Varma Hemant, Faust Phyllis L, Iglesias Alejandro D, Lagana Stephen M, Wou Karen, Hirano Michio, DiMauro Salvatore, Mansukani Mahesh M, Hoff Kirsten E, Nagy Peter L, Copeland William C, Naini Ali B
Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA; Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, USA.
Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA.
Eur J Med Genet. 2016 Oct;59(10):540-5. doi: 10.1016/j.ejmg.2016.08.012. Epub 2016 Aug 31.
Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.
线粒体DNA（mtDNA）耗竭综合征表现为多种早发性疾病，影响骨骼肌、脑和肝功能。几个核DNA编码基因的突变会导致mtDNA耗竭。我们报告了一名3个月大的男童患者，他出现肝功能衰竭，并且在肝脏和肌肉中发现有严重的mtDNA耗竭。全外显子组测序在参与线粒体DNA复制的线粒体DNA聚合酶γ（POLG2）辅助亚基中鉴定出一个纯合错义变异（c.544C>T，p.R182W）。该变异预计会破坏POLG2蛋白同源二聚化所需的关键区域，并导致持续性DNA合成丧失。父母双方表型正常，且该变异为杂合子。POLG2的杂合突变以前与进行性眼外肌麻痹和mtDNA缺失有关。这是首例关于POLG2纯合突变且临床表现为严重肝功能衰竭和线粒体耗竭患者的报告。
