Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis
Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis
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DOI：
10.1016/j.celrep.2018.04.100
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发表时间：
2018-05-29
期刊：
影响因子：
8.8
通讯作者：
van Breugel, Mark
中科院分区：
文献类型：
--
作者：
Joseph, Nimesh;Ai-Jassar, Caezar;van Breugel, Mark
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.
