Cellular mutation modelling of pre-mRNA splicing factors to elucidate their function at the primary cilium and their contribution to human disease

Primary cilia are crucial signalling organelles which, when defective, lead to ciliopathies, a range of developmental and degenerative diseases affecting multiple organs including the retina. Retinitis pigmentosa (RP), a retinal dystrophy, is the most common cause of hereditary blindness, some forms of which are caused by defects in the ciliated cells of the retina. Mutations in certain pre-mRNA splicing factors (PRPFs) lead to RP but the disease mechanism of this form of RP is poorly understood, with inconsistent evidence of splicing defects.

This project aims to elucidate the function of PRPFs beyond splicing, building on my work linking primary cilia to PRPFs in a whole genome siRNA screen. I will test the hypothesis that the role of these proteins at the base of the cilium is connected to the cell’s DNA damage response (DDR), based on published evidence independently linking both splicing and cilia to the DDR. The project studies the function of these proteins using disease-relevant cell systems, in which human disease mutations are modelled, employing two different mutation modelling strategies.

This study will establish molecular tools for the characterisation of other putative ciliopathy disease proteins identified from large-scale genomics screens in a larger study.