意义不明的α-半乳糖苷酶 A 基因变异:法布里病的细胞划分

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Inherited Metabolic Disease Pub Date : 2024-04-15 DOI:10.1002/jimd.12743
Alexandra Klein, Katharina Klug, Maximilian Breyer, Julia Grüner, Vijay Krishna Medala, Peter Nordbeck, Christoph Wanner, Eva Klopocki, Nurcan Üçeyler
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摘要

法布里病(FD)是一种由α-半乳糖苷酶A基因(GLA)变异引起的X连锁多器官疾病。根据变异的不同,疾病表型从良性到危及生命不等。p.A143T、p.D313Y 和 p.S126G 是意义不明变异(VUS)的常见例子。我们结合临床数据和在人体细胞体外系统中获得的数据,对这些 VUS 的潜在致病性进行了研究。我们分析了四种不同的男性受试者衍生细胞类型的α-半乳糖苷酶 A 酶(GLA)活性和细胞内 Gb3 负荷。此外,我们还研究了皮肤组织中的 Gb3 负荷以及与疾病表现相关的临床数据。与对照组相比,在携带 p.A143T 的细胞中观察到 GLA 活性降低(p < 0.05)。在携带 p.D313Y 变异的细胞中,与对照组相比,仅在内皮细胞中发现 GLA 活性降低(p < 0.01)。在携带 p.S126G 变异的细胞中没有观察到病理变化。所研究的 VUS 均未在任何细胞类型中引起细胞内 Gb3 的积累。我们的数据表明,p.A143T 杂合子细胞中的 GLA 活性异常,而 p.D313Y 和 p.S126G 杂合子细胞中的细胞表型总体正常,这些数据为临床上与 GLA 高度相关的 VUS 讨论提供了一个基础科学视角。
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Genetic variants of unknown significance in alpha-galactosidase A: Cellular delineation from Fabry disease

Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (GLA). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 GLA variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems. We have analyzed four different male subject-derived cell types for alpha-galactosidase A enzyme (GLA) activity and intracellular Gb3 load. Additionally, Gb3 load in skin tissue as well as clinical data were studied for correlates of disease manifestations. A reduction of GLA activity was observed in cells carrying p.A143T compared with controls (p < 0.05). In cells carrying the p.D313Y variant, a reduced GLA activity was found only in endothelial cells (p < 0.01) compared with controls. No pathological changes were observed in cells carrying the p.S126G variant. None of the VUS investigated caused intracellular Gb3 accumulation in any cell type. Our data of aberrant GLA activity in cells of p.A143T hemizygotes and overall normal cellular phenotypes in cells of p.D313Y and p.S126G hemizygotes contribute a basic science perspective to the clinically highly relevant discussion on VUS in GLA.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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