Biallelic GGGCC repeat expansion leading to NAXE-related mitochondrial encephalopathy
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.
Authors
- Yukiko Yatsuka (ORCID: https://orcid.org/0000-0003-3137-6919)
- Masaru Shimura (ORCID: https://orcid.org/0000-0002-1998-7349)
- Yoshinobu Oyazato
- Takuya Fushimi (ORCID: https://orcid.org/0000-0002-6346-4975)
- Akira Ohtake (ORCID: https://orcid.org/0000-0003-1147-3113)
- Atsushi Nishiyama (ORCID: https://orcid.org/0000-0003-4668-253X)
- Tomoko Hirata
- Shohei Noma (ORCID: https://orcid.org/0000-0002-1246-3227)
- Yasuhiro Murakawa
- Wataru Suda (ORCID: https://orcid.org/0000-0002-2861-9724)
- Michihira Tagami (ORCID: https://orcid.org/0000-0002-9713-3576)
- Mizuho Fukunaga
- Yasushi Okazaki (ORCID: https://orcid.org/0000-0003-3241-5502)
- Piero Carninci (ORCID: https://orcid.org/0000-0001-7202-7243)
- Yoshihito Kishita
- Yohei Sugiyama (ORCID: https://orcid.org/0000-0002-4693-4584)
- Kei Murayama (ORCID: https://orcid.org/0000-0002-3923-8636)
- Kazuhiro R. Nitta (ORCID: https://orcid.org/0000-0003-3151-0962)
- Kokoro Ozaki (ORCID: https://orcid.org/0000-0001-9081-8348)
- Hiroko Kinoshita
Institutions
- Juntendo University (JP)
- Human Technopole (IT)
- Chiba Hospital (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Kagawa Prefectural Central Hospital (JP)
- Saitama Medical University (JP)
- Kindai University (JP)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1038/s41525-024-00429-5
- Citations
- 6
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Saitama Medical University
- Japan Society for the Promotion of Science
- Moonshot Research and Development Program