ARL3 mutations cause Joubert syndrome by disrupting ciliary protein composition

Alkanderi, S. et al. (2018) ARL3 mutations cause Joubert syndrome by disrupting ciliary protein composition. American Journal of Human Genetics, 103(4), pp. 612-620. (doi: 10.1016/j.ajhg.2018.08.015) (PMID:30269812) (PMCID:PMC6174286)

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Abstract

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 JBTSrelated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997-109106128 (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 localisation in cilia. We propose that ARL3 provides a potential hub in the network of encoded ciliopathy genes, whereby perturbation of ARL3 results in the mislocalisation of multiple ciliary proteins due to abnormal displacement of lipidated protein cargo.

Item Type:Articles
Additional Information:This work was funded by The Medical Research Council (MR/M012212/1), a Kidney Research UK Post-doctoral fellowship awarded to SAR (PDF_003_20151124), KSCDR grant (FSA), KACST grant 13- BIO1113-20 (FSA), Saudi Human Genome Program (FSA) and Northern Counties Kidney Research Fund. Funding for YE, LS and SI is supported by the Cancer Research UK core funding award [A19257].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Elmaghloob, Yasmin Adel Elsayed and Ismail, Dr Shehab
Authors: Alkanderi, S., Molinari, E., Shaheen, R., Elmaghloob, Y., Stephen, L. A., Sammut, V., Ramsbottom, S. A., Srivastava, S., Cairns, G., Edwards, N., Rice, S. J., Ewida, N., Alhashem, A., White, K., Miles, C. G., Steel, D. H., Alkuraya, F. S., Ismail, S., and Sayer, J. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:American Journal of Human Genetics
Publisher:Elsevier
ISSN:0002-9297
ISSN (Online):1537-6605
Published Online:27 September 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in American Journal of Human Genetics 103(4):612-620
Publisher Policy:Reproduced under a Creative Commons License

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