Clinical report and genetic analysis of a Chinese family with retinitis pigmentosa 79 caused by a novel loss-of-function HK1 variant.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2024-10-03 DOI:10.1007/s13258-024-01574-y

Xin Luo, Lu Wang, Daxi Xue

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Abstract

Background: Retinitis pigmentosa (RP) is a genetically heterogeneous disease. RP 79 has been associated with heterozygous variants of hexokinase 1 (HK1). Only two missense HK1 variants have been reported in 11 families.

Objective: To discover the molecular pathogenic mechanism of RP and validate the biological harm of HK1 through in vitro experiments.

Methods: We conducted a genetic analysis of a 3-year-old female patient with RP and her family. We also evaluated the ocular phenotypes caused by HK1 (the identified variant). Peripheral blood samples were collected from the patient, her parents, and her brother, and trio whole-exome sequencing was performed. A protein structure analysis was performed to assess the functional impact of the variant, and a mutant plasmid was constructed for the quantitative polymerase chain reaction (qPCR) and western blot (WB) analysis of the effects of the variant on transcription and protein translation.

Results: The patient harbored the NM_000188.3: c.613del (p.Ala205Leufs*3) variant, which is a heterozygous variant of HK1. Sanger sequencing confirmed the presence of this variant in the patient; however, the patient's parents and brother had the wild-type variant. The protein structure analysis indicated that the variant resulted in a truncated protein caused by premature termination of amino acid coding. The qPCR results indicated that the variant may not have affected the transcription process. However, the WB analysis demonstrated that the mutant HK-1 protein was not expressed and that the wild-type group exhibited normal expression.

Conclusions: Our patient had a loss-of-function (LoF) variant of HK1, which may be the genetic cause of typical features of RP that are observed at an early age. These findings expand the spectrum of HK1 variants and phenotypes and suggest that LoF variants of HK1 may represent a specific pathogenic mechanism of RP.

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一个由新型功能缺失 HK1 变异引起的 79 型视网膜色素变性症中国家族的临床报告和遗传分析。

背景：视网膜色素变性（RP）是一种遗传异质性疾病。RP 79 与己糖激酶 1（HK1）的杂合子变异有关。在 11 个家族中，只有两个错义 HK1 变体被报道：发现 RP 的分子致病机制，并通过体外实验验证 HK1 的生物学危害：方法：我们对一名3岁的RP女性患者及其家族进行了基因分析。方法：我们对一名 3 岁的 RP 女患者及其家族进行了遗传分析，并评估了 HK1（已确定的变异体）引起的眼部表型。我们采集了患者及其父母和兄弟的外周血样本，并进行了三重全外显子组测序。为评估该变异体的功能影响，进行了蛋白质结构分析，并构建了一个突变质粒，用于定量聚合酶链反应（qPCR）和免疫印迹（WB）分析该变异体对转录和蛋白质翻译的影响：结果：患者携带的NM_000188.3: c.613del (p.Ala205Leufs*3) 变异是HK1的杂合变异。桑格测序证实了患者体内存在该变异体；然而，患者的父母和兄弟体内存在野生型变异体。蛋白质结构分析表明，该变异体因氨基酸编码过早终止而导致蛋白质截短。qPCR 结果表明，该变异体可能没有影响转录过程。然而，WB分析表明，突变体HK-1蛋白没有表达，而野生型组表达正常：结论：我们的患者有一个 HK1 功能缺失（LoF）变异体，这可能是导致 RP 早期典型特征的遗传原因。这些发现扩大了HK1变体和表型的范围，并表明HK1的LoF变体可能代表了RP的一种特殊致病机制。

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

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.

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