Immunodeficiency With Hyper-Igm, Type 5

A number sign (#) is used with this entry because autosomal recessive immunodeficiency with hyper-IgM type 5 (HIGM5) is caused by homozygous or compound heterozygous mutation in the gene encoding uracil-DNA glycosylase (UNG; 191525) on chromosome 12q23-q24.1.

Description

Hyper-IgM syndrome is a condition characterized by normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations, indicating a defect in the class-switch recombination (CSR) process.

For a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (308230).

Clinical Features

Imai et al. (2003) studied 3 unrelated patients from France and Japan with a phenotype resembling HIGM2 (605258), including susceptibility to bacterial infections, lymphoid hyperplasia, increased serum IgM concentrations, and profoundly decreased serum IgG and IgA concentrations, but with no mutations in the AICDA gene (605257). As with AICDA deficiency, this form of HIGM, designated HIGM5, was characterized by defective cleavage of a targeted switch region. Patient B cells were incapable of CSR after activation with anti-CD40 (109535) or with soluble CD40LG (300386) plus IL4 (147780). The phenotype was similar to that observed in Ung -/- mice, although the CSR defect was more severe. All patients had normal T-cell numbers and functions and were successfully treated with intravenous immunoglobulin.

Inheritance

HIGM5 is inherited as an autosomal recessive (Imai et al., 2003).

Pathogenesis

Imai et al. (2003) proposed a model of CSR and somatic hypermutation (SHM) in which AICDA deaminates cytosine into uracil in targeted DNA (e.g., in immunoglobulin switch or variable regions) followed by uracil removal by UNG. Mutations in the UNG gene are associated with a profound impairment in CSR and with a biased pattern of SHM, resulting in HIGM5.

Molecular Genetics

In the 3 patients they reported with HIGM5, Imai et al. (2003) identified 4 mutations in the UNG gene (191525.0001-191525.0004). All 4 mutations occurred within the catalytic domain of the UNG protein. RT-PCR detected both the mitochondrial form and the nuclear form of UNG in control and patient B-cell lines, although the nuclear form was only weakly expressed in 2 patients. Immunoprecipitation and immunoblot analysis with antibodies to the N-terminal regulatory and C-terminal catalytic domains of UNG showed an absence of expression in all 3 patients, demonstrating that the mutations led to protein instability.