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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We thank the families and clinicians for their involvement and participation; P. Mills, T. Hurd, M. Bettencourt-Dias and M. Reijns for commenting on the manuscript; N. Hastie, D. Fitzpatrick and J. Livingston for helpful discussions; C. Janke (Institut Curie) for his kind gift of the GT335 antibody; E. Freyer for assistance with FACS analysis; P. Gautier for bioinformatics; P. Carroll and A. Vickers for technical assistance; the IGMM core sequencing service; the IGMM imaging facility for assistance with microscopy; E. Patton and the IGMM fish facility for advice and zebrafish technical assistance; E. Liston and the DNA Resource Centre at SickKids for sample processing; A. Pearce and E. Maher (Cytogenetics Laboratory, South East Scotland Genetics Service) for technical advice; G. Hahn (University Hospital Carl Gustav Carus) for her second opinion on the MRI data; and N. Dalibor and E. Kirst (CCG) for their expert technical assistance. This work was supported by funding from the MRC, the Lister Institute for Preventative Medicine and the European Research Council (ERC, 281847) (A.P.J.), Medical Research Scotland (L.S.B.), the National Institute for Health Research Moorfields Eye Hospital Biomedical Research Centre (A.T.M.), Köln Fortune (M.S.H.) and CMMC (P.N. and A.A.N.).

Author information

Author notes

    • Carol-Anne Martin
    • , Ilyas Ahmad
    • , Anna Klingseisen
    •  & Muhammad Sajid Hussain

    These authors contributed equally to this work.


  1. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.

    • Carol-Anne Martin
    • , Anna Klingseisen
    • , Louise S Bicknell
    • , Andrea Leitch
    • , Jennie E Murray
    • , David Hunt
    • , James Ding
    • , Margaret E Harley
    • , Patricia Heyn
    •  & Andrew P Jackson
  2. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.

    • Ilyas Ahmad
    • , Muhammad Sajid Hussain
    • , Gudrun Nürnberg
    • , Mohammad Reza Toliat
    • , Holger Thiele
    • , Janine Altmüller
    • , Wolfgang Höhne
    •  & Peter Nürnberg
  3. Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.

    • Ilyas Ahmad
    • , Muhammad Sajid Hussain
    • , Rolf Müller
    •  & Angelika Anna Noegel
  4. Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.

    • Ilyas Ahmad
    • , Muhammad Sajid Hussain
    • , Fawad Khan
    • , Zafar Ali
    •  & Shahid Mahmood Baig
  5. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

    • Muhammad Sajid Hussain
    • , Angelika Anna Noegel
    •  & Peter Nürnberg
  6. Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria.

    • Sigrid Tinschert
  7. Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

    • Sigrid Tinschert
  8. Cytogenetics Laboratory, South East of Scotland Genetics Service, Western General Hospital, Edinburgh, UK.

    • Charlotte Keith
  9. Cell Cycle Control and Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Ingrid Hoffmann
  10. Department of Genetics, INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Hopital Necker, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France.

    • Valérie Cormier Daire
  11. CARGO and IGMA Hôpitaux Universitaires de Strasbourg, INSERM U1112, Université de Strasbourg, Strasbourg, France.

    • Hélène Dollfus
  12. Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

    • Lucie Dupuis
    •  & Roberto Mendoza-Londono
  13. Unit of Human Developmental Genetics, Institut Pasteur, Paris, France.

    • Anu Bashamboo
    •  & Kenneth McElreavey
  14. Najmabadi Pathology and Genetics Center, Tehran, Iran.

    • Ariana Kariminejad
  15. University College London (UCL) Institute of Ophthalmology, London, UK.

    • Anthony T Moore
  16. Moorfields Eye Hospital, London, UK.

    • Anthony T Moore
  17. Southwest Thames Regional Genetics Service, St. George's Hospital Medical School, London, UK.

    • Anand Saggar
  18. Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.

    • Catie Schlechter
    •  & Richard Weleber
  19. Institute of Human Genetics, University of Cologne, Cologne, Germany.

    • Janine Altmüller
  20. Wellcome Trust Sanger Institute, Cambridge, UK.

    • Matthew E Hurles
  21. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

    • Angelika Anna Noegel
    •  & Peter Nürnberg


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P.N., H.T., J.A., M.S.H., A.B., K.M., M.E. Hurles, J.E.M. and L.S.B. performed exome sequencing and analysis. L.S.B., C.-A.M., J.E.M., M.R.T., I.A., M.S.H. and G.N. performed sequencing, genotyping, linkage analysis and other molecular genetics experiments. C.-A.M., A.L., C.K., M.E. Harley, I.A., M.S.H., R.M., A.A.N. and I.H. designed and performed the cell biology experiments. A. Klingseisen designed and performed the zebrafish experiments with help from A.L., C.-A.M., J.D. and P.H. W.H. performed structural analysis. D.H., F.K., Z.A., S.T., V.C.-D., H.D., L.D., A. Kariminejad, R.M.-L., A.T.M., A.S., C.S., R.W. and S.M.B. ascertained subjects, obtained samples and/or assisted with phenotypic analysis and clinical studies. C.-A.M. and A.P.J. wrote the manuscript with help from P.N., A. Klingseisen and L.S.B. The study was planned and supervised by P.N. and A.P.J.

Competing interests

P.N. is a founder, CEO and shareholder of ATLAS Biolabs. ATLAS Biolabs is a service provider for genomic analyses.

Corresponding authors

Correspondence to Peter Nürnberg or Andrew P Jackson.

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