RT Journal Article SR Electronic T1 New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 567 OP 578 DO 10.1136/jmedgenet-2013-101570 VO 50 IS 9 A1 Beáta Soltész A1 Beáta Tóth A1 Nadejda Shabashova A1 Anastasia Bondarenko A1 Satoshi Okada A1 Sophie Cypowyj A1 Avinash Abhyankar A1 Gabriella Csorba A1 Szilvia Taskó A1 Adrien Katalin Sarkadi A1 Leonóra Méhes A1 Pavel Rozsíval A1 David Neumann A1 Liudmyla Chernyshova A1 Zsolt Tulassay A1 Anne Puel A1 Jean-Laurent Casanova A1 Anna Sediva A1 Jiri Litzman A1 László Maródi YR 2013 UL http://jmg.bmj.com/content/50/9/567.abstract AB Background Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.