Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation.

BACKGROUND:Generalized verrucosis (GV) is a chronic and progressive cutaneous human papillomavirus (HPV) infection resulting in multiple warts and associated with acquired or genetic immune defects. We identified a consanguineous Arab family manifesting GV and recurrent bacterial and viral infections, in association with inflammatory bowel disease (IBD). OBJECTIVE:To identify the mutated gene responsible for GV, recurrent infections and IBD, in this family. METHODS:Flow cytometry of peripheral blood mononuclear cells was performed, as well as proliferation and cell cycle assays of T cells. Whole exome sequencing was utilized to detect candidate mutated genes, assuming an autosomal recessive mode of inheritance. Skin fibroblasts from a patient, the mother and control were incubated with sorbitol to detect the phosphorylation ability of TAOK2, and a clonogenic assay was performed to assess the survival and proliferative capacity of fibroblasts' colonies. RESULTS:Despite normal immunophenotyping of T and B cells, T cell proliferation upon activation was impaired in a patient compared to a heterozygous family member and a control. Genetic analyses identified a rare homozygous missense variant, c.2098C>T (p.R700C) in the TAOK2 gene, segregating with the disease phenotype in the family. TAOK2 encodes the TAO2 kinase, a mitogen activated protein kinase kinase kinase (MAP3K) in the p38-MAPK cascade. The mutation is predicted to disrupt its normal folding and molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts. Despite this normal kinase activity, a noticeably higher survival/proliferation of patient's skin fibroblasts was found. CONCLUSIONS:A mutation in TAOK2 appears to cause a novel form of primary immunodeficiency, characterized by an impaired T cell proliferation upon activation. This novel cause of GV gives further support to the importance of the p38-MAPK pathway in the immune response against HPV, and possibly also in the pathogenesis of IBD.

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