UCL / Wellcome Trust PhD programme for Clinicians; Investigating novel geneticassociations with ciliopathy in the zebrafish (360G-Wellcome-106549_Z_14_A)

The primary cilium is present in almost all cells and plays an important role in the function of many organs, including the kidney, eye and brain. Ciliopathies result from dysfunction of the cilium. We have identified a family in which inherited lack of an enzyme that is involved in metabolism of dietary substrates is associated with kidney failure, obesity, retinal disease, deafness and neurological problems, suggesting a ciliopathy. Deficiency or mutation of this enzyme, within a ubiquitous metabolic pathway, is not described in the literature, and loss of function variants of the gene are absent from databases of human genetic variation, even in heterozygosity. We have shown that, in addition to displaying an abnormal metabolic profile, primary skin cells from the patients have reduced ability to form a cilium. Knockout mice lacking the same enzyme have a similar defect of the primary cilium in their cells, although the clinical phenotype is different to that observed in patients. We aim to investigate the function of this gene and others related to dysfunction of the cilia in transgenic and mutant zebrafish lines to delineate the possible cofactors affecting disease severity in ciliopathies, perhaps providing insights into means of ameliorating the disease