Immunodeficiency 61

A number sign (#) is used with this entry because of evidence that immunodeficiency-61 (IMD61) is caused by hemizygous mutation in the SH3KBP1 gene (300374) on chromosome Xp22. One such family has been reported.

Description

Immunodeficiency-61 (IMD61) is an X-linked recessive primary immunodeficiency characterized by onset of recurrent infections in early childhood due to impaired antibody production. Affected individuals have normal numbers of circulating B and T cells, but B cells have an intrinsic defect in antibody production (summary by Keller et al., 2018).

For a general phenotypic description of X-linked agammaglobulinemia, see 300755.

Clinical Features

Keller et al. (2018) reported 2 brothers with recurrent infections and impaired antibody responses. The proband was a 12-year-old boy with deficiencies of IgM, IgG2, and IgG4 who experienced recurrent bacterial infections until his fourth year of life. He overcame this period of severe early infections and since that time showed no obvious symptoms of a compromised immune system. Detailed study of the patient's B cells showed normal levels of circulating B cells and subtypes, including transitional, naive, memory cells, and plasmablasts, although there were some subtle abnormalities. However, his IgG response to pneumococcal vaccination (polysaccharide) was insufficient, although responses to tetanus toxoid were normal. Detailed studies of patient T cells showed no abnormalities of proliferation, activation, or intracellular signaling. His brother (patient 2) had constant infections since early childhood and died at age 15 years from a bacterial infection complicated by septic shock and multiorgan failure. The brother had decreased serum titers of all antibodies, including total IgG and IgA. In addition, both brothers were diagnosed at age 11 with ADHD, mildly impaired adaptive skills, and obesity.

Inheritance

The transmission pattern of IMD61 in the family reported by Keller et al. (2018) was consistent with X-linked recessive inheritance.

Mapping

In linkage studies, Mensink et al. (1986) found evidence suggesting at least 2 types of X-linked agammaglobulinemia: one located at Xq21.3-q22 (300755) and another unlinked to the marker in this area and possibly located in the Xp22 band.

Molecular Genetics

In 2 brothers with IMD61, Keller et al. (2018) identified a hemizygous 247.5-kb intragenic deletion in the SH3KBP1 gene that deleted exons 2 through 6, which encode 2 SH3 domains of the protein (300374.0001). The deletion, which was found by array CGH, was also present in the unaffected mother. Genes adjacent to SH3KBP1 were not affected. Whole-exome sequencing excluded mutations in 395 genes linked with primary immunodeficiencies in humans. In vitro functional expression studies of patient B cells showed a specific defect in the canonical activation of NFKB (see 164011) in response to stimulation of the B-cell receptor (BCR). In contrast, ligation of TLR9 (605474) or CD40 (109535) and treatment of the cells with PMA activated NFKB properly. Other signaling pathways, including Ras (see 190020)-MAPK (see 176872), PI3 kinase (see 171833), and Akt (164730)-mTOR (601231) were unaffected. BCR-induced surface expression of the activation marker CD86 (601020) was decreased in patient cells. Keller et al. (2018) concluded that the deletion caused an intrinsic defect in B cells that impaired central BCR activation pathways and the generation of antibodies.

Animal Model

Kometani et al. (2011) found that specific deletion of the Cin85 gene in murine B cells resulted in impaired T cell-independent antibody responses in vivo and diminished IKKB (603258) and NFKB activation and cellular responses to B cell receptor (BCR) crosslinking in vitro. The findings indicated that Cin85 plays an important role in BCR-mediated survival and proliferation by participating in important signaling pathways.