Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
Mol Genet Genomic Med. 2020 Oct;8(10):e1427. doi: 10.1002/mgg3.1427. Epub 2020 Aug 4.
Mitochondrial DNA depletion syndrome (MTDPS) is part of a group of mitochondrial diseases characterized by a reduction in mitochondrial DNA copy number. Most MTDPS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism.
We performed the whole-exome sequencing of a hepato-encephalopathy patient with MTDPS and functional analyses to determine the clinical significance of the identified variant.
Here, whole-exome sequencing of a patient presenting with hepato-encephalopathy and MTDPS identified a novel homozygous frameshift variant, c.13_29del (p.Trp6Profs*71) in MICOS13. MICOS13 (also known as QIL1, MIC13, or C19orf70) is a component of the MICOS complex, which plays crucial roles in the maintenance of cristae junctions at the mitochondrial inner membrane. We found loss of MICOS13 protein and fewer cristae structures in the mitochondria of fibroblasts derived from the patient. Stable expression of a wild-type MICOS13 cDNA in the patients fibroblasts using a lentivirus system rescued mitochondrial respiratory chain complex deficiencies.
Our findings suggest that the novel c.13_29del (p.Trp6Profs*71) MICOS13 variant causes hepato-encephalopathy with MTDPS. We propose that MICOS13 is classified as the cause of MTDPS.
线粒体 DNA 耗竭综合征（MTDPS）是一组线粒体疾病的一部分，其特征是线粒体 DNA 拷贝数减少。大多数 MTDPS 是由破坏脱氧核苷酸代谢的基因突变引起的。
我们对一名患有 MTDPS 的肝脑疾病患者进行了全外显子组测序，并进行了功能分析，以确定所鉴定变异的临床意义。
在这里，对一名患有肝脑疾病和 MTDPS 的患者进行全外显子组测序，发现了一种新的纯合移码变异 c.13_29del（p.Trp6Profs*71）在 MICOS13 中。MICOS13（也称为 QIL1、MIC13 或 C19orf70）是 MICOS 复合物的一个组成部分，该复合物在维持线粒体内膜嵴连接中起着至关重要的作用。我们发现患者成纤维细胞中线粒体的 MICOS13 蛋白缺失和嵴结构减少。使用慢病毒系统在患者成纤维细胞中稳定表达野生型 MICOS13 cDNA 可挽救线粒体呼吸链复合物缺陷。
我们的研究结果表明，新型 c.13_29del（p.Trp6Profs*71）MICOS13 变异导致伴有 MTDPS 的肝脑疾病。我们提出将 MICOS13 归类为 MTDPS 的病因。
