IGHM Gene

The IGHM gene (IGHM stands for "Immunoglobulin Heavy Constant Mu") is a protein coding gene located on chromosome 14q32.33.

The encoded protein is the constant region of the immunoglobulin heavy chains.

Immunoglobulins (Ig) are the antigen recognition molecules of B cells. An Ig molecule consists of two identical heavy chains and two identical light chains linked by disulfide bonds, so that each heavy chain is linked to a light chain and the two heavy chains are linked to each other. Each Ig heavy chain has an N-terminal variable region (V) containing the antigen binding site and a C-terminal constant region (C) encoded by an individual C-region gene that determines the isotype of the antibody and provides effector or signaling functions. The V region of the heavy chain is encoded by one each of 3 genes: V genes (MIM 147070), junction genes (J genes) (MIM 147010) and diversity genes (D genes) (MIM 146910). The C-region genes are grouped downstream from the V-region genes within the heavy chain locus on chromosome 14. The IGHM- gene encodes the C region of the heavy mμ-chain, which defines the IgM isotype.

Naive B cells express the transmembrane forms of IgM and IgD (see IGHD; MIM 1471770) on their surface. During an antibody response, activated B cells can switch to express individual C-region heavy chain genes by a somatic recombination process known as isotype switching. In addition, secreted Ig forms that act as antibodies can be produced by alternative RNA processing of C-region heavy chain sequences. Although the membrane forms of all Ig isotypes are monomeric, secreted IgM forms pentamers and occasionally hexamers in plasma (Janeway et al., 2005).

Diseases associated with IGHM include:

• Agammaglobulinemia 1 (autosomal recessive), mutation in IGHM.

Immunoglobulins are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors that trigger clonal expansion and differentiation of B lymphocytes into immunoglobulin-secreting plasma cells after binding of a specific antigen.

The secreted immunoglobulins mediate the effector phase of humoral immunity leading to the elimination of the bound antigens (McHeyzer-Williams M etal. 2011). The antigen binding site is formed by the variable domain of a heavy chain together with that of the associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a given antigen. The variable domains are assembled by a V-(D)-J rearrangement and can then undergo somatic hypermutations that allow affinity maturation for a particular antigen after antigen exposure and selection (Teng G et al. 2007; Schroeder HW Jr et al. 2010). IgM antibodies play an important role in primary defense mechanisms. They have been shown to be involved in the early recognition of external invaders such as bacteria and viruses, cellular debris, and altered self, as well as in the detection and clearance of precancerous lesions and cancer. The membrane-bound form, along with IgD, is found in the majority of normal B cells. The membrane-bound IgM induces phosphorylation of CD79A and CD79B by the Src family of protein tyrosine kinases. It can induce cell death by apoptosis. It also occurs in soluble form, accounting for approximately 30% of total serum immunoglobulins, where it is found almost exclusively as a homopentamer. After binding of the antigen to the B cell receptor, the secreted form is secreted in large quantities (Tisch R et al. 1988).

1. McHeyzer-Williams M etal. (2011) Molecular programming of B cell memory. Nat Rev Immunol 12:24-34
2. Schroeder HW Jr et al (2010) Structure and function of immunoglobulins. J Allergy Clin Immunol 125(2 Suppl 2):41-52).
3. Teng G et al (2007) Immunoglobulin somatic hypermutation. Annu Rev Genet41:107-120.
4. Tisch R et al (1988) Functional differences between immunoglobulins M and D expressed on the surface of an immature B-cell line. Proc Natl Acad Sci U S A. 85:6914-6918)