DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.
DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.
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DOI：
10.1038/s41436-020-0915-1
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Heon E
中科院分区：
文献类型：
--
作者：
Vig A;Poulter JA;Ottaviani D;Tavares E;Toropova K;Tracewska AM;Mollica A;Kang J;Kehelwathugoda O;Paton T;Maynes JT;Wheway G;Arno G;Genomics England Research Consortium;Khan KN;McKibbin M;Toomes C;Ali M;Di Scipio M;Li S;Ellingford J;Black G;Webster A;Rydzanicz M;Stawiński P;Płoski R;Vincent A;Cheetham ME;Inglehearn CF;Roberts A;Heon E
确定DYNC2H1变体在非综合征型遗传性视网膜疾病（IRD）中的作用。对5例不相关的IRD病例进行基因组和外显子组测序，未发现变异。开发了体外测定以验证所鉴定的变体（成纤维细胞测定、诱导多能干细胞[iPSC]衍生的视网膜类器官和动力蛋白运动测定）。鉴定了4个新的DYNC 2H1变体（V1，g.103327020_103327021dup; V2，g.103055779A> T; V3，g.103112272C> G; V4，g.103070104A> C）和1个先前报道的变体（V5，g.103339363T> G）。在先证者1（V1/V2）中，预测V1引入提前终止密码子（PTC），而V2破坏外显子41剪接供体位点，导致外显子41的不完全跳跃。V1和V2在体外损害动力蛋白2的运动性，并扰乱纤毛内的IFFT 88分布。在先证者2 - 4中纯合子的V3被预测在视网膜主导转录物中引起PTC。对视网膜类器官的分析表明，这种新的转录本表达随着类器官分化而增加。V4是一种新型错义变体，与V5反式，V5之前与青少年窒息性胸营养不良（JATD）有关。本文讨论的DYNC2H1变体是亚型的或影响视网膜占主导地位的转录本，并引起非综合征性IRD。动力蛋白变体，特别是DYNC2H1变体被报道为非综合征性IRD的原因。
Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.
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