Qatar – A research breakthrough conducted by a faculty member at Qatar University College of Medicine (QU-CMED) in collaboration with a team from Cardiff University and the National Center for Scientific Research “Demokritos” has discovered the functional association between hereditary leukonychia and mutations in the gene encoding phospholipase C delta-1 (PLCδ1).
Led by CMED assistant professor of biochemistry, Dr Michail Nomikos, the study is entitled “Mutations in PLCδ1 associated with hereditary leukonychia display divergent PIP2 hydrolytic function”. It examined the hereditary leukonychia, a rare genetic nail disorder characterised by distinctive whitening of the nail plate of all twenty nails.
“Hereditary leukonychia may exist as an isolated feature, or in simultaneous occurrence with other cutaneous or systemic pathologies,” said Dr Nomikos, adding, “However, the molecular mechanisms underlying PLCδ1-mutations and hereditary leukonychia remain uncharacterised.”
The team introduced hereditary leukonychia-linked human PLCδ1 mutations (C209R, A574T and S740R) into equivalent residues of rat PLCδ1 (C188R, A553T and S719R), and investigated the biophysical and biochemical properties of mutants versus normal PLCδ1 protein. The data reveals that 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. The study demonstrates 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.
Commenting on the study Dr Nomikos said: “Hereditary leukonychia is a rare nail pathology in which patients present with a partial or totally white nail plate. Recent studies provided the first genetic links between PLCδ1 and HL by identifying mutations in the PLCδ1 protein sequence of family members exhibiting characteristic features of HL. Both dominant and recessive inheritance is known to underlie manifestation of this nail disorder. Despite the in-depth structural characterisation of PLCδ1, the specific physiological role of this enzyme has only recently become more evident through the identification of its contribution to human disease.”
Chair of Calcium Signaling Laboratory at Cardiff University College of Biomedical and Life Sciences, Prof F Anthony Lai said: “The major discovery of structural and functional changes in the mutant protein (phospholipase delta-1) causing hereditary leukonychia represents an excellent research study that was conducted with Dr Michail Nomikos at Qatar University in collaboration with Cardiff University. The very important report on this work published in the Federation of European Biochemical Societies (FEBS) Journal demonstrates the significance of productive international cooperation in advancing our understanding of the processes that cause human diseases. I anticipate that continued rapid progress in the collaborative research studies between Qatar University and Cardiff University should help to unravel the causes of many other diseases that involve the fundamental calcium signalling process such as male infertility and cardiac dysfunction.”