A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery
PublisherNature Publishing Group
MetadataShow full item record
AbstractThe primary cilium is a microtubule-enriched cell-communication organelle that participates in mechanisms controlling tissue development and maintenance, including cerebellar architecture. Centrosomal protein of 290 kDa (CEP290) is a protein important for centrosomal function and ciliogenesis. Mutations in CEP290 have been linked to a group of multi-organ disorders - termed ciliopathies. The neurophysiological deficits observed in ciliopathies are sometimes associated with the progression of autistic traits. Here, the cellular function of two rare variants of CEP290 identified from recent exome sequencing of autistic individuals are investigated. Cells expressing Cep290 carrying the missense mutation R1747Q in mouse exhibited a defective Sonic hedgehog (Shh) signalling response, mislocalisation of the Shh receptor Smoothened (Smo), and dysregulation of ciliary protein mobility, which ultimately disrupted the proliferation of cerebellar granule progenitors (CGPs). This data was furthermore corroborated in an autism patient-derived iPSC line harbouring the R1746Q rare CEP290 variant. Evidence from this study suggests that the R1746Q mutation interferes with the function of CEP290 to maintain the ciliary diffusion barrier and disrupts the integrity of the molecular composition in the primary cilium, which may contribute to alterations in neuroarchitecture. Copyright 2018, The Author(s).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85057261439&doi=10.1038%2fs41598-018-35614-x&partnerID=40&md5=a7ffee64048f57aa4eca53b5b8334706; http://hdl.handle.net/10713/9283
- In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations.
- Authors: Shimada H, Lu Q, Insinna-Kettenhofen C, Nagashima K, English MA, Semler EM, Mahgerefteh J, Cideciyan AV, Li T, Brooks BP, Gunay-Aygun M, Jacobson SG, Cogliati T, Westlake CJ, Swaroop A
- Issue date: 2017 Jul 11
- Patched1-ArhGAP36-PKA-Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation.
- Authors: Zhang B, Zhuang T, Lin Q, Yang B, Xu X, Xin G, Zhu S, Wang G, Yu B, Zhang T, Jiang Q, Zhang C
- Issue date: 2019 Jan 15
- Patched1 regulates hedgehog signaling at the primary cilium.
- Authors: Rohatgi R, Milenkovic L, Scott MP
- Issue date: 2007 Jul 20
- CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium.
- Authors: Kim J, Krishnaswami SR, Gleeson JG
- Issue date: 2008 Dec 1
- BBS mutations modify phenotypic expression of CEP290-related ciliopathies.
- Authors: Zhang Y, Seo S, Bhattarai S, Bugge K, Searby CC, Zhang Q, Drack AV, Stone EM, Sheffield VC
- Issue date: 2014 Jan 1