title: The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.
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.
  
  
  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.
authors.affiliation: Institute of Child Health, University College London, London, UK Department of Nephrology, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors.forename: Aoife M
authors.initials: AM
authors.lastname: Waters
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Rowan
authors.initials: R
authors.lastname: Asfahani
authors.affiliation: Institute of Genetics & Molecular Medicine, Edinburgh, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Carroll
authors.affiliation: Institute of Genetics & Molecular Medicine, Edinburgh, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Bicknell
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.affiliation: University of Massachusetts, Boston, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Bright
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brooks
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Sonja
authors.initials: S
authors.lastname: Christou-Savina
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Guled
authors.initials: G
authors.lastname: Osman
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Walsh
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Vernay
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Bader
authors.affiliation: Department of Clinical Genetics, Evelina Children's Hospital, London, UK.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: O' Sullivan
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Centre for Nephrology, Royal Free Hospital, University College London, London, UK.
authors.forename: Horia
authors.initials: H
authors.lastname: Stanescu
authors.affiliation: Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Churchill Hospital, Oxford, UK.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Stewart
authors.affiliation: Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Otto
authors.affiliation: Department of Pediatrics, Leeds Institute of Biomedical and Clinical Sciences, Leeds, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics, Leeds Institute of Biomedical and Clinical Sciences, Leeds, UK.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center.
authors.forename: Erica
authors.initials: E
authors.lastname: Davis
authors.affiliation: Centre for Nephrology, Royal Free Hospital, University College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.affiliation: University of Massachusetts, Boston, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Doxsey
authors.affiliation: Institute of Genetics & Molecular Medicine, Edinburgh, UK MRC Human Genetics, University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.affiliation: Molecular, Ceullular, and Developmental Biology, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Winey
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
mesh_terms: D000818:Animals; D002502:Centrioles / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002923:Cilia / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D005333:Fetus; D005826:Genetics, Medical; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D041681:NIH 3T3 Cells; D010375:Pedigree; D011247:Pregnancy; D015027:Zebrafish
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D008840:Microfilament Proteins; C094772:centromere protein F
keywords: CENPF; Ciliopathy; Clinical genetics; Microcephaly; Molecular genetics