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ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition

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.

Publication metadata

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


DOI: 10.1016/j.ajhg.2018.08.015

PubMed id: 30269812


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Funder referenceFunder name
Cancer Research UK
Medical Research Council
Kidney Research UK