Immunodeficiency 28

A number sign (#) is used with this entry because immunodeficiency-28 (IMD28) is caused by homozygous or compound heterozygous mutation in the IFNGR2 gene (147569) on chromosome 21q22.

Description

IMD28 is caused by autosomal recessive (AR) IFNGR2 deficiency, a rare molecular cause of susceptibility to mycobacterial disease. The clinical presentation of complete AR IFNGR2 deficiency resembles that of complete IFNGR1 deficiency (IMD27A; 209950). The disease manifests early in life, with severe, often fatal, infection. The most commonly encountered pathogens include M. bovis bacillus Calmette-Guerin (BCG), M. avium, and M. fortuitum. Complete AR IFNGR2 deficiency is characterized by an undetectable cellular response to interferon-gamma (IFNG; 147570). There is also a rare, partial form of AR IFNGR2 deficiency, reported in 1 child, who retained a residual cellular response to IFNG and presented with a relatively mild infection by M. bovis BCG and M. abscessus (review by Al-Muhsen and Casanova, 2008).

Diagnosis

Fieschi et al. (2001) found that children with complete IFNGR deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNG in their plasma. Fieschi et al. (2001) proposed this measurement as a simple, inexpensive, and accurate diagnostic test for complete IFNGR deficiency. They noted that early identification of such children, who do not respond to exogenous IFNG or antibiotics, may improve management by leading to the consideration of bone marrow transplantation.

Molecular Genetics

Vogt et al. (2005) studied 4 children with severe mycobacterial disease from 3 unrelated families, all consanguineous. One was from an Austrian family, 1 from an Iranian family, and 2 were from a Saudi Arabian family. The severity of the clinical phenotype and the absence of detectable mutations in IFNGR1 led to a study of IFNGR2. The Iranian patient and the 2 Saudi Arabian patients were homozygous with respect to a missense mutation in the IFNGR2 gene (147569.0002). The Austrian patient was homozygous for an in-frame 27-bp microdeletion of nucleotides 663-689 (147569.0003). The parents of the 4 children were healthy and were heterozygous with respect to the corresponding mutations. All 4 children with the disorder referred to by Vogt et al. (2005) as mendelian susceptibility to mycobacterial disease had complete IFN-gamma-R2 deficiency.

Vogt et al. (2008) reported a child of consanguineous parents with M. avium disease who was homozygous for an in-frame 6-bp duplication in IFNGR2, resulting in duplication thr128 and met129 (147569.0004). Both parents and 1 of 2 sibs were heterozygous for the mutation, but they did not develop disease. The affected child died at age 5 years of disseminated M. avium disease in spite of treatment with multiple antimycobacterial drugs. Vogt et al. (2008) found that the mutant IFNGR2 protein was predominantly retained intracellularly, and that the fraction expressed on the surface had a high molecular mass, was abnormally folded, was N-glycosylated, was resistant to endoglycosidase H, and did not respond to IFNG. Treating cells expressing the mutant protein with 13 of 29 compounds affecting protein maturation by N-glycosylation reduced the molecular mass of surface-expressed mutant IFNGR2 and restored cellular responsiveness to IFNG. Vogt et al. (2008) proposed that modifiers of N-glycosylation, some of which are available for clinical use, may complement human cells carrying in-frame and misfolding mutations in genes encoding proteins subject to trafficking via the secretory pathway.