A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia
A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia
复制标题
DOI：
10.1161/atvbaha.112.301101
复制
发表时间：
2013-08-01
影响因子：
8.7
通讯作者：
Averna, Maurizio R.
中科院分区：
文献类型：
--
作者：
Cefalu, Angelo B.;Pirruccello, James P.;Averna, Maurizio R.
目的：在家族性低脂蛋白血症中，脂肪肝是一个特征性特征，并有一些肝硬化和肝癌的报道。我们调查了一个大的亲属，其中低密度脂蛋白胆固醇，脂肪肝和肝癌表现出常染色体显性遗传模式。方法与结果先证者为25岁女性，低血浆胆固醇伴肝脂肪变性。在另外10名家族成员中观察到低血浆总胆固醇水平和脂肪肝；1名患者发生肝硬化，另有4名患者死于肝癌或肝硬化伴癌。为了确定该家族的致病突变，我们对2名低胆固醇血症和脂肪肝患者进行了外显子组测序。在每个样本中鉴定出大约22400个单核苷酸变体。变异过滤后，保留了300个新的共享变异。在APOB的第26外显子（c.6718A>T）中发现了一个无义变异p.K2240X (p.K2240X)，该变异可归因于A>T突变，并通过Sanger测序证实了该变异。对16个家族成员的基因型分析表明，该突变分离出低胆固醇性状。此外，PNPLA3 p.I148M基因分型在c.6718A>T APOB基因突变的携带者和非携带者之间没有明显的频率差异。结论我们利用外显子组测序发现了APOB外显子26 （p.K2240X）中一个与低胆固醇和脂肪肝有关的新的无义突变。这种突变也可能导致这个家族的肝硬化和肝癌。
ObjectiveIn familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance.Approach and ResultsThe proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T APOB gene mutation.ConclusionsWe used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.