Journal
JOURNAL OF MEDICAL GENETICS
Volume 52, Issue 3, Pages 147-156Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2014-102691
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Funding
- Medical Research Council Clinical Research Training fellowship [G0802138/1]
- March of Dimes Foundation [1-FY07-422]
- Guggenheim Foundation
- Wellcome Trust
- ICH-UCL Biomedical Research Centre
- NIH [DK-06308]
- Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish
- Medical Research Council [MR/K010654/1, MC_PC_U127580972, G0802138] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10008] Funding Source: researchfish
- MRC [MC_PC_U127580972, G0802138, MR/K010654/1] Funding Source: UKRI
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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.
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