New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe

Authors	SOLTÉSZ Beáta TÓTH Beáta BONDARENKO Anastasia OKADA Satoshi SHABASHOVA Nadejda CYPOWYJ Sophie ABHYANKAR Avinash CSORBA Gabriella TASKÓ Szilvia SARKADI Adrien Katalin MÉHES Leonóra ROZSÍVAL Pavel NEUMANN David CHERNYSHOVA Liudmyla TULASSAY Zsolt PUEL Anne CASANOVA Jean Laurent SEDIVA Anna LITZMAN Jiří MARÓDI László
Year of publication	2013
Type	Article in Periodical
Magazine / Source	Journal of Medical Genetics
MU Faculty or unit	Faculty of Medicine
Citation
Doi	http://dx.doi.org/10.1136/jmedgenet-2013-101570
Field	Immunology
Keywords	INTERCELLULAR-ADHESION MOLECULE-1; SEQUENCING-BASED DISCOVERY; DNA-BINDING DOMAIN; HYPER-IGE SYNDROME; INBORN-ERRORS; IL-17 IMMUNITY; J PROJECT; DEFICIENCY; EXPRESSION; AUTOIMMUNITY
Attached files	New_and_recurrent.pdf
Description	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 -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.