Novel Von Hippel-Lindau Germline Variants in Iranian Patients with Retinal Capillary Hemangioblastoma.

IF 0.5 Q4 OPHTHALMOLOGY
Case Reports in Ophthalmology Pub Date : 2025-01-03 eCollection Date: 2025-01-01 DOI:10.1159/000543119
Fatemeh Azimi, Kowsar Bagherzadeh, Golnaz Khakpoor, Saeed Talebi, Ahad Sedaghat, Reza Mirshahi, Hengameh Kasraei, Reza Afshar Kiaee, Masood Naseripour
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引用次数: 0

Abstract

Introduction: The aim of this study was to determine the potential genetic cause of retinal capillary hemangioblastoma (RCH) with symptoms of Von Hippel-Lindau (VHL) disease.

Case presentations: Three Iranian families (5 RCH patients) with novel variants are included in this study. The VHL variant analysis was performed by the Sanger sequencing technique. Molecular dynamics (MDs) simulations were conducted to analyze conformational changes resulting from variants in VHL protein structure and were compared with that of the native structure. Novel variant sites, including c.511A>C, c.511A>T, and c.514C>T in exon 3 of the VHL gene were identified. According to the American College of Medical Genetics (ACMG) classifications, c.514C>T (p.P172S) and c.511A>C (p.K171Q) are classified as variants of uncertain significance (VUS), and c.511A>T (p.K171*) is classified as a likely pathogenic variant. MD simulations demonstrated overall fluctuations of the proteins structure and a significantly lower degree of flexibility in the α-domain for the variant-encoded VHL protein structure compared to that of the native form.

Conclusion: The structural information and computational analysis of the identified variants are predicted to induce conformational changes that limit the flexibility of protein VHL interaction interface with Elongin B/C, Elongin C/B, and Cullin-2, which are necessary for hypoxia-inducible factor 1-α binding. The genetic variants identified in Iranian patients with RCH may aid in the molecular confirmation of other patients diagnosed with VHL and their at-risk family members. These pioneering results that include detailed structural and functional analysis of a variant's effect on the VHL protein may serve as a model for future studies.

伊朗视网膜毛细血管母细胞瘤患者的新型 Von Hippel-Lindau 基因变异。
本研究的目的是确定视网膜毛细血管母细胞瘤(RCH)与Von Hippel-Lindau (VHL)病症状的潜在遗传原因。病例介绍:本研究包括三个伊朗家庭(5例RCH患者)的新变异。VHL变异分析采用Sanger测序技术。通过分子动力学(MDs)模拟分析VHL蛋白结构变异引起的构象变化,并与天然结构进行比较。在VHL基因外显子3中发现了新的变异位点,包括C . 511a >C、C . 511a >T和C . 514c >T。根据美国医学遗传学学会(American College of Medical Genetics, ACMG)的分类,C . 514c b> T (p.p p172s)和C . 511a >C (p.p k171q)被归类为不确定意义变异(VUS), C . 511a >T (p.p k171 *)被归类为可能的致病变异。MD模拟表明,与天然形式相比,变异编码的VHL蛋白结构的α-结构域的灵活性明显降低。结论:所鉴定的变异的结构信息和计算分析预测会引起构象变化,限制蛋白质VHL与伸长蛋白B/C、伸长蛋白C/B和Cullin-2相互作用界面的灵活性,而这是缺氧诱导因子1-α结合所必需的。在伊朗RCH患者中发现的遗传变异可能有助于对诊断为VHL的其他患者及其高危家庭成员进行分子确认。这些开创性的结果包括变异对VHL蛋白影响的详细结构和功能分析,可以作为未来研究的模型。
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
CiteScore
0.90
自引率
0.00%
发文量
129
审稿时长
12 weeks
期刊介绍: This peer-reviewed online-only journal publishes original case reports covering the entire spectrum of ophthalmology, including prevention, diagnosis, treatment, toxicities of therapy, supportive care, quality-of-life, and survivorship issues. The submission of negative results is strongly encouraged. The journal will also accept case reports dealing with the use of novel technologies, both in the arena of diagnosis and treatment. Supplementary material is welcomed. The intent of the journal is to provide clinicians and researchers with a tool to disseminate their personal experiences to a wider public as well as to review interesting cases encountered by colleagues all over the world. Universally used terms can be searched across the entire growing collection of case reports, further facilitating the retrieval of specific information. Following the open access principle, the entire contents can be retrieved at no charge, guaranteeing easy access to this valuable source of anecdotal information at all times.
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