Ozaki Kokoro, Yatsuka Yukiko, Oyazato Yoshinobu, Nishiyama Atsushi, Nitta Kazuhiro R, Kishita Yoshihito, Fushimi Takuya, Shimura Masaru, Noma Shohei, Sugiyama Yohei, Tagami Michihira, Fukunaga Moe, Kinoshita Hiroko, Hirata Tomoko, Suda Wataru, Murakawa Yasuhiro, Carninci Piero, Ohtake Akira, Murayama Kei, Okazaki Yasushi
Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
NPJ Genom Med. 2024 Oct 25;9(1):48. doi: 10.1038/s41525-024-00429-5.
Repeat expansions cause at least 50 hereditary disorders, including Friedreich ataxia and other diseases known to cause mitochondrial dysfunction. We identified a patient with NAXE-related mitochondrial encephalopathy and novel biallelic GGGCC repeat expansion as long as ~200 repeats in the NAXE promoter region using long-read sequencing. In addition to a marked reduction in the RNA and protein, we found a marked reduction in nascent RNA in the promoter using native elongating transcript-cap analysis of gene expression (NET-CAGE), suggesting transcriptional suppression. Accordingly, CpG hypermethylation was observed in the repeat region. Genetic analyses determined that homozygosity in the patient was due to maternal chromosome 1 uniparental disomy (UPD). We assessed short variants within NAXE including the repeat region in the undiagnosed mitochondrial encephalopathy cohort of 242 patients. This study identified the GGGCC repeat expansion causing a mitochondrial disease and suggests that UPD could significantly contribute to homozygosity for rare repeat-expanded alleles.
重复序列扩增导致至少50种遗传性疾病，包括弗里德赖希共济失调和其他已知会导致线粒体功能障碍的疾病。我们使用长读长测序技术，在一名患有与NAXE相关的线粒体脑病的患者中，发现了一种新的双等位基因GGGCC重复序列扩增，其在NAXE启动子区域长达约200个重复序列。除了RNA和蛋白质显著减少外，我们还通过基因表达的天然延伸转录本帽分析（NET-CAGE）发现启动子区域的新生RNA显著减少，提示转录抑制。相应地，在重复序列区域观察到CpG高甲基化。基因分析确定该患者的纯合性是由于母源1号染色体单亲二体（UPD）。我们评估了242例未确诊的线粒体脑病队列患者中NAXE内的短变异，包括重复序列区域。本研究鉴定出导致线粒体疾病的GGGCC重复序列扩增，并表明UPD可能对罕见的重复序列扩增等位基因的纯合性有显著贡献。
