GERGELY LAB

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 the van Breugel lab showed 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 thermo-stability of the second C2 domain by targeting residues that point towards its hydrophobic core. By genome engineering cells to contain these exact mutations, Nimesh found that both mutations caused a reduction in CEP120 protein levels. Although the mutant versions of CEP120 still supported centriole duplication, they compromised the recruitment of distal centriole markers and cilia formation. Our results provide insights into the disease..