In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

Hiroko Shimada, Quanlong Lu, Christine Insinna-Kettenhofen, Kunio Nagashima, Milton A. English, Elizabeth M. Semler, Jacklyn Mahgerefteh, Artur V. Cideciyan, Tiansen Li, Brian P. Brooks, Meral Gunay-Aygun, Samuel G. Jacobson, Tiziana Cogliati, Christopher J. Westlake, Anand Swaroop

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Mutations in CEP290, a transition zone protein in primary cilia, cause diverse ciliopathies, including Leber congenital amaurosis (LCA) and Joubert-syndrome and related disorders (JSRD). We examined cilia biogenesis and function in cells derived from CEP290-LCA and CEP290-JSRD patients. CEP290 protein was reduced in LCA fibroblasts with no detectable impact on cilia; however, optic cups derived from induced pluripotent stem cells (iPSCs) of CEP290-LCA patients displayed less developed photoreceptor cilia. Lack of CEP290 in JSRD fibroblasts resulted in abnormal cilia and decreased ciliogenesis. We observed selectively reduced localization of ADCY3 and ARL13B. Notably, Hedgehog signaling was augmented in CEP290-JSRD because of enhanced ciliary transport of Smoothened and GPR161. These results demonstrate a direct correlation between the extent of ciliogenesis defects in fibroblasts and photoreceptors with phenotypic severity in JSRD and LCA, respectively, and strengthen the role of CEP290 as a selective ciliary gatekeeper for transport of signaling molecules in and out of the cilium.

Original languageEnglish (US)
Pages (from-to)384-396
Number of pages13
JournalCell Reports
Issue number2
StatePublished - Jul 11 2017


  • Hedgehog signaling
  • Joubert syndrome
  • LCA
  • ciliary transition zone
  • ciliogenesis
  • ciliopathies
  • iPSC
  • organoid
  • primary cilia
  • retinal degeneration

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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