Dominant-negative STAT1 SH2 domain mutations in unrelated patients with mendelian susceptibility to mycobacterial disease

Abstract

Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant-negative and result in impaired STAT1-mediated cellular responses to IFN-γ and IL-27. By contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients’ cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA-binding, as well as for anti-mycobacterial immunity.

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

“…The M654K and K673R mutations impair the tyrosine phosphorylation of STAT1, whereas the K637E mutation impairs both STAT1 phosphorylation and GAF-DNA binding. 16,17 These mutations are loss-offunction or hypomorphic and have been shown to exert a dominant-negative effect on wild-type STAT1 for IFN-γ responses.…”

Types and effects of protein variations

“…opposite activity compared to normal state. The dominant negative effect appears for example in 637E and K673R variants in signal transducer and activator of transcription 1 (STAT1) SH2 domain resulting in impaired STAT1-mediated responses to IFN-γ and IL27 leading to susceptibility to mycobacterial disease (Tsumura et al 2012). …”

The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans

“…Patients with these PIDs present with an impaired differentiation of IL17+CD4+ T cells (HIES and IL12Rβ1 deficiency) or increased production of anti-IL-17 antibodies (APS-1). STAT1 GOF mutation was also reported to interfere with Th17 differentiation and turned out to be the most common cause of isolated CMC (CMC disease, CMCD) [14][15][16][17][18][19][20][21]. Sporadic cases of CMCD caused by germ line mutations of IL17F, IL17RA and ACT1 and characterized by impaired stimulus-response coupling and signaling via the IL17R were also reported [22,23].…”

“…STAT1 GOF mutation was first discovered by whole-exome sequencing in a Ukrainian patient with CMCD [14,35]. CCD and DBD mutations were subsequently found in a large number of patients in other kindreds [14][15][16][17][18][19][20][21]. Over the past few years, GOF mutations of STAT1 have been proved to be the most common etiology of CMC.…”

“…One of these groups also reported on impaired differentiation of naïve CD4+ T cells into IL-17+ lymphocytes due to gain of function (GOF) and gain of phosphorylation of STAT1 in a large number of patients with CMCD [14]. Subsequently, STAT1 GOF mutation associated with CMC was found by several groups [16][17][18][19][20][21]. Primary genetic defects of the IL-17 cytokine-IL-17R coupling and IL-17R signaling were also reported as causes of CMCD [22,23].…”