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Lookup NU author(s): Sumaya Alkanderi, Dr Elisa MolinariORCiD, Veronica Sammut, Dr Simon RamsbottomORCiD, Dr Shalabh Srivastava, George Cairns, Dr Noel Edwards, Dr Sarah RiceORCiD, Dr Kathryn White, Dr Colin Miles, Professor David SteelORCiD, Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Joubert syndrome (JBTS) is a genetically heterogeneous autosomal-recessive neurodevelopmental ciliopathy. We investigated further the underlying genetic etiology of Joubert syndrome by studying two unrelated families in whom JBTS was not associated with pathogenic variants in known JBTS-associated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997-109106128, UCSC Genome Browser hg 19), and 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 directing 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, such that the mutant protein is associated with reduced INPP5E and NPHP3 localization in cilia. We propose that ARL3 provides a potential hub in the network of proteins implicated in ciliopathies, whereby perturbation of ARL3 leads to the mislocalization of multiple ciliary proteins as a result of abnormal displacement of lipidated protein cargo.
Author(s): Alkanderi S, Molinari E, Shaheen R, Elmaghloob Y, Stephen LA, Sammut V, Ramsbottom SA, Srivastava S, Cairns G, Edwards N, Rice SJ, Ewida N, Alhashem A, White K, Miles CG, Steel DH, Alkuraya FS, Ismail S, Sayer JA
Publication type: Article
Publication status: Published
Journal: The American Journal of Human Genetics
Year: 2018
Volume: 103
Issue: 4
Pages: 612-620
Print publication date: 04/10/2018
Online publication date: 27/09/2018
Acceptance date: 24/08/2018
Date deposited: 11/10/2018
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2018.08.015
DOI: 10.1016/j.ajhg.2018.08.015
PubMed id: 30269812
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