MDThesisJoubert 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