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http://purl.uniprot.org/citations/25564561http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25564561http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25564561http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.org/dc/terms/identifier"doi:10.1136/jmedgenet-2014-102691"xsd:string
http://purl.uniprot.org/citations/25564561http://purl.org/dc/terms/identifier"doi:10.1136/jmedgenet-2014-102691"xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Jackson A."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Jackson A."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Stupka E."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Stupka E."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Kleta R."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Kleta R."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Carroll P."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Carroll P."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Ocaka L."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Ocaka L."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Winey M."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Winey M."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Hildebrandt F."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Hildebrandt F."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Beales P.L."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Beales P.L."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Johnson C.A."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Johnson C.A."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Hubank M."xsd:string
http://purl.uniprot.org/citations/25564561http://purl.uniprot.org/core/author"Hubank M."xsd:string
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