Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance
Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance
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DOI：
10.1016/j.ajhg.2013.07.017
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发表时间：
2013-09-05
影响因子：
9.8
通讯作者：
Taylor, Robert W.
中科院分区：
文献类型：
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作者：
Bonnen, Penelope E.;Yarham, John W.;Taylor, Robert W.
导致线粒体DNA （mtDNA）缺失的核遗传疾病在临床上和遗传学上都是异质的，大多数病例的分子病因仍未确诊。通过全外显子组测序，我们在三个不相关的近亲中发现了FBXL4分离的隐性无义和剪接突变，其中受影响的儿童表现为致命性脑病，乳酸性酸中毒和严重的肌肉mtDNA缺失。我们发现FBXL4是一种与线粒体共定位的F-box蛋白，该蛋白的功能丧失和剪接突变导致严重的呼吸链缺陷，线粒体膜电位丧失，以及受影响个体成纤维细胞中动态线粒体网络和类核分布的紊乱。野生型FBXL4转录物在两名受试者细胞系中的表达完全恢复了mtDNA拷贝数水平，导致线粒体生化缺陷得到纠正。总之，我们的数据表明，FBXL4突变是致病的，并确立了FBXL4作为一种线粒体蛋白，可能在维持mtDNA完整性和稳定性方面发挥作用。
Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.