Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France
Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France
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DOI：
10.1002/humu.21348
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发表时间：
2010-11-01
期刊：
影响因子：
3.9
通讯作者：
Rabes, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Marduel, Marie;Carrie, Alain;Rabes, Jean-Pierre
常染色体显性高胆固醇血症（ADH）以血浆LDL胆固醇单独升高和过早心血管并发症为特征，与3个主要基因的突变相关：LDLR（LDL受体）、APOB（载脂蛋白B）和PCSK 9（前蛋白转化酶枯草杆菌蛋白酶-kexin 9型）。通过法国ADH研究网络，我们收集了来自法国11个不同地区的1358名法国先证者的分子数据。在1003例受试者中确定了LDLR基因突变，代表391个独特事件，其中错义突变占46.0%，移码突变占14.6%，剪接突变占13.6%，无义突变占11.3%，主要重排占9.7%，小框内缺失/插入占3.8%，UTR突变占1.0%。有趣的是，175个是新的突变事件，占我们确定的独特事件的45%，突出了法国LDLR突变谱的特异性。此外，在89名先证者中发现了APOB基因突变，在10名先证者中发现了PCSK 9基因突变。现有临床和生化数据的比较显示ADH引起突变的严重程度梯度：FH= PCSK 9>FDB>“其他”基因。在该法国队列中，每个已知基因对ADH的贡献分别为：LDLR 73.9%，APOB 6.6%，PCSK 9 0.7%。最后，在19.0%的先证者中，没有发现突变，因此强调了ADH突变位于仍然未知的基因中的存在。(C)2010 Wiley-Liss，Inc.
Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>""Others"" genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. (C) 2010 Wiley-Liss, Inc.