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Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis.

Authors :
Joseph N
Al-Jassar C
Johnson CM
Andreeva A
Barnabas DD
Freund SMV
Gergely F
van Breugel M
Source :
Cell reports [Cell Rep] 2018 May 29; Vol. 23 (9), pp. 2805-2818.
Publication Year :
2018

Abstract

Ciliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information, it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography, we show that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermostability of the second C2 domain by targeting residues that point toward its hydrophobic core. Genome-engineered cells homozygous for these mutations have largely normal centriole numbers but show reduced CEP120 levels, compromised recruitment of distal centriole markers, and deficient cilia formation. Our results provide insight into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B, and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles.<br /> (Copyright © 2018 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
2211-1247
Volume :
23
Issue :
9
Database :
MEDLINE
Journal :
Cell reports
Publication Type :
Academic Journal
Accession number :
29847808
Full Text :
https://doi.org/10.1016/j.celrep.2018.04.100