Mutations in PLCδ1 associated with hereditary leukonychia display divergent PIP2 hydrolytic function

Abstract

Hereditary leukonychia is a rare genetic nail disorder characterized by distinctive whitening of the nail plate of all 20 nails. Hereditary leukonychia may exist as an isolated feature, or in simultaneous occurrence with other cutaneous or systemic pathologies. Associations between hereditary leukonychia and mutations in the gene encoding phospholipase C delta-1 (PLC?1) have previously been identified. However, the molecular mechanisms underlying PLC1 mutations and hereditary leukonychia remain uncharacterized. In the present study, we introduced hereditary leukonychia-linked human PLC?1 mutations (C209R, A574T and S740R) into equivalent residues of rat PLC1 (C188R, A553T and S719R), and investigated their effect on the biophysical and biochemical properties of the PLC1 protein. Our data suggest that these PLC1 mutations associated with hereditary leukonychia do not uniformly alter the enzymatic ability of this protein leading to loss/gain of function, but result in significantly divergent enzymatic properties. We demonstrate here for the first time the importance of PLC-mediated calcium (Ca2+) signalling within the manifestation of hereditary leukonychia. PLC?1 is almost ubiquitous in mammalian cells, which may explain why hereditary leukonychia manifests in association with other systemic pathologies relating to keratin expression.