A homozygous CARD9 mutation in a family with susceptibility to fungal infections.

Chronic mucocutaneous candidiasis is a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species as a result of inability of the immune system to get rid of this pathogen. In order to find the genetic defect responsible for this disorder, we performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. Homozygosity mapping was used to locate the mutated gene. We found linkage to a genomic interval on chromosome 9q, including CARD9. All 4 patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild type expression of the CARD9 protein; the 4 patients lacked wild-type expression, which was associated with low numbers of Th17 cells. Functional studies based on genetic reconstitution of myeloid cells from CARD9-/- mice showed that the Q295X mutation impairs innate signalling from the antifungal pattern-recognition receptor dectin-1. We have demonstrated that an autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9.