Editors' ChoiceInfectious Disease

Genomic Medicine at Its Best

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Science Translational Medicine  20 Jul 2011:
Vol. 3, Issue 92, pp. 92ec114
DOI: 10.1126/scitranslmed.3002893

Chronic mucocutaneous candidiasis (CMC) is a rare disorder of the innate immune system in which patients with CMC are predisposed to Candida infection of the skin, nails, and mucous membranes. These patients may also develop autoimmune diseases such as autoimmune hepatitis, thyroiditis, or hemolytic anemia. Several presentations of CMC have been identified, including autosomal dominant, autosomal recessive autoimmune polyendocrinopathy candidiasis with ectodermal dystrophy (APECED), and autosomal recessive form due to somatic mutations. Previous studies have shown that mutations in the autoimmune regulator, AIRE, underlie the development of APECED. These defects interfere with the Th17 pathway of mucosal antifungal immunity. However, the molecular defects in the autosomal dominant CMC are unknown.

In an elegant genomic study, van de Veerdonk et al. evaluated 14 patients from five families with autosomal dominant CMC. The authors stimulated peripheral blood mononuclear cells from these patients with mimics of fungal infection and identified two signaling pathways, downstream of interleukin-12 receptor and interleukin-23 receptor, that were defective. Next, 100 candidate genes from these two receptor signaling pathways were subjected to array-based genomic sequencing. Heterozygous missense mutations in the DNA sequence encoding the coiled-coil domain of signal transducer and activator of transcription 1 (STAT1) were identified as the recurrent mutations in these probands. Interestingly, further genomic analysis also demonstrated a likely founder effect for these mutations: Defective STAT1 signaling leads to reduced response to interleukin-12 and interleukin-23, and thus reduced expression of downstream target cytokines important for skin and mucosal antifungal immunity.

Although STAT1 mutations can be predicted to lead to defective protein products, this prediction has not been confirmed by in vivo functional studies. It also remains unclear whether these mutations are loss of function or dominant negative mutations. Despite these concerns, the findings of van de Veerdonk et al. illustrate the power of genomic technology in identifying druggable disease targets and in connecting clinical medicine to meaningful and relevant molecular signaling pathways in the laboratory.

F. L. van de Veerdonk et al., STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011). [Abstract]

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