ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition

被引：61

作者：

Alkanderi, Sumaya ^{[1
]}

Molinari, Elisa ^{[1
]}

Shaheen, Ranad ^{[2
]}

Elmaghloob, Yasmin ^{[3
]}

Stephen, Louise A. ^{[3
]}

Sammut, Veronica ^{[1
]}

Ramsbottom, Simon A. ^{[1
]}

Srivastava, Shalabh ^{[1
,4
]}

Cairns, George ^{[1
]}

Edwards, Noel ^{[1
]}

Rice, Sarah J. ^{[1
]}

Ewida, Nour ^{[2
]}

Alhashem, Amal ^{[5
,6
]}

White, Kathryn ^{[7
]}

Miles, Colin G. ^{[1
]}

Steel, David H. ^{[1
,8
]}

Alkuraya, Fowzan S. ^{[2
,6
]}

Ismail, Shehab ^{[3
,9
]}

Sayer, John A. ^{[1
,4
]}

机构：

[1] Newcastle Univ, Int Ctr Life, Inst Genet Med, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[2] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia

[3] Beatson Inst Canc Res, Struct Biol Cilia Lab, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland

[4] Newcastle Hosp NHS Fdn Trust, Renal Serv, Newcastle Upon Tyne NE7 7DN, Tyne & Wear, England

[5] Prince Sultan Med Mil City, Dept Pediat, Riyadh 12233, Saudi Arabia

[6] Alfaisal Univ, Coll Med, Dept Anat & Cell Biol, Riyadh 11533, Saudi Arabia

[7] Newcastle Univ, Electron Microscopy Res Serv, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[8] Sunderland Eye Infirm, Queen Alexandra Rd, Sunderland SR2 9HP, Tyne & Wear, England

[9] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 103卷 / 04期

基金：

英国医学研究理事会;

关键词：

SMALL-MOLECULE INHIBITION; RETINITIS-PIGMENTOSA; CILIOPATHY PHENOTYPES; GENE; INPP5E; CARGO; NEPHRONOPHTHISIS; CILIOGENESIS; MECHANISMS; RELEASE;

D O I：

10.1016/j.ajhg.2018.08.015

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：612 / 620

页数：9

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