RT Journal Article SR Electronic T1 The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 147 OP 156 DO 10.1136/jmedgenet-2014-102691 VO 52 IS 3 A1 Aoife M Waters A1 Rowan Asfahani A1 Paula Carroll A1 Louise Bicknell A1 Francesco Lescai A1 Alison Bright A1 Estelle Chanudet A1 Anthony Brooks A1 Sonja Christou-Savina A1 Guled Osman A1 Patrick Walsh A1 Chiara Bacchelli A1 Ariane Chapgier A1 Bertrand Vernay A1 David M Bader A1 Charu Deshpande A1 Mary O’ Sullivan A1 Louise Ocaka A1 Horia Stanescu A1 Helen S Stewart A1 Friedhelm Hildebrandt A1 Edgar Otto A1 Colin A Johnson A1 Katarzyna Szymanska A1 Nicholas Katsanis A1 Erica Davis A1 Robert Kleta A1 Mike Hubank A1 Stephen Doxsey A1 Andrew Jackson A1 Elia Stupka A1 Mark Winey A1 Philip L Beales YR 2015 UL http://jmg.bmj.com/content/52/3/147.abstract AB 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.