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Original article
The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes
  1. Aoife M Waters1,2,
  2. Rowan Asfahani1,
  3. Paula Carroll3,
  4. Louise Bicknell3,
  5. Francesco Lescai1,
  6. Alison Bright4,
  7. Estelle Chanudet1,
  8. Anthony Brooks1,
  9. Sonja Christou-Savina1,
  10. Guled Osman1,
  11. Patrick Walsh1,
  12. Chiara Bacchelli1,
  13. Ariane Chapgier1,
  14. Bertrand Vernay1,
  15. David M Bader5,
  16. Charu Deshpande6,
  17. Mary O’ Sullivan1,
  18. Louise Ocaka1,
  19. Horia Stanescu7,
  20. Helen S Stewart8,
  21. Friedhelm Hildebrandt9,
  22. Edgar Otto10,
  23. Colin A Johnson11,
  24. Katarzyna Szymanska11,
  25. Nicholas Katsanis12,
  26. Erica Davis12,
  27. Robert Kleta7,
  28. Mike Hubank1,
  29. Stephen Doxsey4,
  30. Andrew Jackson3,13,
  31. Elia Stupka1,
  32. Mark Winey14,
  33. Philip L Beales1
  1. 1Institute of Child Health, University College London, London, UK
  2. 2Department of Nephrology, Great Ormond Street Hospital NHS Foundation Trust, London, UK
  3. 3Institute of Genetics & Molecular Medicine, Edinburgh, UK
  4. 4University of Massachusetts, Boston, USA
  5. 5Department of Cell and Developmental Biology, Vanderbilt University, USA
  6. 6Department of Clinical Genetics, Evelina Children's Hospital, London, UK
  7. 7Centre for Nephrology, Royal Free Hospital, University College London, London, UK
  8. 8Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Churchill Hospital, Oxford, UK
  9. 9Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, USA
  10. 10Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
  11. 11Department of Pediatrics, Leeds Institute of Biomedical and Clinical Sciences, Leeds, UK
  12. 12Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center
  13. 13MRC Human Genetics, University of Edinburgh, Edinburgh, UK
  14. 14Molecular, Ceullular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309, USA
  1. Correspondence to Dr Aoife Waters, Birth Defects Research Centre, Institute of Child Health/Great Ormond Street Hospital for Children, London WC1N 1EH, UK; aoife.waters{at}


Background Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.

Methods and results Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.

Conclusions Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

  • Clinical genetics
  • Molecular genetics
  • Ciliopathy
  • Microcephaly

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