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Hum Mol Genet. 2015 Jul 1;24(13):3775-91. doi: 10.1093/hmg/ddv123. Epub 2015 Apr 9.

CEP290 alleles in mice disrupt tissue-specific cilia biogenesis and recapitulate features of syndromic ciliopathies.

Author information

1
National Eye Institute.
2
National Institute of Neurological Disease and Stroke, National Institutes of Health, Bethesda, MD 20892, USA and.
3
School of Life Sciences, University of Nottingham, Nottingham, UK.
4
National Eye Institute, swaroopa@nei.nih.gov.

Abstract

Distinct mutations in the centrosomal-cilia protein CEP290 lead to diverse clinical findings in syndromic ciliopathies. We show that CEP290 localizes to the transition zone in ciliated cells, precisely to the region of Y-linkers between central microtubules and plasma membrane. To create models of CEP290-associated ciliopathy syndromes, we generated Cep290(ko/ko) and Cep290(gt/gt) mice that produce no or a truncated CEP290 protein, respectively. Cep290(ko/ko) mice exhibit early vision loss and die from hydrocephalus. Retinal photoreceptors in Cep290(ko/ko) mice lack connecting cilia, and ciliated ventricular ependyma fails to mature. The minority of Cep290(ko/ko) mice that escape hydrocephalus demonstrate progressive kidney pathology. Cep290(gt/gt) mice die at mid-gestation, and the occasional Cep290(gt/gt) mouse that survives shows hydrocephalus and severely cystic kidneys. Partial loss of CEP290-interacting ciliopathy protein MKKS mitigates lethality and renal pathology in Cep290(gt/gt) mice. Our studies demonstrate domain-specific functions of CEP290 and provide novel therapeutic paradigms for ciliopathies.

PMID:
25859007
PMCID:
PMC4459394
DOI:
10.1093/hmg/ddv123
[Indexed for MEDLINE]
Free PMC Article

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