Identification and characterization of the pathogenetic interactions in ciliary chondrodysplasias

• Applicant: Privatdozent Dr. Christian Thomas Thiel
• Subject Area: Human Genetics
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321860198

Several disorders have been associated with defects of a variety of proteins involved in cilia formation, maintenance and function. These ciliopathies can affect the intraflagellar transport, components of the cilia, the basal body, or the centrosome. Many of the associated phenotypes include brain malformations, polydactyly, kidney cysts and skeletal abnormalities. In particular, this phenotypic spectrum is present among patients with short rib-polydactyly syndromes (SRPS). Here, we identified mutations in NEK1 as the underlying cause of SRPS II. To establish NEK1 interacting candidate ciliary proteins we performed a yeast two-hybrid. Here we identified 82 NEK1 interacting proteins of which 66 have functionally not been associated with the primary cilium before. Based on in silico characterization, we found convincing evidence that 10 of these proteins might be involved with the primary cilium. Using CRIPSR/Cas9 and massive parallel sequencing techniques we aim to establish the functional effect of these genes on the primary cilium. These results of the interactions between human proteins involved in centrioles, centrosomes, basal bodies and cilia might provide a further characterization of the functional roles of ciliary proteins in the manifestation of phenotypic features.

• DFG Programme: Research Grants