SOLTÉSZ, Beáta, Beáta TÓTH, Anastasia BONDARENKO, Satoshi OKADA, Nadejda SHABASHOVA, Sophie CYPOWYJ, Avinash ABHYANKAR, Gabriella CSORBA, Szilvia TASKÓ, Adrien Katalin SARKADI, Leonóra MÉHES, Pavel ROZSÍVAL, David NEUMANN, Liudmyla CHERNYSHOVA, Zsolt TULASSAY, Anne PUEL, Jean Laurent CASANOVA, Anna SEDIVA, Jiří LITZMAN and László MARÓDI. New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. Journal of Medical Genetics. London: British Medical Association, 2013, vol. 50, No 9, p. 567-578. ISSN 0022-2593. doi:10.1136/jmedgenet-2013-101570.
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Basic information
Original name New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe
Authors SOLTÉSZ, Beáta (348 Hungary), Beáta TÓTH (348 Hungary), Anastasia BONDARENKO (643 Russian Federation), Satoshi OKADA (840 United States of America), Nadejda SHABASHOVA (643 Russian Federation), Sophie CYPOWYJ (840 United States of America), Avinash ABHYANKAR (840 United States of America), Gabriella CSORBA (348 Hungary), Szilvia TASKÓ (348 Hungary), Adrien Katalin SARKADI (348 Hungary), Leonóra MÉHES (348 Hungary), Pavel ROZSÍVAL (203 Czech Republic), David NEUMANN (203 Czech Republic), Liudmyla CHERNYSHOVA (804 Ukraine), Zsolt TULASSAY (348 Hungary), Anne PUEL (250 France), Jean Laurent CASANOVA (840 United States of America), Anna SEDIVA (203 Czech Republic), Jiří LITZMAN (203 Czech Republic, guarantor, belonging to the institution) and László MARÓDI (348 Hungary).
Edition Journal of Medical Genetics, London, British Medical Association, 2013, 0022-2593.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30102 Immunology
Country of publisher United Kingdom of Great Britain and Northern Ireland
Confidentiality degree is not subject to a state or trade secret
Impact factor Impact factor: 5.636
RIV identification code RIV/00216224:14110/13:00069232
Organization unit Faculty of Medicine
UT WoS 000323450200001
Tags International impact, Reviewed
Changed by Changed by: Ing. Mgr. Věra Pospíšilíková, učo 9005. Changed: 16/9/2013 14:50.
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.
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