title: CEP290 alleles in mice disrupt tissue-specific cilia biogenesis and recapitulate features of syndromic ciliopathies.
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.
authors: National Eye Institute.
authors: Rivka A
authors: RA
authors: Rachel
authors: National Eye Institute.
authors: Erin A
authors: EA
authors: Yamamoto
authors: National Eye Institute.
authors: Mrinal K
authors: MK
authors: Dewanjee
authors: National Eye Institute.
authors: Helen L
authors: HL
authors: May-Simera
authors: National Eye Institute.
authors: Yuri V
authors: YV
authors: Sergeev
authors: National Eye Institute.
authors: Alice N
authors: AN
authors: Hackett
authors: National Eye Institute.
authors: Katherine
authors: K
authors: Pohida
authors: National Institute of Neurological Disease and Stroke, National Institutes of Health, Bethesda, MD 20892, USA and.
authors: Jeeva
authors: J
authors: Munasinghe
authors: National Eye Institute.
authors: Norimoto
authors: N
authors: Gotoh
authors: School of Life Sciences, University of Nottingham, Nottingham, UK.
authors: Bill
authors: B
authors: Wickstead
authors: National Eye Institute.
authors: Robert N
authors: RN
authors: Fariss
authors: National Eye Institute.
authors: Lijin
authors: L
authors: Dong
authors: National Eye Institute.
authors: Tiansen
authors: T
authors: Li
authors: National Eye Institute, swaroopa@nei.nih.gov.
authors: Anand
authors: A
authors: Swaroop
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C513600:Cep290 protein, mouse; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins