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Heterozygosity for dominant-negative STAT1 mutations underlies autosomal dominant Mendelian susceptibility to mycobacterial diseases. Mutations conferring Mendelian susceptibility to mycobacterial diseases have been identified in the regions of the STAT1 gene encoding the tail segment, DNA-binding domain and SH2 domain. We describe here a new heterozygous mutation, Y701C, in a Japanese two-generation multiplex kindred with autosomal dominant Mendelian susceptibility to mycobacterial diseases. This mutation affects precisely the canonical STAT1 tyrosine phosphorylation site. The Y701C STAT1 protein is produced normally, but its phosphorylation is abolished, resulting in a loss-of-function for STAT1-dependent cellular responses to interferon-γ or interferon-α. In the patients' cells, the allele is dominant-negative for γ-activated factor-mediated responses to interferon-γ, but not for interferon-stimulated gene factor-3-mediated responses to interferon-α/β, accounting for the clinical phenotype of Mendelian susceptibility to mycobacterial diseases without severe viral diseases. Interestingly, both patients displayed multifocal osteomyelitis, which is often seen in patients with Mendelian susceptibility to mycobacterial diseases with autosomal dominant partial IFN-γR1 deficiency. Multifocal osteomyelitis should thus prompt investigations of both STAT1 and IFN-γR1. This experiment of nature also confirms the essential role of tyrosine 701 in human STAT1 activity in natura.

Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis