Immunodeficiency 31a

A number sign (#) is used with this entry because immunodeficiency-31A (IMD31A) is caused by heterozygous mutation in the STAT1 gene (600555) on chromosome 2q32.

Immunodeficiency-31B (IMD31B; 613796), an autosomal recessive disorder, and immunodeficiency-31C (IMD31C; 614162), an autosomal dominant disorder, are allelic.

Description

IMD31A results from autosomal dominant (AD) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AD STAT1 deficiency selectively affects the IFNG pathway, but not the IFNA/IFNB pathway, and confers a predisposition to mycobacterial infections. Pathogens reported in IMD31A patients include bacillus Calmette-Guerin (BCG) and Mycobacterium avium complex, as well as Mycobacterium tuberculosis. IMD31A has low penetrance and a mild clinical phenotype with good prognosis for recovery (review by Al-Muhsen and Casanova, 2008).

Two patients with heterozygous STAT1 mutations have been reported with increased susceptibility to adult-onset herpes simplex encephalitis (HSE) without a history of other significant infections (Mork et al., 2015).

Molecular Genetics

In cells from a French patient with a history of disseminated BCG infection with no mutations in the IL12 (see 161561), IL12RB (601604), or IFNGR (see 107470) genes, Dupuis et al. (2001) observed severely impaired nuclear protein binding to IFNG-activating sequences when the cells were stimulated with IFNG or IFNA. Sequence analysis identified a mutation in the STAT1 gene (600555.0001). The patient's daughter, who was not vaccinated with BCG, had a similar cellular phenotype in vitro and carried the same mutation. An unrelated American patient with a history of M. avium infection was heterozygous for the same mutation. The mutation was not detected in healthy cohorts.

In 2 unrelated patients from Japan and Saudi Arabia with autosomal dominant STAT1 deficiency, Tsumura et al. (2012) identified heterozygous missense mutations affecting the SH2 domain of STAT1. One mutation, lys673 to arg (K673R; 600555.0023), was hypomorphic and impaired STAT1 tyrosine phosphorylation. The other mutation, lys637 to glu (K637E; 600555.0024), was null and affected both STAT1 phosphorylation and DNA-binding activity. Both alleles were dominant-negative and impaired STAT1-mediated cellular responses to IFNG and IL27 (608273), whereas responses to IFNA and IFN-lambda (see 607403) were preserved at normal levels. Tsumura et al. (2012) concluded that the STAT1 SH2 domain is important for tyrosine phosphorylation and DNA binding, as well as antimycobacterial immunity.

In 2 unrelated Danish men (P7 and P8), with IMD31A manifest as adult-onset herpes simplex encephalitis (HSE) after age 60, Mork et al. (2015) identified a heterozygous missense mutation in the STAT1 gene (V266I; 600555.0028). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. Patient peripheral blood mononuclear cells showed significantly lower beta-interferon (IFNB1; 147640), CXCL10 (147310), and TNFA (191160) responses to HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function. Patient cells did not have impaired responses to the TLR3 (603029) agonist poly(I;C). The findings suggested that STAT1 variants may contribute to HSE susceptibility in adults.