title: Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy.
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.
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Carol-Anne
authors.initials: CA
authors.lastname: Martin
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Ilyas
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Klingseisen
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Muhammad Sajid
authors.initials: MS
authors.lastname: Hussain
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Murray
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hunt
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Fawad
authors.initials: F
authors.lastname: Khan
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Ali
authors.affiliation: Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.|Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: James
authors.initials: J
authors.lastname: Ding
authors.affiliation: Cytogenetics Laboratory, South East of Scotland Genetics Service, Western General Hospital, Edinburgh, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Keith
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Harley
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Heyn
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Cell Cycle Control and Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hoffmann
authors.affiliation: Department of Genetics, INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Hopital Necker, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: CARGO and IGMA Hôpitaux Universitaires de Strasbourg, INSERM U1112, Université de Strasbourg, Strasbourg, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Dupuis
authors.affiliation: Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.affiliation: Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McElreavey
authors.affiliation: Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.affiliation: University College London (UCL) Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Southwest Thames Regional Genetics Service, St. George's Hospital Medical School, London, UK.
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.affiliation: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Catie
authors.initials: C
authors.lastname: Schlechter
authors.affiliation: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Weleber
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Angelika Anna
authors.initials: AA
authors.lastname: Noegel
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002502:Centrioles / Q000648:ultrastructure; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006130:Growth Disorders / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D018895:Microsatellite Repeats; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008938:Mitosis; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish
chemical_list: D008869:Microtubule-Associated Proteins; C444456:TUBGCP6 protein, human; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases