PUBLICATION
The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes
- Authors
- Waters, A.M., Asfahani, R., Carroll, P., Bicknell, L., Lescai, F., Bright, A., Chanudet, E., Brooks, A., Christou-Savina, S., Osman, G., Walsh, P., Bacchelli, C., Chapgier, A., Vernay, B., Bader, D.M., Deshpande, C., O' Sullivan, M., Ocaka, L., Stanescu, H., Stewart, H.S., Hildebrandt, F., Otto, E., Johnson, C.A., Szymanska, K., Katsanis, N., Davis, E., Kleta, R., Hubank, M., Doxsey, S., Jackson, A., Stupka, E., Winey, M., Beales, P.L.
- ID
- ZDB-PUB-170214-231
- Date
- 2015
- Source
- Journal of Medical Genetics 52: 147-56 (Journal)
- Registered Authors
- Davis, Erica, Katsanis, Nicholas
- Keywords
- CENPF, Ciliopathy, Clinical genetics, Microcephaly, Molecular genetics
- MeSH Terms
-
- Animals
- Centrioles/genetics
- Chromosomal Proteins, Non-Histone/genetics*
- Cilia/genetics*
- Cilia/pathology
- Exome/genetics
- Female
- Fetus
- Genetics, Medical*
- HEK293 Cells
- High-Throughput Nucleotide Sequencing
- Humans
- Male
- Mice
- Microcephaly/genetics*
- Microcephaly/pathology
- Microfilament Proteins/genetics*
- Mutation
- NIH 3T3 Cells
- Pedigree
- Pregnancy
- Zebrafish
- PubMed
- 25564561 Full text @ J. Med. Genet.
Citation
Waters, A.M., Asfahani, R., Carroll, P., Bicknell, L., Lescai, F., Bright, A., Chanudet, E., Brooks, A., Christou-Savina, S., Osman, G., Walsh, P., Bacchelli, C., Chapgier, A., Vernay, B., Bader, D.M., Deshpande, C., O' Sullivan, M., Ocaka, L., Stanescu, H., Stewart, H.S., Hildebrandt, F., Otto, E., Johnson, C.A., Szymanska, K., Katsanis, N., Davis, E., Kleta, R., Hubank, M., Doxsey, S., Jackson, A., Stupka, E., Winey, M., Beales, P.L. (2015) The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes. Journal of Medical Genetics. 52:147-56.
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-54.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping