In silico prediction, molecular modeling, and dynamics studies on the targeted next-generation sequencing identified genes underlying congenital heart disease in Down syndrome patients.

IF 0.9 Q4 CARDIAC & CARDIOVASCULAR SYSTEMS
Annals of Pediatric Cardiology Pub Date : 2023-07-01 Epub Date: 2024-01-05 DOI:10.4103/apc.apc_63_23
Fiona Hannah Carlus, L Balasubramaniam Sujatha, Anbazhagan Ganesh Kumar, Lakshmanan Loganathan, Karthikeyan Muthusamy, Silas Justin Carlus
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引用次数: 0

Abstract

Background: Individuals with Down syndrome (DS) have a 40%-60% chance of being born with congenital heart disease (CHD). This indicates that CHD in individuals with DS is not solely caused by trisomy 21, and there may be other genetic factors contributing to the development of CHD in these children. A study has identified variants in the specific genes that contribute to the pathogenesis of CHD in children with DS, isolated DS, and the CHD group. Computational studies on these identified variants, which, together with trisomy 21, determine the risk for CHD in DS cases, were limited. Here, we aimed to identify the impact of the identified variants that contribute to the pathogenesis of CHD in children with DS through in silico prediction, molecular modeling, and dynamics studies.

Methodology and results: The target single-nucleotide polymorphisms included in the study were examined for pathogenicity, residue conservation, and protein structural changes. The structural predictions were done using I-TASSER, Robetta, SWISS-MODEL, and Phyre2 tools. Further, the predicted models were validated through the PROCHECK server and molecular dynamics simulation using GROMACS software. The conservation analysis conducted on the identified variant highlights its significance in relation to the genetic disorders. Furthermore, a dynamics simulation study revealed the impact of the variant on protein structural stability (≤3 Å), providing valuable insights into its pathogenicity. We have also observed that the structure of the centrosomal protein of 290 kDa gene is relatively unstable, which may be attributed to its exclusive inclusion of helices within its secondary structural components.

Conclusions: This computational study explores, for the first time, the association between genes and CHD-DS, evaluating the identified specific frameshift variants. The observed pathogenic mutations in CHD-DS patients require further experimental validation and may contribute to the development of prospective drug design research. The insights gained from the structural and functional implications of these variants could potentially serve as a cornerstone in the development of effective treatments for this debilitating condition.

通过对定向新一代测序进行硅学预测、分子建模和动力学研究,确定了唐氏综合征患者先天性心脏病的潜在基因。
背景:唐氏综合征(DS)患儿出生后患先天性心脏病(CHD)的几率为 40%-60%。这表明,唐氏综合征患者的先天性心脏病并不完全是由 21 三体综合征引起的,可能还有其他遗传因素导致这些儿童患上先天性心脏病。一项研究发现了导致 DS 患儿、孤立 DS 患儿和 CHD 组 CHD 发病的特定基因变异。这些已确定的变异与 21 三体综合征共同决定了 DS 患儿发生先天性心脏病的风险,但有关这些变异的计算研究却很有限。在此,我们旨在通过硅预测、分子建模和动力学研究,确定已发现的变异对DS患儿CHD发病机制的影响:对研究中的目标单核苷酸多态性进行了致病性、残基保护和蛋白质结构变化方面的检查。使用 I-TASSER、Robetta、SWISS-MODEL 和 Phyre2 工具进行了结构预测。此外,还通过 PROCHECK 服务器和使用 GROMACS 软件进行的分子动力学模拟对预测模型进行了验证。对鉴定出的变异体进行的保护分析凸显了其与遗传性疾病相关的重要性。此外,动力学模拟研究还揭示了该变体对蛋白质结构稳定性(≤3 Å)的影响,为了解其致病性提供了有价值的见解。我们还观察到,290 kDa 基因的中心体蛋白结构相对不稳定,这可能是由于其二级结构成分中只包含螺旋:这项计算研究首次探讨了基因与 CHD-DS 之间的关联,评估了已确定的特定移帧变异。在 CHD-DS 患者中观察到的致病突变需要进一步的实验验证,并可能有助于前瞻性药物设计研究的发展。从这些变异的结构和功能影响中获得的见解有可能成为开发治疗这种衰弱病症的有效方法的基石。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Annals of Pediatric Cardiology
Annals of Pediatric Cardiology CARDIAC & CARDIOVASCULAR SYSTEMS-
CiteScore
1.40
自引率
14.30%
发文量
51
审稿时长
23 weeks
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