Biallelic GGGCC Repeat Expansion Leading to NAXE-related Mitochondrial Encephalopathy

Overview

Journal NPJ Genom Med

Specialty Genetics

Date 2024 Oct 25

PMID 39455596

Authors

Kokoro Ozaki

Yukiko Yatsuka

Yoshinobu Oyazato

Atsushi Nishiyama

Kazuhiro R Nitta

Yoshihito Kishita

Takuya Fushimi

Masaru Shimura

Shohei Noma

Yohei Sugiyama

Michihira Tagami

Moe Fukunaga

Hiroko Kinoshita

Tomoko Hirata

Wataru Suda

Yasuhiro Murakawa

Piero Carninci

Akira Ohtake

Kei Murayama

Yasushi Okazaki

Affiliations

Soon will be listed here.

Abstract

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.

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