Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene
Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene
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携带 LDLR 基因多重突变的纯合子 FH 患者的 LDLR 变异分析
DOI：
10.1016/j.atherosclerosis.2017.06.014
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发表时间：
2017-08-01
期刊：
影响因子：
5.3
通讯作者：
Wang, Lu-Ya
中科院分区：
文献类型：
--
作者：
Jiang, Long;Benito-Vicente, Asier;Wang, Lu-Ya
背景和目标：家族性高胆固醇血症（FH）是一种常染色体显性疾病，在全球广泛流行，部分原因是早发冠心病的高患病率。虽然大多数FH研究都集中在单杂合LDLR突变上，但同一染色体上的双LDLR突变报告有限。本研究的目的是深入了解LDLR基因中存在多个突变的临床后果。方法：从两个临床纯合子FH患者及其亲属的DNA进行了分析，使用有针对性的外显子组测序和DNA重测序。结果：Proband 1携带p.Q12X、NTDA（p.N276T和c.892delA）突变，Proband 2携带c.971delG、GSDN（p.G77S + D601N）突变。结果表明，p.Q12X、c.892delA和c.971delG是无功能的LDLR变体。相反，N276T和G77S是非致病性变体。有趣的是，虽然单独的D601N仅轻微降低LDLR活性，但其与非致病性p.G77S突变的共同存在导致LDLR活性降低40%的更强致病性变体。双突变体之一NTDA与单独的c.892delA一样无功能。另一个双突变体，GSDN，是更严重的比任何一个组件单mutants.Conclusions：早期基因筛选和实验室功能验证LDLR活性是至关重要的，使明确的FH诊断。功能验证对于FH患者的产前和产后护理也是必要的。(C)2017爱思唯尔B.V.保留所有权利。
Background and aims: Familial hypercholesterolemia (FH) is an autosomal dominant disease with widespread global prevalence that partially accounts for the high prevalence of premature coronary heart disease. Although the majority of research on FH has focused on single heterozygous LDLR mutations, there have been limited reports of double LDLR mutations on the same chromosome. The aim of this study was to gain insight into the clinical consequences of the presence of multiple mutations in the LDLR gene.Methods: DNA from two clinical homozygous FH patients and their relatives was analysed using targeted exome sequencing and DNA resequencing. Functional characterization of novel variants was performed by Western blot, flow cytometry and confocal microscopy.Results: Proband 1 carried p.Q12X, NTDA (p.N276T and c.892delA) mutations in LDLR, and Proband 2 carried c.971delG, GSDN (p.G77S + D601N). Results showed that p.Q12X, c.892delA, and c.971delG are non-functional LDLR variants. Conversely, N276T and G77S are non-pathogenic variants. Interestingly, while D601N alone only slightly diminishes LDLR activity, its co-presence with the non pathogenic p.G77S mutation results in a more strongly pathogenic variant with LDLR activity reduced by 40%. One of the double mutants, NTDA, is as non functional as c.892delA alone. The other double mutant, GSDN, is more severe than either of the component single mutants.Conclusions: An early gene screening and laboratory functional verification of LDLR activity is of vital importance to enable a definite FH diagnosis. Functional verification is also necessary for prenatal and postnatal care in patients with FH. (C) 2017 Elsevier B.V. All rights reserved.