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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cilia / genetics
  • Cilia / metabolism*
  • Cytoskeletal Proteins
  • Disease Models, Animal
  • Female
  • Humans
  • Hydrocephalus / genetics*
  • Hydrocephalus / metabolism
  • Kidney Diseases, Cystic / genetics*
  • Kidney Diseases, Cystic / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Organ Specificity


  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cep290 protein, mouse
  • Cytoskeletal Proteins
  • Nuclear Proteins