Identification of the genetic cause of autosomal dominant CMC

Identification of the genetic cause of autosomal dominant chronic mucocutaneous candidiasis
On june 29th 2011, a manuscript from the departments of Internal Medicine and Human Genetics, RUNMC, has been published by the New England Journal of Medicine about the long sought genetic cause of a rare and severe primary immunodeficiency; chronic mucocutaneous candidiasis (CMC). Several types of CMC have been described based on their mode of inheritance and comorbidities. One of these types is APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), which is known to be caused by mutations in the gene AIRE. However, for the two other types, autosomal dominant CMC and autosomal recessive CMC, the genetic determinant has remained elusive.

Patients with autosomal dominant CMC (AD-CMC) present with persistent mucosal fungal infections, predominantly caused by Candida albicans and dermatophytes, comprising the oral cavity, hands and feet. Moreover, in the majority of cases patients develop hypothyroidism and, more rarely, autoimmune phenomena.

For initial experiments designed to start the quest for the causal gene, peripheral blood mononuclear cells were obtained from AD-CMC patients and were compared to healthy controls concerning the response to C. albicans in vitro, which revealed a deficiency in production of the T cell cytokines IFN-? and IL-17. Further examination provided clear evidence for defective signalling through two cytokine receptors, IL-12 receptor and IL-23 receptor. These results led to a hypothesis-driven effort to sequence a total of 100 genes that most likely contains the causal gene. Indeed, in five out of five families with AD-CMC one of these genes, STAT1, was demonstrated to harbour mutations in specifically the coiled-coil domain of the gene. This was unexpected, since mutations in other protein domains of STAT1 have been previously described in relation to mycobacterial and viral infections.

This study identified the genetic defect underlying AD-CMC, and with that, provides novel insights on diagnosis, disease mechanisms and eventually development of new treatment strategies.

STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, Arts P, Rosentul DC, Carmichael AJ, Smits-van der Graaf CA, Kullberg BJ, van der Meer JW, Lilic D, Veltman JA, Netea MG; NEJM 2011; 365(1):54-61.


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