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

Soltész, Beáta and Tóth, Beáta and Shabashova, Nadejda and Bondarenko, Anastasia and Okada, Satoshi and Cypowyj, Sophie and Abhyankar, Avinash and Csorba, Gabriella and Taskó, Szilvia and Sarkadi, Adrien Katalin and Méhes, Leonóra and Rozsíval, Pavel and Neumann, David and Chernyshova, Liudmyla and Tulassay, Zsolt and Puel, Anne and Casanova, Jean-Laurent and Sediva, Anna and Litzman, Jiri and Maródi, László (2013) New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. Journal of medical genetics, 50 (9). pp. 567-78. ISSN 1468-6244


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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.

Item Type: Article
Subjects: R Medicine / orvostudomány > RZ Other systems of medicine / orvostudomány egyéb területei
Depositing User: Dr Beáta Lajszné Tóth
Date Deposited: 22 Sep 2014 12:52
Last Modified: 22 Sep 2014 12:52

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