Investigating inherited renal disorders and identification of a novel cause of Joubert syndrome

Abstract

Joubert syndrome (JBTS) is a genetically heterogeneous neurodevelopmental ciliopathy that can have severe renal manifestations requiring renal replacement therapy. JBTS can be caused by mutation in 34 genes, however more than 50% of JBTS cases have unknown genetic causes. Through a multidisciplinary renalgenetics family clinic we studied a cohort of patients with inherited renal disorders and identified two families with JBTS phenotype and unknown molecular genetic diagnosis. We further investigated the underlying genetic aetiology of Joubert syndrome using combined homozygosity mapping of both families highlighted a candidate locus on chromosome 10, and whole exome sequencing revealed two missense variants in ARL3 within the candidate locus. The encoded protein, ADP ribosylation factor-like GTPase 3 (ARL3), is a small GTP-binding protein that is involved in trafficking lipid-modified proteins into the cilium in a GTP-dependent manner. Both missense variants replace the highly conserved Arg149 residue, which we show to be necessary for the interaction with its guanine nucleotide exchange factor ARL13B. Using patients derived fibroblasts, we identified that the mutant ARL3 protein is associated with reduced ciliary cargo protein INPP5E and NPHP3 localization in cilia.