ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition.
ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition.
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DOI：
10.1016/j.ajhg.2018.08.015
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发表时间：
2018-10-04
影响因子：
9.8
通讯作者：
Sayer JA
中科院分区：
文献类型：
--
作者：
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
Joubert综合征（JBTS）是一种遗传异质性常染色体隐性遗传性神经发育性纤毛病。我们通过研究两个不相关的家族进一步研究了Joubert综合征的潜在遗传病因，在这两个家族中，JBTS与已知JBTS相关基因的致病性变异无关。两个家族的组合的自体接合性作图突出了10号染色体上的候选基因座（chr 10：101569997-109106128，UCSC基因组浏览器hg 19），并且外显子组测序揭示了候选基因座内的ARL 3中的两个错义变体。编码的蛋白质，ADP核糖基化因子样GTP酶3（ARL 3），是一个小的GTP结合蛋白，参与指导脂质修饰的蛋白质进入纤毛在GTP依赖的方式。这两个错义变体取代高度保守的Arg 149残基，我们证明这是必要的与其鸟嘌呤核苷酸交换因子ARL 13 B的相互作用，这样的突变蛋白与减少INPP 5E和NPHP 3在纤毛中的定位。我们建议，ARL 3提供了一个潜在的枢纽，在网络中的蛋白质参与纤毛病变，从而ARL 3的扰动导致多个纤毛蛋白的错误定位的结果，脂质化的蛋白货物的异常位移。
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.
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影响因子：
2.6
作者：
Hartill V;Szymanska K;Sharif SM;Wheway G;Johnson CA
通讯作者：
Johnson CA
影响因子：
64.5
作者：
Chaki M;Airik R;Ghosh AK;Giles RH;Chen R;Slaats GG;Wang H;Hurd TW;Zhou W;Cluckey A;Gee HY;Ramaswami G;Hong CJ;Hamilton BA;Cervenka I;Ganji RS;Bryja V;Arts HH;van Reeuwijk J;Oud MM;Letteboer SJ;Roepman R;Husson H;Ibraghimov-Beskrovnaya O;Yasunaga T;Walz G;Eley L;Sayer JA;Schermer B;Liebau MC;Benzing T;Le Corre S;Drummond I;Janssen S;Allen SJ;Natarajan S;O'Toole JF;Attanasio M;Saunier S;Antignac C;Koenekoop RK;Ren H;Lopez I;Nayir A;Stoetzel C;Dollfus H;Massoudi R;Gleeson JG;Andreoli SP;Doherty DG;Lindstrad A;Golzio C;Katsanis N;Pape L;Abboud EB;Al-Rajhi AA;Lewis RA;Omran H;Lee EY;Wang S;Sekiguchi JM;Saunders R;Johnson CA;Garner E;Vanselow K;Andersen JS;Shlomai J;Nurnberg G;Nurnberg P;Levy S;Smogorzewska A;Otto EA;Hildebrandt F
通讯作者：
Hildebrandt F
影响因子：
14.8
作者：
Ismail, Shehab A.;Chen, Yong-Xiang;Wittinghofer, Alfred
通讯作者：
Wittinghofer, Alfred
影响因子：
4.8
作者：
Jaiswal, Mamta;Fansa, Eyad K.;Wittinghofer, Alfred
通讯作者：
Wittinghofer, Alfred
DOI：
10.1073/pnas.1210916109
发表时间：
2012-11-27
影响因子：
11.1
作者：
Humbert, Melissa C.;Weihbrecht, Katie;Seo, Seongjin
通讯作者：
Seo, Seongjin