RBCC

Full text data of IGHM

IGHM [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ig mu chain C region

Comments
Isoform P01871-2 was detected.

UniProt P01871
ID IGHM_HUMAN Reviewed; 452 AA.
AC P01871; P20769;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-2008, sequence version 3.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Ig mu chain C region;
GN Name=IGHM;
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=2505237; DOI=10.1093/nar/17.15.6412;
RA Dorai H., Gillies S.D.;
RT "The complete nucleotide sequence of a human immunoglobulin genomic C
RT mu gene.";
RL Nucleic Acids Res. 17:6412-6412(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT SER-191.
RX PubMed=2115996; DOI=10.1093/nar/18.14.4278;
RA Friedlander R.M., Nussenzweig M.C., Leder P.;
RT "Complete nucleotide sequence of the membrane form of the human IgM
RT heavy chain.";
RL Nucleic Acids Res. 18:4278-4278(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Calvo B.F., Schlom J., Kashmiri S.;
RT "Complete nucleotide sequence of a cDNA encoding human IgM heavy chain
RT constant domains.";
RL Submitted (DEC-1990) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP PROTEIN SEQUENCE (WALDENSTROM'S MACROGLOBULIN GAL).
RX PubMed=4803843;
RA Watanabe S., Barnikol H.U., Horn J., Bertram J., Hilschmann N.;
RT "The primary structure of a monoclonal IgM-immunoglobulin
RT (macroglobulin Gal.), II: the amino acid sequence of the H-chain (mu-
RT type), subgroup H III. Architecture of the complete IgM-molecule.";
RL Hoppe-Seyler's Z. Physiol. Chem. 354:1505-1509(1973).
RN [5]
RP SEQUENCE REVISION (GAL).
RX PubMed=6777162;
RA Mihaesco E., Barnikol-Watanabe S., Barnikol H.U., Mihaesco C.,
RA Hilschmann N.;
RT "The primary structure of the constant part of mu-chain-disease
RT protein BOT.";
RL Eur. J. Biochem. 111:275-286(1980).
RN [6]
RP PROTEIN SEQUENCE (WALDENSTROM'S OU), DISULFIDE BONDS, AND
RP GLYCOSYLATION.
RX PubMed=4742735; DOI=10.1126/science.182.4109.287;
RA Putnam F.W., Florent G., Paul C., Shinoda T., Shimizu A.;
RT "Complete amino acid sequence of the Mu heavy chain of a human IgM
RT immunoglobulin.";
RL Science 182:287-291(1973).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 298-386 AND 436-452.
RX PubMed=6777778; DOI=10.1073/pnas.77.10.6027;
RA Dolby T.W., Devuono J., Croce C.M.;
RT "Cloning and partial nucleotide sequence of human immunoglobulin mu
RT chain cDNA from B cells and mouse-human hybridomas.";
RL Proc. Natl. Acad. Sci. U.S.A. 77:6027-6031(1980).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 339-452.
RX PubMed=6795593; DOI=10.1093/nar/9.18.4509;
RA Rabbitts T.H., Forster A., Milstein C.P.;
RT "Human immunoglobulin heavy chain genes: evolutionary comparisons of C
RT mu, C delta and C gamma genes and associated switch sequences.";
RL Nucleic Acids Res. 9:4509-4524(1981).
RN [9]
RP FUNCTION.
RX PubMed=3137579; DOI=10.1073/pnas.85.18.6914;
RA Tisch R., Roifman C.M., Hozumi N.;
RT "Functional differences between immunoglobulins M and D expressed on
RT the surface of an immature B-cell line.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:6914-6918(1988).
RN [10]
RP INVOLVEMENT IN AGM1.
RX PubMed=8890099; DOI=10.1056/NEJM199611143352003;
RA Yel L., Minegishi Y., Coustan-Smith E., Buckley R.H., Trubel H.,
RA Pachman L.M., Kitchingman G.R., Campana D., Rohrer J., Conley M.E.;
RT "Mutations in the mu heavy-chain gene in patients with
RT agammaglobulinemia.";
RL N. Engl. J. Med. 335:1486-1493(1996).
RN [11]
RP REVIEW.
RX PubMed=16895553; DOI=10.1111/j.1365-2567.2006.02386.x;
RA Geisberger R., Lamers M., Achatz G.;
RT "The riddle of the dual expression of IgM and IgD.";
RL Immunology 118:429-437(2006).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-46, AND MASS 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 [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-46, AND MASS 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 [14]
RP GLYCOSYLATION AT ASN-46 AND ASN-209.
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 [15]
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).
CC -!- FUNCTION: IgM antibodies play an important role in primary defense
CC mechanisms. They have been shown to be involved in early
CC recognition of external invaders like bacteria and viruses,
CC cellular waste and modified self, as well as in recognition and
CC elimination of precancerous and cancerous lesions. The membrane-
CC bound form is found in the majority of normal B-cells alongside
CC with IgD. Membrane-bound IgM induces the phosphorylation of CD79A
CC and CD79B by the Src family of protein tyrosine kinases. It may
CC cause death of cells by apoptosis. It is also found in soluble
CC form, which represents about 30% of the total serum
CC immunoglobulins where it is found almost exclusively as a
CC homopentamer. After the antigen binds to the B-cell receptor, the
CC secreted form is secreted in large amounts.
CC -!- SUBUNIT: Immunoglobulin (Ig) molecules consist of two chains, one
CC heavy chain (which can be alpha, delta, epsilon, gamma or mu) and
CC one light chain (which can be kappa or lambda) each consisting of
CC a variable and a constant region. An IgM molecule contains thus a
CC mu heavy chain combined with either a kappa or a lambda light
CC chains. It is found almost exclusively as a homopentamer in the
CC serum. Membrane-bound IgM molecules are non-covalently associated
CC with heterodimer of CD79A and CD79B.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted. Note=During
CC differentiation, B-lymphocytes switch from expression of membrane-
CC bound IgM to secretion of IgM.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Secreted;
CC IsoId=P01871-1; Sequence=Displayed;
CC Name=2; Synonyms=Membrane-bound;
CC IsoId=P01871-2; Sequence=VSP_034488;
CC Note=Ref.8 (AAB59422) sequence is in conflict in positions:
CC 437:S->N, 439:D->E, 448:A->T, 471:KVK->K;
CC -!- POLYMORPHISM: All 4 combinations of the S/G and V/G polymorphisms
CC at positions 191 and 215 have been observed in human mu chains.
CC -!- DISEASE: Agammaglobulinemia 1, autosomal recessive (AGM1)
CC [MIM:601495]: A primary immunodeficiency characterized by
CC profoundly low or absent serum antibodies and low or absent
CC circulating B cells due to an early block of B-cell development.
CC Affected individuals develop severe infections in the first years
CC of life. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA33071.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAA34971.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=IGHMbase; Note=IGHM mutation db;
CC URL="http://bioinf.uta.fi/IGHMbase/";
CC -!- WEB RESOURCE: Name=IMGT/GENE-DB;
CC URL="http://www.imgt.org/IMGT_GENE-DB/GENElect?query=2+IGHM&species;=Homo+sapiens";
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DR EMBL; X14940; CAE82013.1; -; Genomic_DNA.
DR EMBL; X14940; CAE82014.1; -; Genomic_DNA.
DR EMBL; X14940; CAA33069.1; -; Genomic_DNA.
DR EMBL; X14940; CAA33070.1; -; Genomic_DNA.
DR EMBL; X14940; CAA33071.1; ALT_INIT; Genomic_DNA.
DR EMBL; X14939; CAA33065.1; -; Genomic_DNA.
DR EMBL; X17115; CAA34971.1; ALT_INIT; mRNA.
DR EMBL; X57086; CAB37838.1; -; mRNA.
DR EMBL; K01310; AAB59422.1; -; Genomic_DNA.
DR PIR; S14683; S14683.
DR PIR; S16510; MHHUM.
DR UniGene; Hs.510635; -.
DR PDB; 2AGJ; X-ray; 2.60 A; H=1-183.
DR PDBsum; 2AGJ; -.
DR ProteinModelPortal; P01871; -.
DR SMR; P01871; 1-433.
DR IntAct; P01871; 60.
DR MINT; MINT-2860005; -.
DR STRING; 9606.ENSP00000418294; -.
DR MEROPS; I43.001; -.
DR UniCarbKB; P01871; -.
DR DMDM; 193806374; -.
DR UCD-2DPAGE; P01871; -.
DR PaxDb; P01871; -.
DR PRIDE; P01871; -.
DR GeneCards; GC14M106318; -.
DR HGNC; HGNC:5541; IGHM.
DR MIM; 147020; gene.
DR MIM; 601495; phenotype.
DR neXtProt; NX_P01871; -.
DR Orphanet; 33110; Autosomal agammaglobulinemia.
DR eggNOG; NOG47782; -.
DR HOGENOM; HOG000202819; -.
DR HOVERGEN; HBG005814; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P01871; -.
DR PRO; PR:P01871; -.
DR Genevestigator; P01871; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0003823; F:antigen binding; IEA:UniProtKB-KW.
DR GO; GO:0006955; P:immune response; NAS:UniProtKB.
DR Gene3D; 2.60.40.10; -; 4.
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; 4.
DR SMART; SM00407; IGc1; 3.
DR PROSITE; PS50835; IG_LIKE; 4.
DR PROSITE; PS00290; IG_MHC; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin C region; Immunoglobulin domain; Membrane;
KW Polymorphism; Reference proteome; Secreted; Transmembrane.
FT CHAIN <1 452 Ig mu chain C region.
FT /FTId=PRO_0000153619.
FT REGION 1 105 CH1.
FT REGION 106 217 CH2.
FT REGION 218 323 CH3.
FT REGION 324 452 CH4.
FT CARBOHYD 46 46 N-linked (GlcNAc...) (complex).
FT CARBOHYD 209 209 N-linked (GlcNAc...) (complex).
FT CARBOHYD 272 272 N-linked (GlcNAc...).
FT CARBOHYD 279 279 N-linked (GlcNAc...).
FT CARBOHYD 439 439 N-linked (GlcNAc...).
FT /FTId=CAR_000219.
FT DISULFID 14 14 Interchain (with light chain).
FT DISULFID 28 88
FT DISULFID 134 197
FT DISULFID 214 214 Interchain (with heavy chain).
FT DISULFID 244 303
FT DISULFID 291 291 Interchain (with heavy chain of another
FT subunit).
FT DISULFID 351 413
FT DISULFID 451 451 Interchain (with heavy chain).
FT VAR_SEQ 433 452 GKPTLYNVSLVMSDTAGTCY -> EGEVSADEEGFENLWAT
FT ASTFIVLFLLSLFYSTTVTLFKVK (in isoform 2).
FT /FTId=VSP_034488.
FT VARIANT 191 191 G -> S.
FT /FTId=VAR_003903.
FT VARIANT 215 215 V -> G (in dbSNP:rs12365).
FT /FTId=VAR_003904.
FT CONFLICT 40 40 L -> F (in Ref. 2; CAA34971 and 3;
FT CAB37838).
FT CONFLICT 128 128 R -> RS (in Ref. 2; CAA34971).
FT CONFLICT 220 220 T -> I (in Ref. 3; CAB37838).
FT CONFLICT 414 414 V -> VV (in Ref. 2; CAA34971 and 3;
FT CAB37838).
FT CONFLICT 417 417 E -> D (in Ref. 8; AAB59422).
FT NON_TER 1 1
FT STRAND 178 184
FT STRAND 196 201
FT STRAND 206 208
FT STRAND 210 216
FT STRAND 223 227
FT HELIX 236 238
FT STRAND 240 242
FT HELIX 249 251
FT STRAND 253 258
FT TURN 261 264
FT STRAND 265 272
FT HELIX 275 277
FT STRAND 279 285
FT STRAND 287 290
FT STRAND 300 302
FT STRAND 316 318
FT STRAND 345 351
FT STRAND 354 359
FT STRAND 363 366
FT STRAND 386 388
FT STRAND 391 393
FT STRAND 396 401
FT HELIX 402 405
FT STRAND 406 409
FT STRAND 412 417
SQ SEQUENCE 452 AA; 49307 MW; 83E7603C8526CB7A CRC64;
GSASAPTLFP LVSCENSPSD TSSVAVGCLA QDFLPDSITL SWKYKNNSDI SSTRGFPSVL
RGGKYAATSQ VLLPSKDVMQ GTDEHVVCKV QHPNGNKEKN VPLPVIAELP PKVSVFVPPR
DGFFGNPRKS KLICQATGFS PRQIQVSWLR EGKQVGSGVT TDQVQAEAKE SGPTTYKVTS
TLTIKESDWL GQSMFTCRVD HRGLTFQQNA SSMCVPDQDT AIRVFAIPPS FASIFLTKST
KLTCLVTDLT TYDSVTISWT RQNGEAVKTH TNISESHPNA TFSAVGEASI CEDDWNSGER
FTCTVTHTDL PSPLKQTISR PKGVALHRPD VYLLPPAREQ LNLRESATIT CLVTGFSPAD
VFVQWMQRGQ PLSPEKYVTS APMPEPQAPG RYFAHSILTV SEEEWNTGET YTCVAHEALP
NRVTERTVDK STGKPTLYNV SLVMSDTAGT CY
//

MIM 147020
*RECORD*
*FIELD* NO
147020
*FIELD* TI
*147020 IMMUNOGLOBULIN HEAVY CHAIN CONSTANT REGION MU; IGHM
;;IMMUNOGLOBULIN HEAVY CHAIN MU CONSTANT REGION;;
read moreIgM HEAVY CHAIN CONSTANT REGION
*FIELD* TX

DESCRIPTION

Immunoglobulins (Ig) are the antigen recognition molecules of B cells.
An Ig molecule is made up of 2 identical heavy chains and 2 identical
light chains (see 147200) joined by disulfide bonds so that each heavy
chain is linked to a light chain and the 2 heavy chains are linked
together. Each Ig heavy chain has an N-terminal variable (V) region
containing the antigen-binding site and a C-terminal constant (C)
region, encoded by an individual C region gene, that determines the
isotype of the antibody and provides effector or signaling functions.
The heavy chain V region is encoded by 1 each of 3 types of genes: V
genes (see 147070), joining (J) genes (see 147010), and diversity (D)
genes (see 146910). The C region genes are clustered downstream of the V
region genes within the heavy chain locus on chromosome 14. The IGHM
gene encodes the C region of the mu heavy chain, which defines the IgM
isotype. Naive B cells express the transmembrane forms of IgM and IgD
(see IGHD; 1471770) on their surface. During an antibody response,
activated B cells can switch to the expression of individual downstream
heavy chain C region genes by a process of somatic recombination known
as isotype switching. In addition, secreted Ig forms that act as
antibodies can be produced by alternative RNA processing of the heavy
chain C region sequences. Although the membrane forms of all Ig isotypes
are monomeric, secreted IgM forms pentamers, and occasionally hexamers,
in plasma (summary by Janeway et al., 2005).

CLONING

Friedlander et al. (1990) reported the complete nucleotide sequence of
the membrane form of the human IgM heavy chain.

MAPPING

Rabbitts et al. (1981) demonstrated that the gene for the mu constant
(C) region contains 4 domains separated by short intervening sequences.
They also showed that the C(mu) and C(delta) (IGHD; 147170) genes are
closely linked, with the C(delta) gene located about 5 kb downstream
from C(mu); one clone contained both a 3-prime part of the mu gene and a
5-prime part of the delta gene.

Erikson et al. (1982) showed that in Burkitt tumor cell lines the 14q+
chromosome retains the genes coding for the constant region of the
immunoglobulin heavy chains, whereas genes coding for all or a portion
of the variable region translocate to the 8q- chromosome. This suggests
that the orientation in relation to the centromere is cen-IGHC-IGHV-ter.

Lefranc et al. (1982) showed, by Southern analysis, that a single BamHI
band hybridized to a C(mu) probe. This group of workers and others using
different enzymes have found the same (Lefranc, 1991).

Wabl et al. (1980) found that in the mouse both IgM and IgD were
expressed by a hybrid hamster-mouse subclone that contained only one
mouse chromosome 12.

GENE STRUCTURE

Liu et al. (2005) analyzed the putative promoter regions (PPRs) of 333
Ig genes to determine their CpG island content. CpG islands are regions
of about 200 bp rich in CpG dinucleotides that are typically associated
with housekeeping genes. Liu et al. (2005) noted that IGK light chain
genes are located on the plus and minus strands of chromosome 2, IGH
heavy chain genes are located on the minus strand only of chromosome 14,
and IGL light chain genes are located on the plus strand only of
chromosome 22. They found that none of the joining region genes have CpG
islands in their PPRs. While IGKC (147200) and 6 of 11 IGHC constant
region genes have CpG islands, none of the 7 IGLC (IGLC1; 147220)
constant region genes have CpG islands. Among Ig variable region genes,
the frequency of CpG islands is somewhat greater for the heavy chain
genes on chromosome 14 than for the light chain genes on chromosomes 2
and 22. Compared with non-Ig genes on chromosome 22, a CpG-rich
chromosome, Ig genes are significantly less likely to have CpG islands
and significantly more likely to have less-dense CpG islands. Liu et al.
(2005) concluded that the occurrence of CpG islands in the PPRs of human
and mouse Ig genes is nonrandom and nonneutral.

GENE FUNCTION

Allelic exclusion ensures monoallelic expression of Ig genes by each B
cell to maintain single receptor specificity. Using FISH analysis for
DNA replication timing in mouse spleen cells, Mostoslavsky et al. (2001)
showed that IGKC (147200), IGKV (146980), and IGHM, as well as TCRB (see
186930), replicate asynchronously, indicated by a high frequency of
single (pre-replication) and double (after replication) hybridization
signals in the loci of interphase nuclei, in a manner analogous to the
process of X chromosome inactivation. Mostoslavsky et al. (2001)
concluded that monoallelic inactivation is not unique to the X
chromosome, but can also take place, in a regional manner, on autosomes
as well. They noted that asynchronous replication also occurs at the
loci for olfactory receptors (see OR2H3, 600578), IL2 (147680), and IL4
(147780).

Skok et al. (2001) used FISH analysis and multicolor fluorescence
microscopy to demonstrate that after activation of mature B cells, a
single endogenous IGHM allele, as well as 3 IGL (see 147220) alleles,
are recruited to centromeric heterochromatin containing Ikaros (603023),
a protein required for B and T lymphocyte development and implicated in
the silencing of specific target genes, whereas the other IGHM and IGK
alleles are localized away from centromeric heterochromatin. Skok et al.
(2001) concluded that epigenetic factors may have a role in maintaining
the monoallelic expression of Ig in normal B cells.

MOLECULAR GENETICS

Yel et al. (1996) studied 2 families with autosomal recessive defects in
B-cell development resulting in agammaglobulinemia (AGM1; 601495). Both
families were consanguineous; 1 contained 3 affected males and 1
affected female in 3 related sibships. A second contained an affected
brother and sister. Four different mutations were identified in the IGHM
gene in these families. In 1 family, there was a homozygous 75-to-100 kb
deletion that included D-regions genes, J-region genes, and the mu
constant-region gene (147020.0001). In a second family, there was a
homozygous basepair substitution in the alternative splice site of the
mu heavy-chain gene (147020.0002). This mutation would inhibit
production of the membrane form of the mu chain and produce an amino
acid substitution in the secreted form. In another patient, a male with
a Korean mother and a white father, initially thought to have X-linked
agammaglobulinemia (300755), Yel et al. (1996) found compound
heterozygosity for an amino acid substitution at an invariant cysteine
(147020.0003) that is required for the intrachain disulfide bond in the
C-terminal immunoglobulin domain of the mu chain; and, on the other
chromosome, a large deletion that included the immunoglobulin locus. The
results were interpreted as indicating that an intact membrane-bound mu
chain is essential for B-cell development and that defects in the gene
can cause agammaglobulinemia.

In a subsequent paper, the same group (Lopez Granados et al., 2002)
stated that the IGHM sequence used differed from that used in the paper
by Yel et al. (1996). Because the variable region of an immunoglobulin
varies in length, the codon assignment was based on designating the
first codon of the CH1 domain of the mu heavy chain as the first codon.
Lopez Granados et al. (2002) identified different mutations in the IGHM
gene (see, e.g., 147020.0004 and 147020.0005) in affected members of 9
unrelated families with agammaglobulinemia-1. Two of the mutations were
large deletions that removed more than 40 kb of DNA at the IGHM locus.
Six families carried the same splice site mutation (147020.0002) that
was present on different haplotypes, indicating a mutation hotspot.
Compared with patients with X-linked agammaglobulinemia (300755), those
with IGHM mutations had an earlier onset of the disease and more
complications. Lopez Granados et al. (2002) concluded that 20 to 30% of
patients with autosomal recessive defects in B-cell development have
mutations in the IGHM gene.

CYTOGENETICS

About 60% of DCLRE1C (605988) and IGHM gene defects involve gross
deletions, compared with about 6% of BTK gene (300300) defects. Van Zelm
et al. (2008) compared gross deletion breakpoints involving DCLRE1C,
IGHM, and BTK to identify mechanisms underlying these differences in
gross deletion frequencies. Their analysis suggested that gross
deletions involve transposable elements or large homologous regions
rather than recombination motifs. Van Zelm et al. (2008) hypothesized
that the transposable element content of a gene is related to its gross
deletion frequency.

ANIMAL MODEL

In the mouse, gene targeting is accomplished using embryonic stem cells,
but has been successful in other species only by using primary somatic
cells followed by embryonic cloning. Gene targeting in somatic cells as
opposed to embryonic stem cells is a challenge; consequently, there are
few reported successes and none include the targeting of
transcriptionally silent genes or double targeting to produce
homozygotes. Kuroiwa et al. (2004) reported a broadly applicable and
rapid method for generating multiple gene targeting events in cattle.
They reported its use for primary fibroblast cells that they used to
knock out both alleles of a silent gene, the bovine gene encoding
immunoglobulin-mu (IGHM), producing both heterozygous and homozygous
knockout calves. They also carried out sequential knockout targeting of
both alleles of a gene that is active in fibroblasts, that encoding the
bovine prion protein (PRNP; 176640), in the same genetic line to produce
doubly homozygous knockout fetuses. The sequential gene targeting system
they used alleviated the need for germline transmission for complex
genetic modifications.

Lewis et al. (2009) generated mice lacking C1qa (120550) and/or serum
IgM as well as Ldlr (606945) and studied them on both low- and high-fat
semisynthetic diets. On both diets, serum IgM/Ldlr -/- mice developed
substantially larger and more complex en face and aortic root
atherosclerotic lesions, with accelerated cholesterol crystal formation
and increased smooth muscle content in aortic root lesions. TUNEL
analysis revealed increased apoptosis in both C1qa/Ldlr -/- and serum
IgM/Ldlr -/- mice. Overall lesions were larger in mice lacking IgM
rather than C1q, suggesting that IgM protective mechanisms are partially
independent of classic complement pathway activation and apoptotic cell
clearance. Lewis et al. (2009) concluded that IgM antibodies play a
central role in protection against atherosclerosis.

*FIELD* AV
.0001
AGAMMAGLOBULINEMIA 1
IGHM, 75-KB DEL

In a family of Turkish descent, Yel et al. (1996) observed a brother and
sister with first-cousin parents affected with hypogammaglobulinemia-1
(AGM1; 601495) due to homozygosity for a 75-to-100 kb deletion that
involved D-region genes, J-region genes, and the IGHM mu constant-region
gene.

In a follow-up paper, Lopez Granados et al. (2002) stated that the
Turkish family was homozygous for a 75-kb deletion involving the IGHM
gene.

.0002
AGAMMAGLOBULINEMIA 1
IGHM, IVS4AS, G-A, -1

In a consanguineous family of Scottish-Irish ancestry living in
Appalachia, Yel et al. (1996) observed 3 males and 1 female in 3 related
sibships with autosomal recessive agammaglobulinemia-1 (601495).
Affected individuals were found to be homozygous for a 1831G-A
transition in the IGHM gene (according to the numbering system of
Friedlander et al. (1990)). This point mutation was at the -1 position
of the alternative splice donor site that is used to produce the
membrane rather than the secretory mu transcript. A mutation at this
critical site would be expected to have 3 effects. First, this change
would cause a substitution of serine for glycine in the secreted form of
the mu chain. Second, in the membrane form of the mu chain, a positively
charged lysine would be substituted for the wildtype, negatively charged
glutamic acid. Finally, because the alternative splice donor site has
only weak homology to the consensus splice donor sequence, the loss of
the consensus G at the -1 position would be expected to reduce markedly
the efficient splicing at this site, leading to an absence of the
membrane form of the mu heavy chain.

In a follow-up paper, Lopez Granados et al. (2002) stated that this
mutation occurred at codon 433 in exon 4. Five additional families with
agammaglobulinemia-1 were found to carry the splice site mutation.
Haplotype analysis showed different haplotypes, indicating a mutation
hotspot. Affected families originated from Sweden, Spain, and Italy.

.0003
AGAMMAGLOBULINEMIA 1
IGHM, CYS412GLY

In the son of a Korean mother and a white father with autosomal
recessive agammaglobulinemia (601495), who was at first thought to have
X-linked agammaglobulinemia (300755), Yel et al. (1996) found compound
heterozygosity for mutations involving the IGHM locus. On one
chromosome, a G-to-T transition at nucleotide 1768 resulted in the
substitution of glycine for the wildtype cysteine at codon 536 in the
C-terminal immunoglobulin domain of the mutant chain. The cysteine at
this site is the 3-prime cysteine involved in the intrachain disulfide
bridge that is characteristic of all immunoglobulin domains. This
mutation would be expected to result in an unstable form of both a
membrane and secreted mu chain. The other chromosome was found to have a
large deletion (greater than 260 kb), including the immunoglobulin
locus.

Lopez Granados et al. (2002) referred to this mutation as CYS412GLY.

.0004
AGAMMAGLOBULINEMIA 1
IGHM, 2-BP DEL, AA

In affected members of 2 Spanish families with agammaglobulinemia-1
(601495), Lopez Granados et al. (2002) identified a homozygous 2-bp
deletion (AA) at codon 168 in exon 2 of the IGHM gene. This mutation
resulted in a frameshift and premature termination. Haplotype analysis
suggested a common ancestor.

.0005
AGAMMAGLOBULINEMIA 1
IGHM, TRP258TER

In an Argentinian girl with agammaglobulinemia-1 (601495), Lopez
Granados et al. (2002) identified a heterozygous G-to-A transition in
exon 3 of the IGHM gene, resulting in a trp258-to-ter (W258X)
substitution on the paternally derived allele. The maternal allele was
determined to have a deletion at the IGHM locus.

*FIELD* SA
Migone et al. (1983)
*FIELD* RF
1. Erikson, J.; Finan, J.; Nowell, P. C.; Croce, C. M.: Translocation
of immunoglobulin V(H) genes in Burkitt lymphoma. Proc. Nat. Acad.
Sci. 79: 5611-5615, 1982.

2. Friedlander, R. M.; Nussenzweig, M. C.; Leder, P.: Complete nucleotide
sequence of the membrane form of the human IgM heavy chain. Nucleic
Acids Res. 18: 4278 only, 1990.

3. Janeway, C. A., Jr.; Travers, P.; Walport, M.; Shlomchik, M. J.
: Immunobiology: The Immune System in Health and Disease. New York:
Garland Science Publishing (6th ed.) , 2005. Pp. 103-106, 135-139.

4. Kuroiwa, Y.; Kasinathan, P.; Matsushita, H.; Sathiyaselan, J.;
Sullivan, E. J.; Kakitani, M.; Tomizuka, K.; Ishida, I.; Robl, J.
M.: Sequential targeting of the genes encoding immunoglobulin-mu
and prion protein in cattle. Nature Genet. 36: 775-780, 2004.

5. Lefranc, M.-P.: Personal Communication. Montpellier, France
2/1991.

6. Lefranc, M.-P.; Lefranc, G.; Rabbitts, T. H.: Inherited deletion
of immunoglobulin heavy chain constant region genes in normal human
individuals. Nature 300: 760-762, 1982.

7. Lewis, M. J.; Malik, T. H.; Ehrenstein, M. R.; Boyle, J. J.; Botto,
M.; Haskard, D. O.: Immunoglobulin M is required for protection against
atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 120:
417-426, 2009.

8. Liu, G. B.; Yan, H.; Jiang, Y. F.; Chen, R.; Pettigrew, J. D.;
Zhao, K.-N.: The properties of CpG islands in the putative promoter
regions of human immunoglobulin (Ig) genes. Gene 358: 127-138, 2005.

9. Lopez Granados, E.; Porpiglia, A. S.; Hogan, M. B.; Matamoros,
N.; Krasovec, S.; Pignata, C.; Smith, C. I. E.; Hammarstrom, L.; Bjorkander,
J.; Belohradsky, B. H.; Casariego, G. F.; Garcia Rodriguez, M. C.;
Conley, M. E.: Clinical and molecular analysis of patients with defects
in mu heavy chain gene. J. Clin. Invest. 110: 1029-1035, 2002.

10. Migone, N.; Feder, J.; Cann, H.; van West, B.; Hwang, J.; Takahashi,
N.; Honjo, T.; Piazza, A.; Cavalli-Sforza, L. L.: Multiple DNA fragment
polymorphisms associated with immunoglobulin mu chain switch-like
regions in man. Proc. Nat. Acad. Sci. 80: 467-471, 1983.

11. Mostoslavsky, R.; Singh, N.; Tenzen, T.; Goldmit, M.; Gabay, C.;
Elizur, S.; Qi, P.; Reubinoff, B. E.; Chess, A.; Cedar, H.; Bergman,
Y.: Asynchronous replication and allelic exclusion in the immune
system. Nature 414: 221-225, 2001.

12. Rabbitts, T. H.; Forster, A.; Milstein, C. P.: Human immunoglobulin
heavy chain genes: evolutionary comparisons of C(mu), C(delta) and
C(gamma) genes and associated switch sequences. Nucleic Acids Res. 9:
4509-4524, 1981.

13. Skok, J. A.; Brown, K. E.; Azuara, V.; Caparros, M. L.; Baxter,
J.; Takacs, K.; Dillon, N.; Gray, D.; Perry, R. P.; Merkenschlager,
M.; Fisher, A. G.: Nonequivalent nuclear location of immunoglobulin
alleles in B lymphocytes. Nature Immun. 2: 848-54, 2001.

14. van Zelm, M. C.; Geertsema, C.; Nieuwenhuis, N.; de Ridder, D.;
Conley, M. E.; Schiff, C.; Tezcan, I.; Bernatowska, E.; Hartwig, N.
G.; Sanders, E. A. M.; Litzman, J.; Kondratenko, I.; van Dongen, J.
J. M.; van der Burg, M.: Gross deletions involving IGHM, BTK, or
Artemis: a model for genomic lesions mediated by transposable elements. Am.
J. Hum. Genet. 82: 320-332, 2008.

15. Wabl, M. R.; Johnson, J. P.; Haas, I. G.; Tenkhoff, M.; Meo, T.;
Inan, R.: Simultaneous expression of mouse immunoglobulins M and
D is determined by the same homolog of chromosome 12. Proc. Nat.
Acad. Sci. 77: 6793-6796, 1980.

16. Yel, L.; Minegishi, Y.; Coustan-Smith, E.; Buckley, R. H.; Trubel,
H.; Pachman, L. M.; Kitchingman, G. R.; Campana, D.; Rohrer, J.; Conley,
M. E.: Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. New
Eng. J. Med. 335: 1486-1493, 1996.

*FIELD* CN
Matthew B. Gross - updated: 8/12/2010
Paul J. Converse - updated: 8/5/2010
Cassandra L. Kniffin - updated: 7/29/2010
Patricia A. Hartz - updated: 5/2/2008
Paul J. Converse - updated: 8/4/2006
Victor A. McKusick - updated: 7/7/2004
Victor A. McKusick - edited: 8/22/2003
Paul J. Converse - updated: 11/7/2001

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

*FIELD* ED
mgross: 10/07/2013
carol: 9/9/2013
mgross: 8/12/2010
alopez: 8/6/2010
terry: 8/5/2010
carol: 8/3/2010
ckniffin: 7/29/2010
alopez: 7/9/2010
carol: 11/24/2009
mgross: 5/2/2008
mgross: 8/30/2006
terry: 8/4/2006
alopez: 7/12/2004
terry: 7/7/2004
carol: 8/22/2003
terry: 8/22/2003
alopez: 11/7/2001
carol: 7/15/1998
jenny: 12/9/1996
terry: 12/4/1996
carol: 11/12/1993
carol: 11/11/1993
supermim: 3/16/1992
carol: 2/27/1991
supermim: 3/20/1990
ddp: 10/27/1989

MIM 601495
*RECORD*
*FIELD* NO
601495
*FIELD* TI
#601495 AGAMMAGLOBULINEMIA 1, AUTOSOMAL RECESSIVE; AGM1
;;AGAMMAGLOBULINEMIA, AUTOSOMAL RECESSIVE, DUE TO IGHM DEFECT
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
agammaglobulinemia, referred to here as AGM1, is caused by homozygous or
compound heterozygous mutation in the mu heavy-chain gene (IGHM; 147020)
on chromosome 14q32.

DESCRIPTION

Agammaglobulinemia is a primary immunodeficiency characterized by
profoundly low or absent serum antibodies and low or absent circulating
B cells due to an early block of B-cell development. Affected
individuals develop severe infections in the first years of life. The
most common form of agammaglobulinemia is X-linked agammaglobulinemia
(AGMX1, XLA; 300755), also known as Bruton disease, which is caused by
mutation in the BTK gene (300300). AGMX1 accounts for anywhere from 85
to 95% of males who have the characteristic findings (Lopez Granados et
al., 2002; Ferrari et al., 2007). Autosomal recessive inheritance of
agammaglobulinemia, which has a similar phenotype to that of the
X-linked form, has been observed in a small number of families, and
accounts for up to 15% of patients with agammaglobulinemia (Ferrari et
al., 2007). Conley (1999) gave a comprehensive review of autosomal
recessive agammaglobulinemia.

- Genetic Heterogeneity of Autosomal Agammaglobulinemia

Autosomal agammaglobulinemia is a genetically heterogeneous disorder:
see also AGM2 (613500), caused by mutation in the IGLL1 gene (146770);
AGM3 (613501), caused by mutation in the CD79A gene (112205); AGM4
(613502), caused by mutation in the BLNK gene (604515); AGM5 (613506),
caused by disruption of the LRRC8 gene (608360); AGM6 (612692), caused
by mutation in the CD79B gene (147245); and AGM7 (615214), caused by
mutation in the PIK3R1 gene (171833).

CLINICAL FEATURES

Conley and Sweinberg (1992) reported 2 girls with a recessive disorder
phenotypically identical to the X-linked form (300755), but with a
likely autosomal origin.

Yel et al. (1996) reported 2 consanguineous families with autosomal
recessive agammaglobulinemia. The first was of Scottish-Irish descent
living in Appalachia. The oldest patient was evaluated at age 9 months
for fever, weakness, and rashes. He was found to have
hypogammaglobulinemia and absent B cells, and died at age 4.5 years of
chronic enteroviral encephalitis. Two other family members, including 1
girl, were later evaluated because of persistent early-onset infections
and hypogammaglobulinemia. Another patient was diagnosed at age 1 month
due to the family history. He did not develop infections after treatment
with intravenous immunoglobulin (IV Ig). Two of the patients had
previously been reported by McKinney et al. (1987). The second family
reported by Yel et al. (1996) was of Turkish origin. Two sibs had
recurrent infections in infancy and were found have
hypogammaglobulinemia with absent B cells. A third patient, of Korean
origin, had sporadic disease. All patients were treated with IV Ig.

Meffre et al. (1996) described a young female patient with severe
agammaglobulinemia in whom they demonstrated, by a detailed analysis of
B cell subpopulations and B cell-specific transcripts, a blockage at an
early pro-B cell stage of the B-cell differentiation pathway before the
onset of immunoglobulin gene rearrangement. This case was considered
reminiscent of the phenotype of Pax5 knockout mice (Urbanek et al.,
1994), but since the coding sequence of the patient's PAX5 (167414) cDNA
was normal, Meffre et al. (1996) speculated that the defect might result
from an altered regulation of this gene. All the data indicated that the
patient had a new genetic defect that resulted in an arrest of
differentiation within the pro-B cell compartment, i.e., earlier than in
X-linked agammaglobulinemia.

Lopez Granados et al. (2002) reported 6 additional families with
agammaglobulinemia-1 confirmed by mutation analysis of the IGHM gene.
The families were of various origins, including Swedish, Spanish,
Italian, and Argentinian. All of the patients had onset of recurrent
infections in the first year of life. Infections included pneumonia,
otitis, conjunctivitis, sinusitis, pseudomonas infections, and
enteroviral infections. Many patients had failure to thrive and
diarrhea. Some had neutropenia, 1 had skin infections, and several
developed bronchiectasis. The phenotype in general was more severe than
that observed in X-linked agammaglobulinemia; those with IGHM mutations
had earlier onset and more severe complications. However, most patients
responded well to gammaglobulin treatment.

MOLECULAR GENETICS

In affected individuals from 2 consanguineous families with autosomal
recessive agammaglobulinemia, Yel et al. (1996) demonstrated 2 different
homozygous mutations in the IGHM gene on chromosome 14
(147020.0001-147020.0002). A third Korean boy with the disorder was
compound heterozygous for a mutation (147020.0003) and a deletion of the
IGHM gene.

Lopez Granados et al. (2002) identified different mutations in the IGHM
gene (see, e.g., 147020.0004 and 147020.0005) in affected members of 9
unrelated families with agammaglobulinemia-1. Two of the mutations were
large deletions that removed more than 40 kb of DNA at the IGHM locus.
Six families carried the same splice site mutation (147020.0002) that
was present on different haplotypes, indicating a hotspot for mutations.
Lopez Granados et al. (2002) concluded that 20 to 30% of patients with
autosomal recessive defects in B-cell development have mutations in the
IGHM gene.

HISTORY

In a provocative although not thoroughly convincing report of the family
of a patient with hypogammaglobulinemia associated with
alpha-1-antitrypsin deficiency (613490), Phung et al. (1983) suggested
genetic linkage of the PI locus (107400) on chromosome 14q and a locus
exercising a regulatory role in immunoglobulin synthesis. Two members of
the kindred were thought to be recombinants; they had
hypogammaglobulinemia with normal PI MM phenotype. Because of the
relatively close situation (on the distal end of 14q) of the PI locus
and the loci for immunoglobulin heavy chains, the observation was of
considerable interest.

*FIELD* SA
Phung et al. (1982)
*FIELD* RF
1. Conley, M. E.: Autosomal recessive agammaglobulinemia.In: Ochs,
H. D.; Smith, C. I. E.; Puck, J. M. (eds.): Primary Immunodeficiency
Diseases: A Molecular and Genetic Approach. New York: Oxford University
Press 1999. Pp. 285-291, and 1999.

2. Conley, M. E.; Sweinberg, S. K.: Females with a disorder phenotypically
identical to X-linked agammaglobulinemia. J. Clin. Immun. 12: 139-143,
1992.

3. Ferrari, S.; Lougaris, V.; Caraffi, S.; Zuntini, R.; Yang, J.;
Soresina, A.; Meini, A.; Cazzola, G.; Rossi, C.; Reth, M.; Plebani,
A.: Mutations of the Ig-beta gene cause agammaglobulinemia in man. J.
Exp. Med. 204: 2047-2051, 2007.

4. Lopez Granados, E.; Porpiglia, A. S.; Hogan, M. B.; Matamoros,
N.; Krasovec, S.; Pignata, C.; Smith, C. I. E.; Hammarstrom, L.; Bjorkander,
J.; Belohradsky, B. H.; Casariego, G. F.; Garcia Rodriguez, M. C.;
Conley, M. E.: Clinical and molecular analysis of patients with defects
in mu heavy chain gene. J. Clin. Invest. 110: 1029-1035, 2002.

5. McKinney, R. E., Jr.; Katz, S. L.; Wilfert, C. M.: Chronic enteroviral
meningoencephalitis in agammaglobulinemic patients. Rev. Infect.
Dis. 9: 334-356, 1987.

6. Meffre, E.; LeDeist, F.; de Saint-Basile, G.; Deville, A.; Fougereau,
M.; Fischer, A.; Schiff, C.: A human non-XLA immunodeficiency disease
characterized by blockage of B cell development at an early proB cell
stage. J. Clin. Invest. 98: 1519-1526, 1996.

7. Phung, N. D.; Harbeck, R. J.; Helbling-Muntges, C.: Familial hypogammaglobulinemia:
genetic linkage with alpha-1-antitrypsin deficiency. Arch. Intern.
Med. 143: 575-577, 1983.

8. Phung, N. D.; Kubo, R. T.; Spector, S. L.: Alpha-1-antitrypsin
deficiency and common variable hypogammaglobulinemia in a patient
with asthma. Chest 81: 112-115, 1982.

9. Urbanek, P.; Wang, Z.-Q.; Fetka, I.; Wagner, E. F.; Busslinger,
M.: Complete block of early B cell differentiation and altered patterning
of the posterior midbrain in mice lacking Pax5/BSAP. Cell 79: 901-912,
1994.

10. Yel, L.; Minegishi, Y.; Coustan-Smith, E.; Buckley, R. H.; Trubel,
H.; Pachman, L. M.; Kitchingman, G. R.; Campana, D.; Rohrer, J.; Conley,
M. E.: Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. New
Eng. J. Med. 335: 1486-1493, 1996.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

HEAD AND NECK:
[Head];
Sinusitis, recurrent;
[Ears];
Otitis, recurrent;
[Eyes];
Conjunctivitis, recurrent

RESPIRATORY:
Recurrent respiratory infections;
[Airways];
Bronchiectasis;
[Lung];
Pneumonia, recurrent

ABDOMEN:
[Gastrointestinal];
Enteritis, recurrent;
Diarrhea

IMMUNOLOGY:
Recurrent bacterial infections;
Absent or severely reduced numbers of B cells;
Enteroviral infections;
Pseudomonas infections;
Hypogammaglobulinemia, profound;
Agammaglobulinemia

LABORATORY ABNORMALITIES:
Neutropenia

MISCELLANEOUS:
Onset in infancy

MOLECULAR BASIS:
Caused by mutation in the immunoglobulin mu gene (IGHM, 147020.0001)

*FIELD* CD
Cassandra L. Kniffin: 7/27/2010

*FIELD* ED
joanna: 10/21/2011
ckniffin: 8/3/2010

*FIELD* CN
Cassandra L. Kniffin - updated: 4/30/2013
Cassandra L. Kniffin - updated: 7/29/2010
Cassandra L. Kniffin - updated: 1/6/2006
Victor A. McKusick - updated: 1/7/2004
Victor A. McKusick - updated: 9/23/1999

*FIELD* CD
Victor A. McKusick: 11/11/1996

*FIELD* ED
carol: 05/01/2013
ckniffin: 5/1/2013
ckniffin: 4/30/2013
terry: 4/27/2011
carol: 8/13/2010
carol: 8/3/2010
ckniffin: 7/29/2010
ckniffin: 1/6/2006
tkritzer: 1/12/2004
tkritzer: 1/9/2004
terry: 1/7/2004
mgross: 10/8/1999
terry: 9/23/1999
jenny: 12/9/1996
terry: 12/4/1996
jamie: 11/22/1996
mark: 11/12/1996

RBCC Red Blood Cell Collection

Full text data of IGHM