J Med Genet 50:567-578 doi:10.1136/jmedgenet-2013-101570
  • Host defence
  • Original article

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

Open Access
  1. László Maródi1
  1. 1Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary, EU
  2. 2Department of Mycology, Allergology and Immunology, Kashkin Research Institute of Medical Mycology, Ilia Mechnikov North-Western State Medical University, Saint-Petersburg, Russia
  3. 3Department of Pediatric Infectious Diseases and Clinical Immunology of the National Medical Academy for Post-graduate Education (named after P.L.Shupik), Kiev, Ukraine
  4. 4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
  5. 5Department of Pediatrics, Hradec Kralove University Hospital and Charles University, Prague, Czech Republic, EU
  6. 62nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary, EU
  7. 7Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM U980 and University Paris Descartes, Sorbonne Paris Cité, Paris, France, EU
  8. 8Department of Immunology, Motol University Hospital and 2nd School of Medicine, Charles University, Prague, Czech Republic, EU
  9. 9Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University and St Anne's University Hospital, Brno, Czech Republic, EU
  1. Correspondence to Professor László Maródi, Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Nagyerdei Krt. 98, Debrecen, Hungary H-4032, EU; lmarodi{at}
  • Received 30 January 2013
  • Revised 5 April 2013
  • Accepted 22 April 2013
  • Published Online First 24 May 2013


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.


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