Mitochondrial Mutations in Cholestatic Liver Disease with Biliary Atresia.
Mitochondrial Mutations in Cholestatic Liver Disease with Biliary Atresia.
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胆汁淤积性肝病的线粒体突变，胆道闭锁。
DOI：
10.1038/s41598-017-18958-8
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发表时间：
2018-01-17
影响因子：
4.6
通讯作者：
Lee DW
中科院分区：
文献类型：
--
作者：
Koh H;Park GS;Shin SM;Park CE;Kim S;Han SJ;Pham HQ;Shin JH;Lee DW
胆道闭锁(BA)导致严重的胆汁阻塞，由肝外胆管缺失引起。即使在成功的肝门肠吻合术后，相当数量的患者仍有可能出现肝功能的进行性恶化。最近的研究表明，编码蛋白质的线粒体DNA(MtDNA)基因和/或核DNA(NDNA)中的线粒体基因突变与肝细胞功能障碍有关。这一观察结果使我们调查了BA患者的肝功能障碍是否与mtDNA突变有关。应用下一代测序技术对14例BA患者的14例肝组织和5例胆总管囊肿患者的5例肝组织标本的mtDNA蛋白编码基因进行了测序。我们在所有接受检查的患者中发现了34个常见的mtDNA蛋白编码基因的非同义变异。系统的三维结构分析显示，在复合体I到V的关键区域中存在几个类似单核苷酸多态的突变，这些突变参与亚基组装、质子泵活性和/或超复合体的形成。BA患者的慢性肝损伤和肝功能不全指标也与肝功能衰竭程度显著相关，提示mtDNA突变可能加重肝病。因此，线粒体突变可能是BA相关病理机制的基础。
Biliary atresia (BA) results in severe bile blockage and is caused by the absence of extrahepatic ducts. Even after successful hepatic portoenterostomy, a considerable number of patients are likely to show progressive deterioration in liver function. Recent studies show that mutations in protein-coding mitochondrial DNA (mtDNA) genes and/or mitochondrial genes in nuclear DNA (nDNA) are associated with hepatocellular dysfunction. This observation led us to investigate whether hepatic dysfunctions in BA is genetically associated with mtDNA mutations. We sequenced the mtDNA protein-coding genes in 14 liver specimens from 14 patients with BA and 5 liver specimens from 5 patients with choledochal cyst using next-generation sequencing. We found 34 common non-synonymous variations in mtDNA protein-coding genes in all patients examined. A systematic 3D structural analysis revealed the presence of several single nucleotide polymorphism-like mutations in critical regions of complexes I to V, that are involved in subunit assembly, proton-pumping activity, and/or supercomplex formation. The parameters of chronic hepatic injury and liver dysfunction in BA patients were also significantly correlated with the extent of hepatic failure, suggesting that the mtDNA mutations may aggravate hepatopathy. Therefore, mitochondrial mutations may underlie the pathological mechanisms associated with BA.
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影响因子：
2.4
作者：
Caponcelli, Enrica;Knisely, Alex S.;Davenport, Mark
通讯作者：
Davenport, Mark
影响因子：
5.1
作者：
Davenport, Mark;Tizzard, Sarah A.;Hadzic, Nedim
通讯作者：
Hadzic, Nedim
影响因子：
13.5
作者：
Bedossa, P;Poynard, T
通讯作者：
Poynard, T
影响因子：
64.8
作者：
Efremov, Rouslan G.;Baradaran, Rozbeh;Sazanov, Leonid A.
通讯作者：
Sazanov, Leonid A.
DOI：
10.1073/pnas.1711201114
发表时间：
2017-08-22
影响因子：
11.1
作者：
He, Jiuya;Carroll, Joe;Walker, John E.
通讯作者：
Walker, John E.