Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Item Type:	Article
Title:	Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy
Creators Name:	Martin, C.A. and Ahmad, I. and Klingseisen, A. and Hussain, M.S. and Bicknell, L.S. and Leitch, A. and Nürnberg, G. and Toliat, M.R. and Murray, J.E. and Hunt, D. and Khan, F. and Ali, Z. and Tinschert, S. and Ding, J. and Keith, C. and Harley, M.E. and Heyn, P. and Müller, R. and Hoffmann, I. and Cormier-Daire, V. and Dollfus, H. and Dupuis, L. and Bashamboo, A. and McElreavey, K. and Kariminejad, A. and Mendoza-Londono, R. and Moore, A.T. and Saggar, A. and Schlechter, C. and Weleber, R. and Thiele, H. and Altmüller, J. and Höhne, W. and Hurles, M.E. and Noegel, A.A. and Baig, S.M. and Nürnberg, P. and Jackson, A.P.
Abstract:	Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.
Keywords:	Centrioles, Family Health, Fibroblasts, Fluorescence In Situ Hybridization, Genotype, Growth Disorders, HeLa Cells, Microcephaly, Microsatellite Repeats, Microtubule-Associated Proteins, Mitosis, Mutation, Pakistan, Pedigree, Phenotype, Protein Serine-Threonine Kinases, Retinal Degeneration, Animals, Zebrafish
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	46
Number:	12
Page Range:	1283-1292
Date:	December 2014
Official Publication:	https://doi.org/10.1038/ng.3122
PubMed:	View item in PubMed

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