Mutations in PLCd1 associated with hereditary leukonychia display divergent PIP2 hydrolytic function

Nomikos, Michail, Thanassoulas, Angelos, Beck, Konrad ORCID: https://orcid.org/0000-0001-5098-9484, Theodoridou, Maria, Kew, Jasmine, Kashir, Junaid, Calver, Brian Lewis, Matthews, Emily, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Sideratou, Zili, Nounesis, George and Lai, Francis Anthony ORCID: https://orcid.org/0000-0003-2852-8547 2016. Mutations in PLCd1 associated with hereditary leukonychia display divergent PIP2 hydrolytic function. FEBS Journal 283 (24) , pp. 4502-4514. 10.1111/febs.13939

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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 (PLCδ1) have previously been identified. However, the molecular mechanisms underlying PLCδ1 mutations and hereditary leukonychia remain uncharacterized. In the present study, we introduced hereditary leukonychia-linked human PLCδ1 mutations (C209R, A574T and S740R) into equivalent residues of rat PLCδ1 (C188R, A553T and S719R), and investigated their effect on the biophysical and biochemical properties of the PLCδ1 protein. Our data suggest that these PLCδ1 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. PLCδ1 is almost ubiquitous in mammalian cells, which may explain why hereditary leukonychia manifests in association with other systemic pathologies relating to keratin expression.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Dentistry Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RK Dentistry
Uncontrolled Keywords:	hereditary leukonychia; mutation; phosphatidylinositol 4,5-bisphosphate; phospholipase C; phospholipase C delta-1
Publisher:	Wiley
ISSN:	1742-464X
Funders:	Marie Curie Intra-European Fellowship Award (628634), THALES �Education and Lifelong Learning� Program No. 380170 (European Social Fund/Greek Government), Health Fellowship Award (National Institute for Social Care and Health Research, HP-14-16)
Date of First Compliant Deposit:	22 December 2016
Date of Acceptance:	24 October 2016
Last Modified:	06 Nov 2024 17:45
URI:	https://orca.cardiff.ac.uk/id/eprint/97044

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