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


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Authors
Joseph, Nimesh 
Al-Jassar, Caezar 
Johnson, Christopher M 
Andreeva, Antonina 
Barnabas, Deepak D 
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.

Description
Keywords
CEP120, JATD, Jeuene syndrome, Joubert syndrome, basal body, centriole, centrosome, cilia, ciliopathy, Amino Acid Sequence, Animals, Cell Cycle, Cell Cycle Proteins, Cell Line, Centrioles, Centrosome, Cilia, Mice, Models, Molecular, Mutation, Organogenesis, Protein Domains, Protein Stability, Temperature, Zebrafish
Journal Title
Cell Rep
Conference Name
Journal ISSN
2211-1247
2211-1247
Volume Title
23
Publisher
Elsevier BV
Sponsorship
Cancer Research UK (unknown)
Cancer Research UK (CB4180)
Cancer Research UK (C14303/A17197)