Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants
Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants
复制标题
DOI：
10.1016/j.jhep.2017.07.004
复制
发表时间：
2017-12-01
影响因子：
25.7
通讯作者：
Keitel, Verena
中科院分区：
文献类型：
--
作者：
Droege, Carola;Bonus, Michele;Keitel, Verena
背景和目的：胆汁盐输出泵（BSEP、ABCB11）、多药耐药蛋白 3（MDR3、ABCB4）和 ATP 酶家族性肝内胆汁淤积 1（FIC1、ATP8B1）介导胆汁形成。本研究旨在确定 FIC1、BSEP 和 MDR3 基因中的突变和常见变异对不同疾病发作和严重程度的胆汁淤积性疾病的贡献。方法：对具有假定遗传原因的胆汁淤积患者的 ATP8B1、ABCB11 和 ABCB4 侧翼内含子区域的编码外显子进行测序。通过生物信息学工具和3D蛋白质模型评估新变异的影响。结果：在427名疑似遗传性胆汁淤积患者中，149名患者分别在FIC1、BSEP或MDR3中携带至少一种致病突变。总体而言，鉴定出 154 种不同的突变，其中 25 种是新的。根据生物信息学分析和同源建模，所有 13 个新的错义突变都是致病的。在这三个基因中的任何一个中至少有一个致病突变的患者中，百分之八十二是儿童。在相应基因中没有致病突变的患者中，35.3% 的 FIC1、64.3% 的 BSEP 和 72.6% 的 MDR3 中发现一种或多种常见多态性。正如 gnomAD 所描述的，与一般人群相比，我们队列中 BSEP 和 MDR3 常见多态性的次要等位基因频率有所不同。然而，种族背景的差异可能会导致这种效应。结论：在一大群患者中，在 FIC1、BSEP 和 MDR3 中检测到 154 种不同的变异，其中 25 种是新的。在我们的队列中，BSEP (p.V444A) 和 MDR3 (p.I237I) 多态性的风险等位基因频率在相应基因没有致病突变的患者中显着过高，表明这些常见变异可能导致胆汁淤积表型。 (C) 2017 年由 Elsevier B.V. 代表欧洲肝脏研究协会出版。
Background & Aims: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity.Methods: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling.Results: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect.Conclusions: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. (C) 2017 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.