80 A; B/H=1-103.
DR PDB; 3RY6; X-ray; 3.80 A; A/B=114-327.
DR PDB; 3S7G; X-ray; 3.13 A; A/B/C/D=104-330.
DR PDB; 3SGJ; X-ray; 2.20 A; A/B=106-330.
DR PDB; 3SGK; X-ray; 2.40 A; A/B=106-330.
DR PDB; 3TV3; X-ray; 1.29 A; H=1-104.
DR PDB; 3TWC; X-ray; 1.65 A; H=1-104.
DR PDB; 3TYG; X-ray; 3.25 A; H=1-104.
DR PDB; 3U0W; X-ray; 2.00 A; H=1-103.
DR PDB; 3U7W; X-ray; 2.60 A; H=1-104.
DR PDB; 3U7Y; X-ray; 2.45 A; H=1-104.
DR PDB; 3V7M; X-ray; 2.02 A; A=119-327.
DR PDB; 3V8C; X-ray; 2.77 A; A/B=119-330.
DR PDB; 3V95; X-ray; 2.70 A; A/B=119-330.
DR PDB; 3WJJ; X-ray; 2.60 A; A/B=99-328.
DR PDB; 3WJL; X-ray; 2.86 A; A/B=99-328.
DR PDB; 4ACP; X-ray; 2.49 A; A/B=101-329.
DR PDB; 4B7I; X-ray; 2.36 A; A/B=120-329.
DR PDB; 4BM7; X-ray; 1.95 A; A/B=106-329.
DR PDB; 4BSV; X-ray; 1.75 A; A/B=106-330.
DR PDB; 4BSW; X-ray; 2.15 A; A/B=106-330.
DR PDB; 4BYH; X-ray; 2.30 A; A/B=106-329.
DR PDB; 4D9Q; X-ray; 2.28 A; E/H=2-102.
DR PDB; 4D9R; X-ray; 2.42 A; E/H=2-103.
DR PDB; 4DAG; X-ray; 3.39 A; H=2-98.
DR PDB; 4DZ8; X-ray; 1.91 A; A/B=108-330.
DR PDB; 4EOW; X-ray; 1.97 A; H=1-101.
DR PDB; 4J12; X-ray; 1.90 A; A=119-327.
DR PDBsum; 1AJ7; -.
DR PDBsum; 1AQK; -.
DR PDBsum; 1BEY; -.
DR PDBsum; 1D5B; -.
DR PDBsum; 1D5I; -.
DR PDBsum; 1D6V; -.
DR PDBsum; 1DFB; -.
DR PDBsum; 1DN2; -.
DR PDBsum; 1E4K; -.
DR PDBsum; 1FC1; -.
DR PDBsum; 1FC2; -.
DR PDBsum; 1FCC; -.
DR PDBsum; 1GAF; -.
DR PDBsum; 1H3T; -.
DR PDBsum; 1H3U; -.
DR PDBsum; 1H3V; -.
DR PDBsum; 1H3W; -.
DR PDBsum; 1H3Y; -.
DR PDBsum; 1HKL; -.
DR PDBsum; 1HZH; -.
DR PDBsum; 1I7Z; -.
DR PDBsum; 1L6X; -.
DR PDBsum; 1N7M; -.
DR PDBsum; 1OP3; -.
DR PDBsum; 1OQO; -.
DR PDBsum; 1OQX; -.
DR PDBsum; 1T83; -.
DR PDBsum; 1T89; -.
DR PDBsum; 1VGE; -.
DR PDBsum; 2DTS; -.
DR PDBsum; 2GJ7; -.
DR PDBsum; 2I5Y; -.
DR PDBsum; 2IWG; -.
DR PDBsum; 2J6E; -.
DR PDBsum; 2JB5; -.
DR PDBsum; 2JB6; -.
DR PDBsum; 2O5X; -.
DR PDBsum; 2O5Y; -.
DR PDBsum; 2O5Z; -.
DR PDBsum; 2OSL; -.
DR PDBsum; 2QAD; -.
DR PDBsum; 2QL1; -.
DR PDBsum; 2QQK; -.
DR PDBsum; 2QQL; -.
DR PDBsum; 2QQN; -.
DR PDBsum; 2QR0; -.
DR PDBsum; 2R56; -.
DR PDBsum; 2RCJ; -.
DR PDBsum; 2RCS; -.
DR PDBsum; 2VXQ; -.
DR PDBsum; 2WAH; -.
DR PDBsum; 3AGV; -.
DR PDBsum; 3AVE; -.
DR PDBsum; 3AY4; -.
DR PDBsum; 3B2U; -.
DR PDBsum; 3B2V; -.
DR PDBsum; 3BDY; -.
DR PDBsum; 3BE1; -.
DR PDBsum; 3BKY; -.
DR PDBsum; 3BN9; -.
DR PDBsum; 3BQU; -.
DR PDBsum; 3C08; -.
DR PDBsum; 3C09; -.
DR PDBsum; 3C2S; -.
DR PDBsum; 3CFJ; -.
DR PDBsum; 3CFK; -.
DR PDBsum; 3CSY; -.
DR PDBsum; 3D0L; -.
DR PDBsum; 3D0V; -.
DR PDBsum; 3D6G; -.
DR PDBsum; 3D85; -.
DR PDBsum; 3DJ9; -.
DR PDBsum; 3DNK; -.
DR PDBsum; 3DO3; -.
DR PDBsum; 3DRO; -.
DR PDBsum; 3DRQ; -.
DR PDBsum; 3DVG; -.
DR PDBsum; 3DVN; -.
DR PDBsum; 3EYF; -.
DR PDBsum; 3EYO; -.
DR PDBsum; 3EYQ; -.
DR PDBsum; 3FJT; -.
DR PDBsum; 3O11; -.
DR PDBsum; 3RY6; -.
DR PDBsum; 3S7G; -.
DR PDBsum; 3SGJ; -.
DR PDBsum; 3SGK; -.
DR PDBsum; 3TV3; -.
DR PDBsum; 3TWC; -.
DR PDBsum; 3TYG; -.
DR PDBsum; 3U0W; -.
DR PDBsum; 3U7W; -.
DR PDBsum; 3U7Y; -.
DR PDBsum; 3V7M; -.
DR PDBsum; 3V8C; -.
DR PDBsum; 3V95; -.
DR PDBsum; 3WJJ; -.
DR PDBsum; 3WJL; -.
DR PDBsum; 4ACP; -.
DR PDBsum; 4B7I; -.
DR PDBsum; 4BM7; -.
DR PDBsum; 4BSV; -.
DR PDBsum; 4BSW; -.
DR PDBsum; 4BYH; -.
DR PDBsum; 4D9Q; -.
DR PDBsum; 4D9R; -.
DR PDBsum; 4DAG; -.
DR PDBsum; 4DZ8; -.
DR PDBsum; 4EOW; -.
DR PDBsum; 4J12; -.
DR ProteinModelPortal; P01857; -.
DR SMR; P01857; 1-330.
DR DIP; DIP-29187N; -.
DR IntAct; P01857; 78.
DR MINT; MINT-120799; -.
DR STRING; 9606.ENSP00000374990; -.
DR DrugBank; DB00051; Adalimumab.
DR DrugBank; DB00074; Basiliximab.
DR DrugBank; DB00111; Daclizumab.
DR DrugBank; DB00065; Infliximab.
DR DrugBank; DB00043; Omalizumab.
DR DrugBank; DB00073; Rituximab.
DR DrugBank; DB00081; Tositumomab.
DR DrugBank; DB00072; Trastuzumab.
DR PhosphoSite; P01857; -.
DR DMDM; 121039; -.
DR DOSAC-COBS-2DPAGE; P01857; -.
DR REPRODUCTION-2DPAGE; P01857; -.
DR UCD-2DPAGE; P01857; -.
DR PaxDb; P01857; -.
DR PRIDE; P01857; -.
DR Ensembl; ENST00000390549; ENSP00000374991; ENSG00000211896.
DR Ensembl; ENST00000605583; ENSP00000474225; ENSG00000271292.
DR UCSC; uc001yse.3; human.
DR GeneCards; GC14M106204; -.
DR HGNC; HGNC:5525; IGHG1.
DR MIM; 147100; gene.
DR MIM; 254500; phenotype.
DR neXtProt; NX_P01857; -.
DR Orphanet; 67038; B-cell chronic lymphocytic leukemia.
DR eggNOG; NOG313034; -.
DR HOVERGEN; HBG005814; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P01857; -.
DR PRO; PR:P01857; -.
DR ArrayExpress; P01857; -.
DR Bgee; P01857; -.
DR CleanEx; HS_IGHG1; -.
DR Genevestigator; P01857; -.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR GO; GO:0003823; F:antigen binding; TAS:UniProtKB.
DR GO; GO:0006958; P:complement activation, classical pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR Gene3D; 2.60.40.10; -; 3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003006; Ig/MHC_CS.
DR InterPro; IPR003597; Ig_C1-set.
DR Pfam; PF07654; C1-set; 3.
DR SMART; SM00407; IGc1; 2.
DR PROSITE; PS50835; IG_LIKE; 3.
DR PROSITE; PS00290; IG_MHC; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Chromosomal rearrangement; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin C region; Immunoglobulin domain; Reference proteome;
KW Secreted.
FT CHAIN <1 330 Ig gamma-1 chain C region.
FT /FTId=PRO_0000153578.
FT REGION 1 98 CH1.
FT REGION 99 110 Hinge.
FT REGION 111 223 CH2.
FT REGION 224 330 CH3.
FT CARBOHYD 180 180 N-linked (GlcNAc...) (complex).
FT DISULFID 27 83
FT DISULFID 103 103 Interchain (with light chain).
FT DISULFID 109 109 Interchain (with heavy chain).
FT DISULFID 112 112 Interchain (with heavy chain).
FT DISULFID 144 204
FT DISULFID 250 308
FT VARIANT 97 97 K -> R (in G1M(3) marker).
FT /FTId=VAR_003886.
FT VARIANT 239 239 D -> E (in G1M(non-1) marker).
FT /FTId=VAR_003887.
FT VARIANT 241 241 L -> M (in G1M(non-1) marker).
FT /FTId=VAR_003888.
FT NON_TER 1 1
FT STRAND 3 5
FT STRAND 7 11
FT STRAND 15 17
FT STRAND 22 26
FT HELIX 29 31
FT STRAND 32 36
FT STRAND 37 46
FT HELIX 48 50
FT STRAND 53 58
FT STRAND 64 70
FT HELIX 73 75
FT STRAND 77 79
FT TURN 81 86
FT STRAND 87 92
FT TURN 93 96
FT STRAND 97 102
FT HELIX 107 109
FT STRAND 111 118
FT STRAND 122 126
FT HELIX 130 134
FT STRAND 136 140
FT STRAND 141 149
FT STRAND 151 153
FT STRAND 157 162
FT STRAND 165 167
FT STRAND 171 173
FT STRAND 176 178
FT STRAND 179 181
FT STRAND 183 190
FT HELIX 193 197
FT STRAND 202 207
FT STRAND 211 213
FT STRAND 215 219
FT STRAND 223 229
FT STRAND 230 234
FT HELIX 238 242
FT STRAND 243 258
FT STRAND 261 266
FT STRAND 269 271
FT STRAND 274 276
FT STRAND 283 285
FT STRAND 287 296
FT HELIX 297 301
FT STRAND 306 311
FT STRAND 313 315
FT HELIX 316 318
FT STRAND 320 324
SQ SEQUENCE 330 AA; 36106 MW; 3770EE106C2FA33D CRC64;
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
//

MIM 147100
*RECORD*
*FIELD* NO
147100
*FIELD* TI
*147100 IgG HEAVY CHAIN LOCUS; IGHG1
;;IMMUNOGLOBULIN Gm1
IGHG1/CCND1 FUSION GENE, INCLUDED;;
read moreIGHG1/LHX4 FUSION GENE, INCLUDED
*FIELD* TX
At least 2 separate autosomal loci determining serologic type of gamma
globulin were identified in the 1950s and 1960s. One was referred to as
the Gm locus and the other as the Inv locus. The genetics of the gamma
globulins has been as revealing of general principles as has been that
of the hemoglobins. The Gm system is associated with the heavy chains of
the IgG molecules encoded, as was later found, by chromosome 14; the Inv
system is associated with the kappa light chains (147200). (See
Anonymous, 1966 for recommended notation for Gm and Inv types.)

Hood and Ein (1968) presented evidence that antibody light chains are an
exception to the rule of 'one gene, one polypeptide chain.' Two separate
loci (a specific region locus and a common region locus) appeared to
code for a single, continuous polypeptide chain. Three closely linked
loci (IgG1, IgG2 and IgG3) were thought to be responsible for the Gm
specificities. Van Loghem et al. (1970) presented evidence on the
linkage relationship of immunoglobulin markers (gamma 1, 2, 3, Am). That
the gamma-G3 and gamma-G1 loci are closely linked was indicated by the
findings in a Lepore-type myeloma protein (Kunkel et al., 1969). A
fourth IgG locus (gamma-G4) was identifiable in the cluster. A family
possibly supporting the sequence (beginning at the N terminus) of
alpha-2, gamma-4, gamma-2, gamma-3, and gamma-1 was presented by Lefranc
et al. (1977).

Gedde-Dahl et al. (1972, 1975) presented data on the linkage of Gm-Pi
(AAT; 107400). They considered heterogeneity of recombination fraction
among males of different Pi type to be very likely. The major difference
seemed to be between the Pi(Z) and other alleles. Possible explanations
included a chromosomal deletion, inversion or locus regulation
recombination in linkage disequilibrium with the Pi locus. Bender et al.
(1979) excluded Gm, Pi and C3 from the segment 6q25-qter and Gm and Pi
from 6p. See 182870 for evidence of linkage to hereditary spherocytosis.
Croce et al. (1979) studied somatic cell hybrids between mouse myeloma
cells and either human peripheral lymphocytes or human lymphoblastoid or
myeloma cells. They observed that the presence or absence of chromosome
14 correlated with formation of human mu, gamma, and alpha heavy chains.
Smith et al. (1981) confirmed assignment of the immunoglobulin heavy
chain family of genes to chromosome 14.

Green (1979) reviewed the genetics of the immunoglobulins in mice and
proposed a nomenclature. From study of somatic cell hybrids, Hengartner
et al. (1978) concluded that the loci for immunoglobulin heavy chains
are on chromosome 12 in the mouse. Meo et al. (1980) reported the
conclusive mapping of the Igh-1 and the linked prealbumin locus to mouse
chromosome 12. In the mouse, the heavy chain variable and constant
regions, Igh-V and Igh-C (Green, 1979), occupy a chromosomal segment at
least 7-11 units long (Pisetsky and Sachs, 1977), and are linked,
probably at the Igh-C end, with the serum prealbumin locus at a distance
of about 11 units (Taylor et al., 1975). Steinberg et al. (1975)
described polymorphism of both Gm and Inv in baboons of Kenya.

In man and in mouse, fine mapping of the immunoglobulin gene progressed
faster than chromosomal and regional assignment. The immunoglobulin loci
were thought to be located in three different chromosomal regions
carrying heavy chain, kappa light chain and lambda light chain loci.
Each region was thought to contain one or more loci specifying the
constant region and a larger number of loci specifying the variable
region of the particular immunoglobulin chain. Evidence from mice
indicated that the codon sequences of each light chain, kappa and
lambda, are constructed during differentiation of plasma cell precursors
by the joining of DNA segments previously far apart. Davis et al. (1980)
showed that the heavy chain genes contain 3 gene segments, V(H), J(H)
and C(H), analogous to the 3 segments of the light chain genes and that
at least 2 recombinational events take place during differentiation of
the antibody-producing or B-cell. The structure of the immunoglobulin
genes and their rearrangement during maturation of the lymphocyte were
reviewed by Robertson (1981); also see Marx (1981). In man, the
immunoglobulin heavy chain family of genes has, beginning from the
5-prime end, 250 or more variable genes, 5 J genes (4 are active), at
least 10 D (for diversity) genes, and the genes for the constant part of
the mu, delta, gamma, epsilon, and alpha heavy chains of IgM, D, G, E,
and A, respectively. In the mouse, the organization of the C(H) gene is
5-prime-J(H)-(6.5 kb)-mu-(4.5 kb)-delta-(unknown kb)-gamma-3-(34
kb)-gamma-1-(21 kb)-gamma-2b-(15 kb)-gamma-2a-(14.5 kb)-epsilon-(12.5
kb)-alpha-3-prime (Shimizu et al., 1981). According to the dogma current
by 1981, a complete H chain gene is formed by at least 2 types of
combinational events: (1) the recombination between a given V(H), a
given J(H), and a given D gene segment to form a V region gene, and (2)
a class switch to a particular C(H) gene beginning with mu and later
shifting to any one of the others. Klein (1981) found that B
cell-derived tumors (mouse myeloma and human Burkitt lymphoma and B-cell
acute lymphoblastic leukemia) have anomalous patterns of immunoglobulin
synthesis which correlate with the type of chromosomal aberration.
Similar observations were made by Lenoir et al. (1982) who had collected
the largest number of variant Burkitt lymphoma translocations. Of 10
tested, all agreed with the hypothesis as to light chain expression: all
the 8;22 translocation cells produced lambda as the only light chain;
all the 2;8 translocation cells produced only kappa; and 8;14
translocation cells produced either kappa or lambda, with an approximate
ratio of 2:1.

Light chain amyloidosis (AL; see 254500) is associated with clonal
plasma cell dyscrasias that are often subtle and nonproliferating.
Illegitimate translocations involving the immunoglobulin heavy chain
gene at 14q32 and deletions of the long arm of chromosome 13 commonly
occur in multiple myeloma, monoclonal gammopathy of undetermined
significance (MGUS), and plasma cell leukemia. In a study of 32 patients
with AL (24 with systemic and 8 with localized disease), Harrison et al.
(2002) found translocations involving IGH and in addition found
deletions of 13q, using dual-color interface fluorescence in situ
hybridization. IGH translocations were observed in 11 patients, of whom
9 had the IGH/CCND1 (168461) fusion from t(11;14)(q13;q32).

Kawamata et al. (2002) demonstrated involvement of the IGHG1 gene in a
t(1;14)(q25;q32) translocation found in pre-B acute lymphoblastic
leukemia. The rearrangement of the IGHG1 and LHX4 (602146) genes
resulted in the 5-prime regulatory region of LHX4 being replaced by the
enhancer region of the IGHG1 gene on 14q32. This led to overexpression
of the LHX4 gene in leukemic cells.

See also entries for the constant, variable, J, and D regions of each of
the heavy, lambda, and kappa immunoglobulin chains, e.g., 147220. One
can, with validity, view each of the 3 as a supergene and the C, V, J,
and D coding segments of DNA as exons of that supergene (VAM).

The immunoglobulin genes are in a chromosomal region noted for its high
frequency of breaks associated with chromosome rearrangement, occurring
both spontaneously in cultured lymphocytes and in certain malignancies.
By means of the same X-14 translocation (known as KOP for Kirby, Opitz
and Pallister, the patient, interpreter, and discoverer, respectively)
that was used to map G6PD and HGPRT to the long arm of the X chromosome
(Ricciuti and Ruddle, 1973), Balazs et al. (1982) concluded that D14S1
is closely linked to the heavy chain immunoglobulin 'locus' and distal
to 14q32, i.e., in the subtelomeric region of 14q. A family linkage
study showed that the maximum likelihood estimate of recombination
between D14S1 and Gm was 3.1% with a 90% upper limit of 11.5%. Cox et
al. (1982) reported on the family of a person with a ring chromosome 14
in which one breakpoint was located at 14q32.3. The affected person did
not express the C-gamma allotypic heavy chain marker, Gm, of the
maternal haplotype, indicating that genetic material necessary for Gm
expression is located distal to 14q32.3. From study of 2 families with
abnormalities of the long arm of chromosome 14, Cox et al. (1982)
localized GM to 14q32.3 and PI to a more proximal position between
14q24.3 and 14q32.1. Cox et al. (1984) refined the assignment to
14q32.33-qter. Linsley et al. (1983) found RFLPs associated with the
heavy chain C-gamma genes. The person with the ring-14 had none of the
maternal complement of C-gamma gene hybridizing fragments. A C-gamma
pseudogene was identified. D14S1 (107750) was not deleted from the
ring-14.

Burrows et al. (1983) showed that rearrangement, not differential RNA
processing, occurs in heavy chain class switching. They demonstrated
loss of DNA sequences between the J(H) and C(G2b) gene segments in a
mouse cell line. Deletions of specific constant region genes are prone
to occur through nonhomologous pairing and unequal crossing-over. This
is a mechanism of evolution and a mechanism of pathogenesis of selective
immunoglobulin deficiencies. The study of deletions has been useful for
confirmation of the gene order demonstrated by DNA cloning (e.g.,
Ellison and Hood, 1982; Flanagan and Rabbitts, 1982; Hisajima et al.,
1983; Max et al., 1982) and by linkage analysis with both DNA and
allotypic markers (e.g., Bech-Hansen et al., 1983; Migone et al., 1983).
Lefranc et al. (1983) found, in apparently healthy members of highly
inbred communities of Tunisian Berbers, 2 types of multiple IgHC gene
deletions. One deletion found by Keyeux et al. (1989) in 6 individuals
in 2 different families (family HASS and family TOU) represented a
simultaneous absence of the IgG1, IgG2, IgG4, and IgA1 immunoglobulins.
This deletion allowed determination of the order of immunoglobulin IgCH
genes and localization of a gamma pseudogene between A1 and G2. The TOU
family had a second deletion that included only the epsilon
pseudogene-1, A1 and the gamma pseudogene. Keyeux et al. (1989)
demonstrated that the multigene deletion in the IgCH cluster involves 2
highly homologous regions, called hsg3 and hsg4, which are hotspots of
recombination, outside the switch sequences. (Hsg3 is located downstream
of G3 and hsg4 is located downstream of G4; hence, their designations.)
Migone et al. (1984) identified 2 additional types of multiple heavy
chain gene deletions. One included the IgE gene. The deletions were
transmitted in a mendelian manner and despite homozygosity seemed to
have no ill effects. (Selective absence of single IgG subclasses had
been found occasionally by immunologic testing for allotypes and
isotypes.) Migone et al. (1984) could confirm the location of the
pseudo-gamma gene between the alpha-1 and gamma-2 genes. It is possible
that some instances of combined variable hypogammaglobulinemia or
selective deficiency of immunoglobulins are caused by deletion or other
changes in this region.

Hofker et al. (1989) determined the complete physical map of the heavy
chain constant region by means of pulsed field gel electrophoresis. The
genes of this region are contained within a 300 kb segment. In both man
and mouse the order is 5-prime--IGHM--IGHD--IGHG--IGHE--IGHA--3-prime.
The C-gamma gene was duplicated to produce 4 copies in the mouse. In
man, after an initial C-gamma duplication, the entire
C-gamma/C-gamma/C-epsilon/C-alpha segment was duplicated. Hofker et al.
(1989) found that a 60-kb segment separates the C-delta locus and the
5-prime end of the cluster containing IGHG3, IGHG1, IGHCEP1, and IGHCA1,
in that order. At a distance 80 kb 3-prime to IGHA1 lies the second
cluster of IGHG2, IGHG4, IGHE, and IGHA2. The C-gamma pseudogene lies
about 35 kb on the 3-prime side of IGHA1.

Zelaschi et al. (1983) used monoclonal antibodies raised in mice to
define 'new' Gm determinants. Jazwinska et al. (1988) demonstrated that
RFLP analysis can be substituted for serologic determination of Gm type
and pointed out several advantages of the molecular genetic method.
Ghanem et al. (1989) found extensive RFLP-type variation in black
Africans involving mainly the IGHG3 and IGHG1 genes, the most 5-prime
members of the IGHG family. Polymorphism is much more extensive in black
Africans than in Caucasoids. The same result was suggested by the study
of Gm haplotypes which have been referred to as G1m, G3m, A2m, and Em,
corresponding to the IgG and IgA subclasses and the IgE class for which
they are markers. The alleles at the respective loci are inherited in
fixed combinations, or Gm-Am-Em haplotypes. Although Km gene frequencies
showed a random distribution in the populations studied, Zhao and Lee
(1989) found that Gm haplotypes were highly useful in mapping the
origins of the Chinese nation. A comparison with Gm haplotype
frequencies in other populations suggested that during human evolution
the Negroid group and the Caucasoid-Mongoloid group diverged first,
followed by a divergence between the Caucasoid and Mongoloid. The data
appeared to indicate 2 distinct subgroups of the Mongoloid race,
northern and southern, corresponding to populations that originated in
the Yellow River valley and the Yangtze River valley, respectively. Zhao
and Lee (1989) found that the northern and southern Mongoloid
populations have Gm(1;21) and Gm(1,3;5) haplotypes as race-associated
markers, respectively. They attributed the presence of the
Caucasian-associated haplotype Gm(3;5) in several of the minorities
living in the northwest part of China to admixture along the Silk Road.
The amount of Caucasian admixture was estimated.

The heavy chain constant region 'locus' shows organization in multiple
levels of internal homology, suggesting a complex evolutionary history
with repeated duplication events. The persisting genetic instability of
the region is highlighted by the not uncommon observation of deletions
or duplications, which probably originated through unequal crossover
events. Bottaro et al. (1989), by pulsed field gel analysis of such
deletions, determined the following map (their Figure 4): --mu-5
kb-delta--gamma-3--26 kb--gamma-1--19 kb--psi-epsilon--13
kb--alpha-1--?60 kb--psi-gamma--?40 kb--gamma-2--18 kb--gamma-4--23
kb--epsilon--10 kb--alpha-2--.

Peschon et al. (1994) found an approximately 10-fold reduction in
precursor B cells with complete IgH rearrangements and in surface IgM+ B
lymphocytes in IL7R-alpha (IL7RA; 146661) -/- mice when compared to
age-matched heterozygous controls. In such mice, Corcoran et al. (1998)
showed that D(H)-J(H) recombination proceeded normally but that
V(H)-D(H)-J(H) joining was decreased; this decrease was greater with
increasing distance of the V(H) segment from D(H)/J(H). Germline
transcripts from distal, unrearranged V segments, a marker of chromatin
changes that precede recombination, were specifically silenced. Thus,
ligands of the IL7 receptor deliver an extrinsic signal that targets V
segment recombination in the heavy chain locus by altering the
accessibility of DNA substrates to the recombinase.

Using FISH, Kosak et al. (2002) demonstrated that the IgH and Ig-kappa
loci, but not the smaller Ig-lambda locus, which has only 3 V gene
segments, have an inverse nuclear distribution in mouse hemopoietic
progenitors and pro-T lymphocytes compared with pro-B lymphocytes. In
pro-T cells, in which these large multisegmented loci are inactive, they
are preferentially positioned at the nuclear periphery, whereas in pro-B
cells, which actively express Ig loci, they have a central configuration
and undergo large-scale IL7R-dependent compaction. Kosak et al. (2002)
proposed that a peripheral positioning of these loci inhibits their
transcription and rearrangement by being sequestered away from the
transcription and recombination apparatus and/or by the assembly of a
refractory structure. In addition, the large-scale central compaction
may function to facilitate long-range V(D)J rearrangement.

Roix et al. (2003) examined the question of why translocations between
chromosomes tend to recur at specific breakpoints in the genome. They
provided evidence that higher-order spatial genome organization is a
contributing factor in the formation of recurrent translocations. They
showed that MYC (190080), BCL (168461), and immunoglobulin loci, which
are recurrently translocated in various B-cell lymphomas, are
preferentially positioned in close spatial proximity relative to each
other in normal B cells. Loci in spatial proximity are nonrandomly
positioned toward the interior of the nucleus in normal B cells. This
locus proximity is the consequence of higher-order genome structure
rather than a property of individual genes. The results suggested that
the formation of specific translocations in human lymphomas, and perhaps
other tissues, is determined in part by higher-order spatial
organization of the genome. Roix et al. (2003) first assessed the global
nuclear organization of translocation-prone genes by localizing them
using fluorescence in situ hybridization. The preferred positioning they
found was statistically distinct from a uniform random distribution.
They then measured the physical distance between MYC and its various
translocation partners in karyotypically normal cells and compared their
physical proximity with the clinically observed frequencies of
translocation. They found that MYC was separated from its 2 most
frequent translocation partners, IgH and IgL (147220), by 40.7% and
41.0% of the nuclear diameter, respectively, whereas its separation from
its rare translocation partner, IgK (147200), was 47.1%. This last value
was similar to that observed for a negative control locus, TGFBR2
(190182), which had never been reported to translocate with MYC; its
mean separation was 49.4% of the nuclear diameter.

Streubel et al. (2005) noted that 3 chromosomal translocations,
t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), are
associated with mucosa-associated lymphoid tissue (MALT) lymphomas. They
identified a t(3;14)(p14;q32) in a case of MALT lymphoma of the thyroid.
FISH studies showed that the IGH locus was rearranged, and long-distance
inverse PCR identified FOXP1 (605515) as the partner gene on chromosome
3. Using FISH assays to screen 91 MALT lymphomas negative for 3 common
translocations, Streubel et al. (2005) identified t(3;14)(p14;q32) in 9
cases (3 thyroid, 4 ocular adnexa, and 2 skin). Most
t(3;14)(p14;q32)-positive MALT lymphomas also harbored additional
genetic abnormalities, such as trisomy 3. All 4 of the MALT-associated
translocations were mutually exclusive. Real-time RT-PCR analysis showed
upregulated expression of FOXP1 in MALT cases with t(3;14)(p14;q32) or
trisomy 3. Streubel et al. (2005) concluded that FOXP1 is a
translocation partner of IGH in a site-dependent subset of MALT
lymphomas.

Kaneko et al. (2006) demonstrated that distinct properties of the IgG Fc
fragment, resulting in proinflammatory effects of certain immune
complexes, and the fact that therapeutic intravenous gamma globulin and
its Fc fragments are antiinflammatory, result from differential
sialylation of the Fc core polysaccharide. IgG acquires antinflammatory
properties upon Fc sialylation, which is reduced upon the induction of
an antigen-specific immune response. This differential sialylation may
provide a switch from innate antinflammatory activity in the steady
state to generating adaptive proinflammatory effects upon antigenic
challenge.

Yan et al. (2007) assessed whether the classical nonhomologous
end-joining (NHEJ) pathway is critical for class-switch recombination
(CSR) by assaying CSR in Xrcc4 (194363)- or Lig4 (601837)-deficient
mouse B cells. Classical NHEJ indeed catalyzed CSR joins, because
classical NHEJ-deficient B cells had decreased CSR and substantial
levels of IgH locus chromosomal breaks. However, an alternative
end-joining pathway, which is markedly biased towards microhomology
joins, supports CSR at unexpectedly robust levels in classical
NHEJ-deficient B cells. In the absence of classical NHEJ, this
alternative end-joining pathway also frequently joins IgH locus breaks
to other chromosomes to generate translocations.

Using FISH and activated NHEJ-deficient mouse splenic B cells, Wang et
al. (2009) observed an accumulation of V(D)J recombination-associated
breaks at the Igl locus, as well as CSR-associated Igh breaks, often in
the same cell. The Igl and Igh breaks frequently joined to form
translocations, a phenomenon associated with specific Igh-Igl
colocalization. Igh and Myc also colocalized in these cells, and the
introduction of frequent Myc double-strand breaks robustly promoted
Igh-Myc translocations.

Gostissa et al. (2009) addressed the oncogenic role of the Igh-3-prime
regulatory region by inactivating it in 2 distinct mouse models for
B-cell lymphoma with Igh-c-Myc (190080) translocations. Gostissa et al.
(2009) showed that the Igh-3-prime regulatory region is dispensable for
pro-B-cell lymphomas with V(D)J recombination-initiated translocations,
but is required for peripheral B-cell lymphomas with class switch
recombination-associated translocations. As the Igh-3-prime regulatory
region is not required for class switch recombination-associated Igh
breaks or Igh-c-Myc translocations in peripheral B-cell lymphoma
progenitors, Gostissa et al. (2009) concluded that this regulatory
region confers oncogenic activity by long-range and developmental
stage-specific activation of translocated c-Myc genes.

Daniel et al. (2010) showed that activated B cells deficient in the PTIP
(608254) component of the MLL3 (606833)-MLL4 (606834) complex display
impaired trimethylation of histone H3 (see 602810) at lysine-4 (H3K4me3)
and transcription initiation of downstream switch regions at the
immunoglobulin heavy chain (Igh) locus, leading to defective
immunoglobulin class switching. Daniel et al. (2010) also showed that
PTIP accumulation at double-strand breakpoints contributes to class
switch recombination and genome stability independent of Igh switch
transcription. Daniel et al. (2010) concluded that their results
demonstrated that PTIP promotes specific chromatin changes that control
the accessibility of the Igh locus to class switch recombination and
suggested a nonredundant role for the MLL3-MLL4 complex in altering
antibody effector function.

Guo et al. (2011) reported in mice a key Igh V(D)J recombination
regulatory region, termed intergenic control region-1 (IGCR1), which
lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF
(604167) looping/insulator factor-binding elements and correspondingly
mediates Igh loops containing distant enhancers. IGCR1 promotes normal
B-cell development and balances antibody repertoires by inhibiting
transcription and rearrangement of D(H)-proximal V(H) gene segments and
promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered
and lineage-specific V(H)(D)J(H) recombination by suppressing V(H)
joining to D segments not joined to J(H) segments, and V(H) to DJ(H)
joins in thymocytes, respectively. IGCR1 is also required for feedback
regulation and allelic exclusion of proximal V(H)-to-DJ(H)
recombination. Guo et al. (2011) concluded that their studies elucidated
a long-sought Igh V(D)J recombination control region and indicated a new
role for the generally expressed CTCF protein.

Peron et al. (2012) showed that the 3-prime cis regulatory region of the
mouse Ig heavy chain locus was transcribed and underwent Aid
(605257)-mediated mutation and recombination around phylogenetically
conserved switch-like DNA repeats. Such recombination, which the authors
termed 'locus suicide recombination,' deleted the entire constant region
gene cluster and thus stopped expression of Ig on the B-cell surface,
enabling B-cell survival. Peron et al. (2012) concluded that the
frequency of this event approaches that of class switching and makes it
a potential regulator of B-cell homeostasis.

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

*FIELD* SA
Bender et al. (1979); Borgaonkar et al. (1973); Ceppellini et al.
(1966); Chaabani et al. (1985); Fahey (1965); Gedde-Dahl et al. (1975);
Grubb (1970); Hill et al. (1966); Kimberling et al. (1978); Klein
(1981); Lennox and Cohn (1967); Migone et al. (1985); Natvig and Kunkel
(1973); Oudin (1966); Steinberg (1969)
*FIELD* RF
1. Anonymous: Notation for genetic factors of human immunoglobulins. Nature 209:
653-655, 1966.

2. Balazs, I.; Purrello, M.; Rubinstein, P.; Alhadeff, B.; Siniscalco,
M.: Highly polymorphic DNA site D14S1 maps to the region of Burkitt
lymphoma translocation and is closely linked to the heavy chain gamma
1 immunoglobulin locus. Proc. Nat. Acad. Sci. 79: 7395-7399, 1982.

3. Bech-Hansen, N. T.; Linsley, P. S.; Cox, D. W.: Restriction fragment
length polymorphisms associated with immunoglobulin C-gamma genes
reveal linkage disequilibrium and genomic organization. Proc. Nat.
Acad. Sci. 80: 6952-6956, 1983.

4. Bender, K.; Burckhardt, K.; Schroetter, K.: Exclusion of the localization
of the Gm, Pi, and C3 genes on 6q25-6qter through blood group analysis
of the patients of Schmid, D'Apuzzo and Rossi (Hum. Genet. 46: 279-284,
1979). (Letter) Hum. Genet. 53: 129-130, 1979.

5. Bender, K.; Muller, C. R.; Schmidt, A.; Strohmier, U.; Wienker,
T. F.: Linkage studies on the human Pi, Gm, GLO, and HLA genes. Hum.
Genet. 49: 159-166, 1979.

6. Borgaonkar, D. S.; Bias, W. B.; Chase, G. A.; Sadasivan, G.; Herr,
H. M.; Golomb, H. M.; Bahr, G. F.; Kunkel, L. M.: Identification
of a C6-G21 translocation chromosome by Q-M and Giemsa banding techniques
in a patient with Down's syndrome, with possible assignment of Gm
locus. Clin. Genet. 4: 53-57, 1973.

7. Bottaro, A.; de Marchi, M.; Migone, N.; Carbonara, A. O.: Pulsed-field
gel analysis of human immunoglobulin heavy-chain constant region gene
deletions reveals the extent of unmapped regions within the locus. Genomics 4:
505-508, 1989.

8. Burrows, P. D.; Beck-Engeser, G. B.; Wabl, M. R.: Immunoglobulin
heavy-chain class switching in a pre-B cell line is accompanied by
DNA rearrangement. Nature 306: 243-246, 1983.

9. Ceppellini, R.; Dray, S.; Fabey, J. L.; Franklin, E. C.; Fudenberg,
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*FIELD* CN
Paul J. Converse - updated: 6/14/2012
Ada Hamosh - updated: 11/21/2011
Ada Hamosh - updated: 9/29/2010
Ada Hamosh - updated: 1/8/2010
Paul J. Converse - updated: 7/16/2009
Ada Hamosh - updated: 10/11/2007
Paul J. Converse - updated: 12/21/2006
Ada Hamosh - updated: 9/6/2006
Victor A. McKusick - updated: 8/12/2002
Paul J. Converse - updated: 4/9/2002
Wilson H. Y. Lo - updated: 8/6/1999

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

*FIELD* ED
mgross: 02/05/2013
mgross: 6/14/2012
alopez: 11/29/2011
terry: 11/21/2011
terry: 11/8/2010
alopez: 10/5/2010
terry: 9/29/2010
alopez: 1/11/2010
terry: 1/8/2010
mgross: 7/16/2009
terry: 7/16/2009
terry: 6/3/2009
carol: 2/26/2009
alopez: 10/16/2007
terry: 10/11/2007
mgross: 12/21/2006
alopez: 9/11/2006
terry: 9/6/2006
alopez: 7/28/2003
alopez: 6/17/2003
tkritzer: 10/8/2002
cwells: 8/12/2002
mgross: 4/9/2002
terry: 4/14/2000
carol: 8/6/1999
dkim: 12/10/1998
dkim: 7/21/1998
alopez: 5/14/1998
mark: 1/10/1998
mark: 9/22/1996
davew: 6/28/1994
carol: 5/24/1994
warfield: 4/21/1994
mimadm: 3/13/1994
pfoster: 2/9/1994
supermim: 3/16/1992

MIM 254500
*RECORD*
*FIELD* NO
254500
*FIELD* TI
#254500 MYELOMA, MULTIPLE
AMYLOIDOSIS, SYSTEMIC, INCLUDED; AL, INCLUDED;;
AL AMYLOIDOSIS, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because several chromosome
aberrations, including recurrent translocations and deletions, have been
found to be related to the development or progression of multiple
myeloma; see CYTOGENETICS section.

DESCRIPTION

Multiple myeloma is a neoplastic plasma cell disorder characterized by
clonal proliferation of malignant plasma cells in the bone marrow
microenvironment, monoclonal protein in the blood or urine, and
associated organ dysfunction (Palumbo and Anderson, 2011).

CLINICAL FEATURES

Leoncini and Korngold (1964) described multiple myeloma in 2 sisters and
reviewed the literature on familial cases. Manson (1961) reported
affected sisters, one of whom also had pernicious anemia. Myeloma has
also been observed in father and son (Nadeau et al., 1956). Thomas
(1964) observed myeloma in a brother and sister. Alexander and
Benninghoff (1965) described 3 affected black sibs. Whitehouse (1971)
observed affected brother and sister.

In a large population survey in Sweden, Axelsson and Hallen (1965) found
2 families, one with 2 and one with 3 sibs, showing high monoclonal
(M)-component. In a third family, 2 persons with high M-component were
more remotely related. These 7 were from a total group of 59 (out of
7,918) found to have M-component. Their condition was considered to be a
variety of essential benign monoclonal hypergammaglobulinemia.

Berlin et al. (1968) described familial occurrence of M-components. One
possible explanation for familial paraproteinemia is that plasma cell
clones with similar structural genes for the paraprotein synthesized by
these cells proliferate in related individuals. This hypothesis predicts
that paraproteins from 2 members of the same family would be identical.
The paraproteins of a mother with multiple myeloma and a son with
probably benign monoclonal gammopathy were isolated by Grant et al.
(1971). Light chains were of the lambda type, but had differences on
peptide map in both the common and variable regions of the proteins.
These data showed that the structural genes operative in paraprotein
light chain production in these first-degree relatives are different.
The presence of a genetic basis was suggested by the occurrence of 2
different monoclonal gammopathies in 1 patient. Humphrey (1973)
described a patient who had an intracranial plasmacytoma that was
surgically removed. Six years later she developed a plasmacytoma of 1
kidney. The second tumor produced a different gamma globulin from that
released into the cerebrospinal fluid by the brain plasmacytoma.

Zawadzki et al. (1977) described 19 cases of familial immunopathy,
distributed in 9 families. Ten members of 5 families had multiple
myeloma, 5 members of 2 families had lanthanic paraproteinemia, and 4
members of 2 families had one or the other of these. 'Lanthanic' is from
a Greek word meaning 'to escape.' It is used in place of 'benign'
because malignant immunocytic dyscrasia has been known to emerge. The
term is intended to convey that the condition was asymptomatic and came
to attention only by serendipity. (Actually, in the course of a specific
study of relatives of clinically affected probands, this is not
serendipity; Walpole's Prince of Serendip set out to find one thing and
instead found something else (Cannon, 1945).)

Blattner (1980) gave an excellent review, with a classification of
monoclonal gammopathies. Multiple myeloma and Waldenstrom
macroglobulinemia (153600) are presumably closely related; both are
malignant monoclonal gammopathies. Multiple myeloma is about 2 times
more frequent in U.S. blacks than in US whites; it is the eleventh and
twentieth most frequent malignancy in the 2 races, respectively.

Horwitz et al. (1985) reported 3 affected sibs and stated that a review
of the literature revealed reports of 38 affected pairs of sibs, 8
families with 3 affected sibs, and 4 families with another affected
relative (in addition to the pair of affected sibs). Comotti et al.
(1987) and Judson et al. (1985) reported identical twins concordant for
multiple myeloma.

Jensen et al. (1988) described a brother and sister with progressive
mixed axonal and demyelinating polyneuropathy in association with a
monoclonal IgM gammopathy of kappa and lambda type, respectively. Sera
from both patients contained antibodies directed to bovine peripheral
nerve myelin as determined by ELISA technique and to normal human
peripheral nerve myelin as demonstrated by indirect immunofluorescence
histochemistry. These sibs may have had a genetic predisposition to the
formation of autoantibodies with peripheral nerve myelin as the target.

Deshpande et al. (1998) described 5 families in which plasma cell
dyscrasia occurred in parent and child generations (6 such pairs), and
pooled data with those of 16 other families (with 20 parent-child pairs
affected) recorded in the literature. In all 6 previously unreported
parent-child pairs with plasma cell dyscrasia and in 18 of 20 such pairs
found in the literature, the disease occurred at an earlier age in the
child generation. The median age of onset of myeloma in parent and child
generations of all 26 pairs was 71 years and 50 years, respectively. The
ages of onset of malignant plasma cell dyscrasias in the parent and
child generations of these families compared with patients in the
general population was significantly different for the child generation
but not for the parent generation. It thus appears that anticipation
occurs in familial myeloma.

Grosbois et al. (1999) studied 15 families with 2 or more cases of
multiple myeloma. In 10 of the 15, myeloma was observed in sibs, in whom
the mean age at diagnosis was similar to that in unrelated multiple
myeloma cases. In those families with multiple myeloma in successive
generations, the mean age at diagnosis was lower. The monoclonal
component was identical (IgG kappa) in 7 families. A family history of
monoclonal gammopathy of undetermined significance was observed in 3
families. Five other prospective studies of 1,263 patients identified 4
affected families (3.2 per 1,000 cases of multiple myeloma).

Lynch et al. (2008) reported a large African American family in which 5
individuals had multiple myeloma, 3 had monoclonal gammopathy of
undetermined significance (MGUS), i.e., without signs of malignant
lymphocytic or plasmocytic disease, and 5 had prostate cancer. One
additional member had pancreatic cancer. The putative progenitor had
died of colon cancer at age 88 years.

- Systemic (AL) Amyloidosis

AL amyloidosis, formerly called primary amyloidosis, is a protein
conformation disorder associated with a clonal plasma cell dyscrasia
(Falk et al., 1997). Multiple organ disease results from the
extracellular deposition of monoclonal immunoglobulin light chain
fragments in an abnormal insoluble fibrillar form. AL amyloidosis may be
associated with myeloma or other B-cell malignancy, but in most cases
the underlying plasma cell dyscrasia is subtle and nonproliferating,
analogous to MGUS (Guidelines Working Group of UK Myeloma Forum, 2004).

Gertz et al. (1986) reported primary immunoglobulin-related amyloidosis
in 2 members of each of 3 families: 2 brothers, a brother and a sister,
and 2 first cousins. Primary amyloidosis of this type may be closely
akin to multiple myeloma and to Waldenstrom macroglobulinemia.

Miliani et al. (1996) described 3 Italian sibs (2 brothers and a sister)
with immunoglobulin-related amyloidosis. Systemic amyloidosis was
associated with monoclonal gammopathy in all 3. One of the sibs had
Waldenstrom macroglobulinemia, whereas the other 2 had no evidence of
multiple myeloma or related diseases. All 3 sibs showed a common pattern
of polyneuropathy to different degrees; 2 presented a sicca syndrome and
1 also suffered from nephropathy.

Dispenzieri et al. (2004) concluded that high-dose chemotherapy with
peripheral blood stem cell transplantation (PBSCT) in AL patients is
associated with higher response rates and higher overall survival than
standard chemotherapy. Their conclusion was based on a matched
case-control study comparing overall survival of 63 AL patients
undergoing transplantation with 63 patients not undergoing
transplantation.

CYTOGENETICS

Dysregulation of oncogenes by translocations to the IgH locus (147100)
on 14q32 is a seminal event in the pathogenesis of B-cell tumors,
including multiple myeloma. Translocations to the IgH locus occur in 20
to 60% of cases of myeloma; a diverse array of chromosomal partners have
been identified, with 11q13 (see cyclin D1; 168461) being frequently
involved. Bergsagel et al. (1996) developed a comprehensive Southern
blot assay to identify and distinguish different kinds of IgH switch
recombination events. Illegitimate switch recombination fragments
(defined as containing sequences from only 1 switch region) are
potential markers of translocation events into IgH switch regions and
were identified in 15 of 21 myeloma cell lines, including 7 of 8
karyotyped lines that had no detectable 14q32 translocation. These
translocation breakpoints involved 6 chromosomal loci: 4p16.3; 6;
8q24.13; 11q13.3; 16q23.1; and 21q22.1.

Chesi et al. (1997) found the novel, karyotypically silent translocation
t(4;14)(p16.3;q32.3) in 5 myeloma cells lines and in at least 3 of 10
primary tumors. The chromosome-4 breakpoints were clustered in a 70-kb
region centromeric to FGFR3 (134934), which was thought to be the
dysregulated oncogene. This translocation selectively expressed an FGFR3
allele containing activating mutations identified previously in
thanatophoric dwarfism: tyr373 to cys (134934.0016), lys650 to glu
(134934.0004), and lys650 to met (134934.0015). For K650E, the
constitutive activation of FGFR3 in the absence of ligand had been
proved by transfection experiments. Chesi et al. (1997) proposed that
after the t(4;14) translocation, somatic mutation during tumor
progression frequently generates an FGFR3 protein that is active in the
absence of ligand. Although they could not exclude the possibility that
other genes are dysregulated by the translocation t(4;14), several
findings pointed to FGFR3. FGFR3 is located no more than 100 kb from the
most centromeric breakpoint at 4p16.3, and is on the derivative(14)
chromosome that contains the 3-prime IgH enhancer. This is similar to
the situation for cyclin D1, which is located 100 to 400 kb from the
breakpoint in the translocation t(11;14) that occurs in mantle-cell
lymphoma and multiple myeloma tumors. FGFR3 is another example of a gene
that can function both as an oncogene and a 'teratogene.'

Palumbo and Anderson (2011) noted that primary early translocations at
the Ig switch region at 14q32.33 are commonly juxtaposed to MAF (177075)
on chromosome 16q23 and MMSET (602952) on chromosome 4p16.3; the latter
results in the deregulation of FGFR3 in 30% of cases.

In multiple myeloma cell lines, Iida et al. (1997) identified a
t(6;14)(p25;q32) translocation in 2 of 11 cell lines. The translocation
juxtaposes the immunoglobulin heavy-chain (IGHG1; 147100) locus to the
MUM1 gene (IRF4; 601900), a member of a gene family known to be active
in the control of B-cell proliferation and differentiation. As a result
of the translocation, the MUM1/IRF4 gene is overexpressed, an event that
may contribute to tumorigenesis, as Iida et al. (1997) showed that
MUM1/IRF4 has oncogenic activity in vitro.

In a study of 32 patients with AL (24 with systemic and 8 with localized
disease), Harrison et al. (2002) found translocations involving IGH and
in addition found deletions of 13q, using dual-color interface
fluorescence in situ hybridization. IGH translocations were observed in
11 patients, of whom 9 had the IGH/CCND1 (168461) fusion from
t(11;14)(q13;q32).

Mohamed et al. (2007) reviewed the chromosome aberrations in a series of
120 multiple myeloma cases with abnormal karyotypes.

MOLECULAR GENETICS

Shaffer et al. (2008) used a loss-of-function, RNA interference-based
genetic screen to demonstrate that inhibition of IRF4 (601900) is toxic
to myeloma cell lines, regardless of transforming oncogenic mechanism.
Gene expression profiling and genomewide chromatin immunoprecipitation
analysis uncovered an extensive network of IRF4 target genes and
identified MYC (190080) as a direct target of IRF4 in activated B cells
and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC
transactivation, generating an autoregulatory circuit in myeloma cells.
Shaffer et al. (2008) suggested that although IRF4 is not genetically
altered in most myelomas, they are nonetheless addicted to an aberrant
IRF4 regulatory network that fuses the gene expression programs of
normal plasma cells and activated B cells.

Roddam et al. (2002) investigated the potential impact of 2 LIG4
polymorphisms--ala3 to val (A3V; 601837.0005) and thr9 to ile (T9I;
601837.0006), both caused by C-to-T transitions--on predisposition to
several lymphoproliferative disorders, including leukemia, lymphoma, and
multiple myeloma (254500), a tumor characterized by aberrant
immunoglobulin class switch recombination. The A3V CT and T9I CT and TT
genotypes were significantly associated with reduction in risk of
developing multiple myeloma. The polymorphisms were in linkage
disequilibrium, and a protective effect associated with them was found
to be the result of the inheritance of the A3V-T9I CT and A3V-T9I TT
haplotypes. These data suggested that genetic variants of NHEJ LIG4 may
modulate predisposition to multiple myeloma.

One complication of multiple myeloma patients on bisphosphonate therapy
is osteonecrosis of the jaw. In a genomewide association study of 2
series of patients with multiple myeloma, 1 group of 22 with
osteonecrosis of the jaw and another group of 65 patients without
osteonecrosis of the jaw, Sarasquete et al. (2008) found a significant
association between development of the complication and 4 SNPs (dbSNP
rs1934951, dbSNP rs1934980, dbSNP rs1341162, and dbSNP rs17110453)
mapping to chromosome 10q23 in the CYP2C8 gene (601129) (p values
ranging from 1.07 x 10(-6) to 6.22 x 10(-6)). One SNP, dbSNP rs1934951,
remained significant even after Bonferroni correction (p corrected value
= .02). Genotyping revealed an overrepresentation of the T allele of
this SNP in cases compared to controls (48% vs 12%). Individuals
homozygous for the T allele had a significantly increased likelihood of
developing osteonecrosis of the jaw (odds ratio of 12.75).

Preuss et al. (2009) screened a human fetal brain-derived macroarray
with the IgA or IgG paraprotein-containing sera of 192 consecutive
patients with monoclonal gammopathy of undetermined significance (MGUS)
or multiple myeloma, and found that 29 (15.1%) of the 192 paraproteins
reacted with a protein they designated 'paratarg-7,' which was found to
be identical to stomatin-like protein-2 (STOML2; 608292).

Grass et al. (2009) studied 35 probands with MGUS or multiple myeloma
who had an antiparatarg-7 paraprotein and found that all 35 patients
expressed hyperphosphorylated paratarg-7 (615121), whereas
hyperphosphorylation was not observed in 217 other patients with MGUS or
multiple myeloma whose paraprotein did not bind to paratarg-7.
Paratarg-7 hyperphosphorylation was also found in 4 (2%) of 200 healthy
blood donors, none of whom had monoclonal immunoglobulins in their
serum. Thus, hyperphosphorylation of paratarg-7 appeared to be
associated with a significantly increased risk of developing MGUS or
multiple myeloma (odds ratio, 7.9; p = 0.0001). Analysis of 8 of the 35
families with paratarg-7-specific paraprotein in their serum showed that
the hyperphosphorylated state of paratarg-7 was inherited in an
autosomal dominant fashion. Grass et al. (2009) noted that there were
healthy carriers of hyperphosphorylated paratarg-7 who were older than
the respective index patient, indicating that factors other than age
determine if and when a carrier of hyperphosphorylated paratarg-7
develops a paratarg-7-specific paraprotein.

Chapman et al. (2011) reported the massively parallel sequencing of 38
tumor genomes and their comparison to matched normal DNAs from
individuals with multiple myeloma. Several new and unexpected oncogenic
mechanisms were suggested by the pattern of somatic mutation across the
data set. These included the mutation of genes involved in protein
translation (seen in nearly half of the patients), genes involved in
histone methylation, and genes involved in blood coagulation. In
addition, a broader than anticipated role of NF-kappa-B (see 164011)
signaling was indicated by mutations in 11 members of the NF-kappa-B
pathway. Of potential immediate clinical relevance, activating mutations
of the kinase BRAF (164757) were observed in 4% of patients, suggesting
the evaluation of BRAF inhibitors in multiple myeloma clinical trials.

Weinhold et al. (2013) found an association between the 870G allele of a
polymorphism in the CCND1 gene (168461.0001) and risk of t(11;14)
multiple myeloma.

ANIMAL MODEL

Plasma cell tumor induction in mice by pristane is under multigenic
control. Backcross and congenic strain analyses indicated that at least
4 genes determine the susceptibility to mouse plasmacytomagenesis. One
of these genes, Pctr1, resides in the mid-portion of mouse chromosome 4
near the alpha-interferon locus. Zhang et al. (1998) presented evidence
that Cdkn2a (600160) is a strong candidate for the Pctr1 locus.

*FIELD* SA
Goldstone et al. (1973); Herrell et al. (1958); Maldonado and Kyle
(1974); Rostoker et al. (1986)
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*FIELD* CS
INHERITANCE:
Somatic mutation

NEOPLASIA:
Multiple myeloma

LABORATORY ABNORMALITIES:
High M-component;
Monoclonal gammopathy;
Primary immunoglobulin-related amyloidosis (AL);
Paraproteinemia

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

*FIELD* ED
joanna: 04/28/2011

*FIELD* CN
Marla J. F. O'Neill - updated: 3/15/2013
Ada Hamosh - updated: 5/9/2011
Carol A. Bocchini - updated: 4/21/2011
Cassandra L. Kniffin - updated: 4/21/2009
Ada Hamosh - updated: 8/27/2008
Cassandra L. Kniffin - updated: 7/28/2008
Victor A. McKusick - updated: 9/17/2004
Victor A. McKusick - updated: 8/12/2002
Victor A. McKusick - updated: 9/15/1999
Victor A. McKusick - updated: 2/15/1999
Victor A. McKusick - updated: 7/3/1997

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

*FIELD* ED
alopez: 02/11/2014
carol: 3/15/2013
alopez: 5/10/2011
terry: 5/10/2011
terry: 5/9/2011
carol: 4/25/2011
carol: 4/23/2011
terry: 4/22/2011
carol: 4/21/2011
terry: 11/8/2010
terry: 6/3/2009
wwang: 4/27/2009
ckniffin: 4/21/2009
terry: 3/13/2009
alopez: 8/27/2008
carol: 7/29/2008
ckniffin: 7/28/2008
alopez: 9/20/2004
terry: 9/17/2004
cwells: 8/12/2002
mgross: 9/16/1999
terry: 9/15/1999
carol: 2/16/1999
terry: 2/15/1999
alopez: 5/6/1998
carol: 4/7/1998
terry: 3/28/1998
jenny: 9/30/1997
terry: 9/26/1997
mark: 7/7/1997
terry: 7/3/1997
carol: 8/22/1996
marlene: 8/2/1996
terry: 7/24/1996
mimman: 2/8/1996
terry: 5/7/1994
warfield: 4/21/1994
mimadm: 4/18/1994
carol: 1/28/1993
supermim: 3/17/1992
supermim: 5/1/1990