title: 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 (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.
authors: College of Medicine, Qatar University, Doha, Qatar.|College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.
authors: Michail
authors: M
authors: Nomikos
authors: National Center for Scientific Research 'Demokritos', Athens, Greece.
authors: Angelos
authors: 0000-0003-4390-4854
authors: A
authors: Thanassoulas
authors: College of Biomedical and Life Sciences, School of Dentistry, Cardiff University, UK.
authors: Konrad
authors: K
authors: Beck
authors: College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.
authors: Maria
authors: M
authors: Theodoridou
authors: College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.
authors: Jasmine
authors: J
authors: Kew
authors: College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.|College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.|Department of Comparative Medicine, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
authors: Junaid
authors: J
authors: Kashir
authors: College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.
authors: Brian L
authors: BL
authors: Calver
authors: College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.
authors: Emily
authors: E
authors: Matthews
authors: College of Biomedical and Life Sciences, School of Medicine, Cardiff University, UK.
authors: Pierre
authors: P
authors: Rizkallah
authors: National Center for Scientific Research 'Demokritos', Athens, Greece.
authors: Zili
authors: Z
authors: Sideratou
authors: National Center for Scientific Research 'Demokritos', Athens, Greece.
authors: George
authors: G
authors: Nounesis
authors: College of Biomedical and Life Sciences, School of Biosciences, Cardiff University, UK.
authors: F Anthony
authors: FA
authors: Lai
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D055162:Biocatalysis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002942:Circular Dichroism; D004795:Enzyme Stability; D006801:Humans; D006868:Hydrolysis; D017496:Hypopigmentation / Q000235:genetics; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D009260:Nail Diseases / Q000151:congenital / Q000235:genetics; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry / Q000378:metabolism*; D054803:Phospholipase C delta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D051381:Rats; D013696:Temperature
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D054803:Phospholipase C delta; D002118:Calcium
keywords: hereditary leukonychia; mutation; phosphatidylinositol 4,5-bisphosphate; phospholipase C; phospholipase C delta-1