uAUG-creating variant in the LDLR gene causes mild Familial hypercholesterolemia.

IF 3.6 2区生物学 Q2 GENETICS & HEREDITY

Human Genetics Pub Date : 2025-10-01 Epub Date: 2025-08-25 DOI:10.1007/s00439-025-02770-w

Alexandra Filatova, Petr Vasiluev, Evgeniya Osipova, Olga Ivanova, Natalia Semenova, Mikhail Skoblov

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Abstract

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) levels, leading to early-onset cardiovascular disease. FH is primarily caused by pathogenic variants in the LDLR gene, affecting cholesterol metabolism. We describe a family with a mild form of FH, in which gene panel sequencing identified a novel c.-8C>A variant in the LDLR 5'UTR. To assess its functional impact, we performed a luciferase assay and found that this variant partially reduces LDLR protein translation efficiency by introducing a novel upstream AUG (uAUG) start codon. This partial reduction in LDLR activity is consistent with the mild phenotype observed in the family. Additionally, we analyzed three previously reported LDLR 5'UTR variants (c.-5C>T, c.-14C>A, and c.-23A>C) but did not observe any significant effect on LDLR expression, suggesting that these variants are unlikely to contribute to disease development. These findings highlight the role of 5'UTR variants in LDLR expression and emphasize the importance of functional studies in variant classification for FH diagnostics.

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LDLR基因中产生uag的变异导致轻度家族性高胆固醇血症。

家族性高胆固醇血症（FH）是一种以低密度脂蛋白（LDL）水平升高为特征的遗传性疾病，可导致早发性心血管疾病。FH主要由LDLR基因的致病性变异引起，影响胆固醇代谢。我们描述了一个患有轻度FH的家庭，其中基因面板测序在LDLR 5'UTR中发现了一种新的c - 8c > a变体。为了评估其功能影响，我们进行了荧光素酶测定，发现该变体通过引入一个新的上游AUG （uAUG）起始密码子，部分降低了LDLR蛋白的翻译效率。LDLR活性的部分降低与在家族中观察到的轻度表型一致。此外，我们分析了先前报道的三种LDLR 5'UTR变异（C - 5c >T, C - 14c >A和C - 23a >C），但未观察到对LDLR表达的任何显著影响，这表明这些变异不太可能促进疾病的发展。这些发现强调了5'UTR变异在LDLR表达中的作用，并强调了FH诊断中变异分类的功能研究的重要性。

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

Human Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.