Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene.
Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene.
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与 ARL3 基因复合杂合变异相关的常染色体隐性杆状锥体营养不良
DOI：
10.3389/fcell.2021.635424
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发表时间：
2021
影响因子：
5.5
通讯作者：
Lei B
中科院分区：
文献类型：
--
作者：
Fu L;Li Y;Yao S;Guo Q;You Y;Zhu X;Lei B
目的：ARL3（ADP-核糖基化因子样3）变异体引起常染色体显性视网膜色素变性（RP）或常染色体隐性Joubert综合征。我们发现了一个视杆-视锥营养不良（RCD）家系，并证实其与ARL3基因的复合杂合变异有关。方法：对30例患者进行光学相干断层扫描（OCT）和视网膜电图（ERG）检查。使用定制设计的面板对先证者进行靶向下一代测序（NGS）。在家系成员中进行桑格测序和共分离。在体外研究了变异体介导的蛋白质结构变化。通过放线菌酮追踪试验和免疫共沉淀（Co-IP）试验评估ARL3蛋白的稳定性及其与RP 2蛋白的相互作用。结果如下：18岁男性先证者右眼视力为0.25，左眼视力为0.20，而其非血缘关系的父母和姐妹视力正常。先证者表现出RCD的体征，包括夜盲症、周边视野丧失、视网膜内骨针沉积和ERG反应降低。父亲50岁，双眼视力1.0。与先证者不同，他表现为迟发性轻度视锥-视杆营养不良（CRD），包括黄斑萎缩、中心暗点、明视ERG反应中度降低。所有家庭成员均无听力异常、智力发育不良及步态不稳。我们在先证者的ARL3基因中发现了两个新的复合杂合子变异（c.91A> G，p.T31A; c.353G> T，p.C118F），而他的父亲只有c.91A> G变异。生物信息学分析表明，这两个变异体的氨基酸位置在物种间高度保守。计算机模拟工具预测这些变体是有害的。蛋白质结构分析表明，这两种变体具有改变蛋白质结构的潜力。根据ACMG指南，这两种变体可能是致病性的。此外，ARL3突变使ARL3蛋白不稳定，并且突变c.353G> T破坏了HEK293T细胞中ARL3和RP 2之间的相互作用。结论：我们发现ARL3中新的复合杂合子变异与常染色体隐性RCD的早期发病相关，而c.91 A> G沿着可能与显性CRD的晚期发病相关。ARL3中的两种变体可能通过使ARL3蛋白不稳定并削弱其与RP 2蛋白的相互作用而致病。
Purpose: ARL3 (ADP-ribosylation factor-like 3) variants cause autosomal dominant retinitis pigmentosa (RP) or autosomal recessive Joubert syndrome. We found a family with rod-cone dystrophy (RCD) and verified it was associated with compound heterozygous variants in ARL3 gene. Methods: Ophthalmic examinations including optical coherence tomography and electroretinogram (ERG) were performed. Targeted next generation sequencing (NGS) was performed for the proband using a custom designed panel. Sanger sequencing and co-segregation were conducted in the family members. Changes of protein structure mediated by the variants were studied in vitro. ARL3 protein stability and its interaction with RP2 protein were assessed by cycloheximide chase assay and co-immunoprecipitation (Co-IP) assay. Results: Visual acuity of the 18-year-old male proband was 0.25 in the right and 0.20 in the left eye, while his non-consanguineous parents and sister was normal. The proband showed signs of RCD, including nyctalopia, peripheral field loss, bone-spicule deposits in the retina, and reduced ERG responses. The father, aged 50 years old, showed visual acuity of 1.0 in both eyes. Unlike the proband, he presented late onset and mild cone-rod dystrophy (CRD), including macular atrophy, central scotomata, moderate reduction in photopic ERG responses. None of all the family members had hearing abnormality, mental dysplasia or gait instability. We identified two novel compound heterozygous variants (c.91A>G, p.T31A; c.353G>T, p.C118F) in ARL3 in the proband, while his father only had variant c.91A>G. Bioinformatics analysis indicated amino acid positions of the two variants are highly conserved among species. The in silico tools predicted the variants to be harmful. Protein structure analysis showed the two variants had potential to alter the protein structure. Based on the ACMG guidelines, the two variants were likely pathogenic. In addition, the ARL3 mutations destabilized ARL3 protein, and the mutation c.353G>T disrupted the interaction between ARL3 and RP2 in HEK293T cells. Conclusions: We showed novel compound heterozygous variants in ARL3 were associated with early onset of autosomal recessive RCD, while c.91A>G along may be associated with a late onset of dominant CRD. The two variants in ARL3 could be causative by destabilizing ARL3 protein and impairing its interaction with RP2 protein.
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影响因子：
1.4
作者：
Hu, Yan-Shan;Song, Hui;Li, Tuo
通讯作者：
Li, Tuo
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
从从头出现ARL3和色素性视网膜炎的明显常染色体显性传播。
影响因子：
3.7
作者：
Strom SP;Clark MJ;Martinez A;Garcia S;Abelazeem AA;Matynia A;Parikh S;Sullivan LS;Bowne SJ;Daiger SP;Gorin MB
通讯作者：
Gorin MB
影响因子：
3.9
作者：
Thomas, Sophie;Wright, Kevin J.;Le Corre, Stephanie;Micalizzi, Alessia;Romani, Marta;Abhyankar, Avinash;Saada, Julien;Perrault, Isabelle;Amiel, Jeanne;Litzler, Julie;Filhol, Emilie;Elkhartoufi, Nadia;Kwong, Mandy;Casanova, Jean-Laurent;Boddaert, Nathalie;Baehr, Wolfgang;Lyonnet, Stanislas;Munnich, Arnold;Burglen, Lydie;Chassaing, Nicolas;Encha-Ravazi, Ferechte;Vekemans, Michel;Gleeson, Joseph G.;Valente, Enza Maria;Jackson, Peter K.;Drummond, Iain A.;Saunier, Sophie;Attie-Bitach, Tania
通讯作者：
Attie-Bitach, Tania