Alternative titles; symbols
HGNC Approved Gene Symbol: IGHM
Cytogenetic location: 14q32.33 Genomic coordinates (GRCh38): 14:105,851,966-105,856,217 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.33 | Agammaglobulinemia 1 | 601495 | Autosomal recessive | 3 |
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; 147170) 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).
Friedlander et al. (1990) reported the complete nucleotide sequence of the membrane form of the human IgM heavy chain.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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