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

Nat Genet. 2014 Dec;46(12):1283-1292. doi: 10.1038/ng.3122.

Carol-Anne Martin ^# ¹, Ilyas Ahmad ^# ² ³ ⁴, Anna Klingseisen ^# ¹, Muhammad Sajid Hussain ^# ² ³ ⁴ ⁵, Louise S Bicknell ¹, Andrea Leitch ¹, Gudrun Nürnberg ², Mohammad Reza Toliat ², Jennie E Murray ¹, David Hunt ¹, Fawad Khan ⁴, Zafar Ali ⁴, Sigrid Tinschert ⁶ ⁷, James Ding ¹, Charlotte Keith ⁸, Margaret E Harley ¹, Patricia Heyn ¹, Rolf Müller ³, Ingrid Hoffmann ⁹, Valérie Cormier-Daire ¹⁰, Hélène Dollfus ¹¹, Lucie Dupuis ¹², Anu Bashamboo ¹³, Kenneth McElreavey ¹³, Ariana Kariminejad ¹⁴, Roberto Mendoza-Londono ¹², Anthony T Moore ¹⁵ ¹⁶, Anand Saggar ¹⁷, Catie Schlechter ¹⁸, Richard Weleber ¹⁸, Holger Thiele ², Janine Altmüller ² ¹⁹, Wolfgang Höhne ², Matthew E Hurles ²⁰, Angelika Anna Noegel ³ ⁵ ²¹, Shahid Mahmood Baig ⁴, Peter Nürnberg ² ⁵ ²¹, Andrew P Jackson ¹

Affiliations

1 Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
2 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
3 Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
4 Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
5 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
6 Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.
7 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
8 Cytogenetics Laboratory, South East of Scotland Genetics Service, Western General Hospital, Edinburgh, UK.
9 Cell Cycle Control and Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10 Department of Genetics, INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Hopital Necker, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
11 CARGO and IGMA Hôpitaux Universitaires de Strasbourg, INSERM U1112, Université de Strasbourg, Strasbourg, France.
12 Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
13 Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.
14 Najmabadi Pathology and Genetics Center, Tehran, Iran.
15 University College London (UCL) Institute of Ophthalmology, London, UK.
16 Moorfields Eye Hospital, London, UK.
17 Southwest Thames Regional Genetics Service, St. George's Hospital Medical School, London, UK.
18 Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.
19 Institute of Human Genetics, University of Cologne, Cologne, Germany.
20 Wellcome Trust Sanger Institute, Cambridge, UK.
21 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
# Contributed equally.

PMID: 25344692 DOI: 10.1038/ng.3122

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.

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