The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes

Aoife M. Waters, Rowan Asfahani, Paula Carroll, Louise Bicknell, Francesco Lescai, Alison Bright, Estelle Chanudet, Anthony Brooks, Sonja Christou-Savina, Guled Osman, Patrick Walsh, Chiara Bacchelli, Ariane Chapgier, Bertrand Vernay, David M. Bader, Charu Deshpande, Mary O'Sullivan, Louise Ocaka, Horia Stanescu, Helen S. StewartFriedhelm Hildebrandt, Edgar Otto, Colin A. Johnson, Katarzyna Szymanska, Nicholas Katsanis, Erica Davis, Robert Kleta, Mike Hubank, Stephen Doxsey, Andrew Jackson, Elia Stupka, Mark Winey, Philip L. Beales

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)147-156
Number of pages10
JournalJournal of Medical Genetics
Volume52
Issue number3
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Waters, A. M., Asfahani, R., Carroll, P., Bicknell, L., Lescai, F., Bright, A., Chanudet, E., Brooks, A., Christou-Savina, S., Osman, G., Walsh, P., Bacchelli, C., Chapgier, A., Vernay, B., Bader, D. M., Deshpande, C., O'Sullivan, M., Ocaka, L., Stanescu, H., ... Beales, P. L. (2015). The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes. Journal of Medical Genetics, 52(3), 147-156. https://doi.org/10.1136/jmedgenet-2014-102691