ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition

Am J Hum Genet. 2018 Oct 4;103(4):612-620. doi: 10.1016/j.ajhg.2018.08.015.

Sumaya Alkanderi ¹, Elisa Molinari ¹, Ranad Shaheen ², Yasmin Elmaghloob ³, Louise A Stephen ³, Veronica Sammut ¹, Simon A Ramsbottom ¹, Shalabh Srivastava ⁴, George Cairns ¹, Noel Edwards ¹, Sarah J Rice ¹, Nour Ewida ², Amal Alhashem ⁵, Kathryn White ⁶, Colin G Miles ¹, David H Steel ⁷, Fowzan S Alkuraya ⁸, Shehab Ismail ⁹, John A Sayer ¹⁰

Affiliations

1 Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
2 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
3 Structural Biology of the Cilia Lab, Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
4 Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; Renal Services, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK.
5 Department of Pediatrics, Prince Sultan Medical Military City, Riyadh 12233, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
6 Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
7 Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; Sunderland Eye Infirmary, Queen Alexandra Road, Sunderland SR2 9HP, UK.
8 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
9 Structural Biology of the Cilia Lab, Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: [email protected].
10 Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; Renal Services, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK. Electronic address: [email protected].

PMID: 30269812 DOI: 10.1016/j.ajhg.2018.08.015

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 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.

Keywords

ARL13B; ARL3; Joubert syndrome; cilia; guanine nucleotide exchange factor; trafficking.

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