dc.contributor.author |
Soltész, Beáta |
|
dc.contributor.author |
Tóth, Beáta |
|
dc.contributor.author |
Shabashova N, |
|
dc.contributor.author |
Bondarenko A, |
|
dc.contributor.author |
Okada S, |
|
dc.contributor.author |
Tulassay, Zsolt |
|
dc.date.accessioned |
2014-11-24T16:01:59Z |
|
dc.date.available |
2014-11-24T16:01:59Z |
|
dc.date.issued |
2013 |
|
dc.identifier |
84883157575 |
|
dc.identifier.citation |
pagination=567-578;
journalVolume=50;
journalIssueNumber=9;
journalTitle=JOURNAL OF MEDICAL GENETICS; |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/468 |
|
dc.identifier.uri |
doi:10.1136/jmedgenet-2013-101570 |
|
dc.description.abstract |
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. |
|
dc.relation.ispartof |
urn:issn:0022-2593 |
|
dc.title |
New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe |
|
dc.type |
Journal Article |
|
dc.date.updated |
2014-11-10T18:16:20Z |
|
dc.language.rfc3066 |
en |
|
dc.identifier.mtmt |
2521633 |
|
dc.identifier.wos |
000323450200001 |
|
dc.contributor.department |
Semmelweis Egyetem |
|
dc.contributor.department |
II. Sz. Belgyógyászati Klinika |
|
dc.contributor.institution |
Semmelweis Egyetem |
|