ABCA4 c.859-25A>G, a Frequent Palestinian Founder Mutation Affecting the Intron 7 Branchpoint, Is Associated With Early-Onset Stargardt Disease.
ABCA4 c.859-25A>G, a Frequent Palestinian Founder Mutation Affecting the Intron 7 Branchpoint, Is Associated With Early-Onset Stargardt Disease.
复制标题
DOI：
10.1167/iovs.63.4.20
复制
发表时间：
2022-04-01
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
在缺乏功能测定的情况下，非编码变体的影响通常是未知的。在这里，我们的特点是ABCA 4内含子7变异，c.859- 25 A>G，在巴勒斯坦先证者与Stargardt病（STGD）或锥杆营养不良（CRD）。我们研究了这种变异对ABCA 4 mRNA和视网膜表型的影响，以及其在巴勒斯坦的患病率。对1998例STGD或CRD患者的ABCA 4基因进行了全序列或部分序列测定。使用SpliceAI在计算机中和使用剪接测定在体外研究c.859- 25 A>G对剪接的影响。对16个c.859- 25 A>G纯合子的受影响个体进行纯合子定位。临床表型进行了评估，使用功能和结构分析，包括视力，全视野视网膜电图，和多模式成像。基于smMIP的ABCA 4测序显示，来自希伯伦和耶路撒冷的10名巴勒斯坦先证者中存在c.859- 25 A>G。SpliceAI预测了这种假定的分支点失活变体对附近内含子7剪接受体位点的显著影响。剪接检测显示外显子8跳跃和两个部分包含内含子7，每个都有有害的影响。进一步的基因分型发现另外46个受影响的纯合子或复合杂合子个体携带变异c.859- 25 A>G。纯合子共有一个59.6至87.9 kb的基因组片段，检眼镜评价显示严重的视网膜缺陷。ABCA 4变异体c.859- 25 A>G破坏了预测的分支点，由于不同的剪接缺陷导致蛋白质截短，并且当以纯合性存在时与早发性STGD 1相关。在25/525名巴勒斯坦遗传性视网膜营养不良先证者中发现了这种变异，这是西岸巴勒斯坦最常见的遗传性视网膜疾病致病变异之一。
The effect of noncoding variants is often unknown in the absence of functional assays. Here, we characterized an ABCA4 intron 7 variant, c.859-25A>G, identified in Palestinian probands with Stargardt disease (STGD) or cone-rod dystrophy (CRD). We investigated the effect of this variant on the ABCA4 mRNA and retinal phenotype, and its prevalence in Palestine. The ABCA4 gene was sequenced completely or partially in 1998 cases with STGD or CRD. The effect of c.859-25A>G on splicing was investigated in silico using SpliceAI and in vitro using splice assays. Homozygosity mapping was performed for 16 affected individuals homozygous for c.859-25A>G. The clinical phenotype was assessed using functional and structural analyses including visual acuity, full-field electroretinography, and multimodal imaging. The smMIPs-based ABCA4 sequencing revealed c.859-25A>G in 10 Palestinian probands from Hebron and Jerusalem. SpliceAI predicted a significant effect of this putative branchpoint-inactivating variant on the nearby intron 7 splice acceptor site. Splice assays revealed exon 8 skipping and two partial inclusions of intron 7, each having a deleterious effect. Additional genotyping revealed another 46 affected homozygous or compound heterozygous individuals carrying variant c.859-25A>G. Homozygotes shared a genomic segment of 59.6 to 87.9 kb and showed severe retinal defects on ophthalmoscopic evaluation. The ABCA4 variant c.859-25A>G disrupts a predicted branchpoint, resulting in protein truncation because of different splice defects, and is associated with early-onset STGD1 when present in homozygosity. This variant was found in 25/525 Palestinian inherited retinal dystrophy probands, representing one of the most frequent inherited retinal disease-causing variants in West-Bank Palestine.
登录
查看更多内容
影响因子：
4.4
作者：
Beit-Ya'acov, Anat;Mizrahi-Meissonnier, Liliana;Sharon, Dror
通讯作者：
Sharon, Dror
影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
3.5
作者：
Braun TA;Mullins RF;Wagner AH;Andorf JL;Johnston RM;Bakall BB;Deluca AP;Fishman GA;Lam BL;Weleber RG;Cideciyan AV;Jacobson SG;Sheffield VC;Tucker BA;Stone EM
通讯作者：
Stone EM
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
4
作者：
Fadaie, Zeinab;Whelan, Laura;Roosing, Susanne
通讯作者：
Roosing, Susanne