title: New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe.
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.
authors.affiliation: Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary, EU.
authors.forename: Beáta
authors.initials: B
authors.lastname: Soltész
authors.forename: Beáta
authors.initials: B
authors.lastname: Tóth
authors.forename: Nadejda
authors.initials: N
authors.lastname: Shabashova
authors.forename: Anastasia
authors.initials: A
authors.lastname: Bondarenko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.forename: Sophie
authors.initials: S
authors.lastname: Cypowyj
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Gabriella
authors.initials: G
authors.lastname: Csorba
authors.forename: Szilvia
authors.initials: S
authors.lastname: Taskó
authors.forename: Adrien Katalin
authors.initials: AK
authors.lastname: Sarkadi
authors.forename: Leonóra
authors.initials: L
authors.lastname: Méhes
authors.forename: Pavel
authors.initials: P
authors.lastname: Rozsíval
authors.forename: David
authors.initials: D
authors.lastname: Neumann
authors.forename: Liudmyla
authors.initials: L
authors.lastname: Chernyshova
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Tulassay
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Anna
authors.initials: A
authors.lastname: Sediva
authors.forename: Jiri
authors.initials: J
authors.lastname: Litzman
authors.forename: László
authors.initials: L
authors.lastname: Maródi
mesh_terms: D000293:Adolescent; D000328:Adult; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000378:metabolism; D005061:Europe, Eastern; D020022:Genetic Predisposition to Disease; D006801:Humans; D007159:Immunologic Tests; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor / Q000235:genetics*
chemical_list: D016207:Cytokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human