Abstract
We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.
Highlights
Chronic mucocutaneous candidiasis (CMC) is a hereditary primary immunodeficiency characterized by severe skin and mucosal Candida infections, dermatophytosis and onychomycosis [1]
autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is due to mutations in the gene autoimmune regulator (AIRE) [3], and these explain the autoimmune phenomena, including autoantibodies against the antifungal cytokines interleukin (IL)-17A, IL-17F and IL-22 [4,5]
In a study performed in 5 families with autosomal dominant CMC (AD-CMC), we reported that the disease is caused by mutations in the gene coding for the Signal Transducer and Activator of Transcription (STAT)1 signaling molecule [6]
Summary
Chronic mucocutaneous candidiasis (CMC) is a hereditary primary immunodeficiency characterized by severe skin and mucosal Candida infections, dermatophytosis and onychomycosis [1]. In a study performed in 5 families with AD-CMC, we reported that the disease is caused by mutations in the gene coding for the Signal Transducer and Activator of Transcription (STAT)1 signaling molecule [6]. The cellular and molecular mechanisms responsible for the increased susceptibility to fungal infections in patients with AD-CMC and STAT1 mutations remain to be deciphered.
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