@article {Waters147, author = {Aoife M Waters and Rowan Asfahani and Paula Carroll and Louise Bicknell and Francesco Lescai and Alison Bright and Estelle Chanudet and Anthony Brooks and Sonja Christou-Savina and Guled Osman and Patrick Walsh and Chiara Bacchelli and Ariane Chapgier and Bertrand Vernay and David M Bader and Charu Deshpande and Mary O{\textquoteright} Sullivan and Louise Ocaka and Horia Stanescu and Helen S Stewart and Friedhelm Hildebrandt and Edgar Otto and Colin A Johnson and Katarzyna Szymanska and Nicholas Katsanis and Erica Davis and Robert Kleta and Mike Hubank and Stephen Doxsey and Andrew Jackson and Elia Stupka and Mark Winey and Philip L Beales}, title = {The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes}, volume = {52}, number = {3}, pages = {147--156}, year = {2015}, doi = {10.1136/jmedgenet-2014-102691}, publisher = {BMJ Publishing Group Ltd}, 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.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/52/3/147}, eprint = {https://jmg.bmj.com/content/52/3/147.full.pdf}, journal = {Journal of Medical Genetics} }