J Hum Genet. 2025 Aug 6. doi: 10.1038/s10038-025-01381-7. Online ahead of print.
ABSTRACT
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by progressive ptosis and ophthalmoplegia, caused by single deletions, point mutations, or multiple deletions in mitochondrial DNA (mtDNA). Most point mutations occur in tRNA genes. Here, we report a novel variant of the tRNAGlu gene associated with CPEO. A 45-year-old male presented with ptosis and external ophthalmoplegia; however, blood test results, including lactate levels and autoantibodies, were normal. CPEO was suspended, prompting additional myopathological examination, mtDNA sequencing analysis, long polymerase chain reaction (PCR) analysis, and single-fiber analysis to compare mutation loads between ragged-red fibers (RRFs) and non-RRFs. Histopathological examination revealed scattered COX-negative RRFs. No deletions were found in the mtDNA. MtDNA sequencing analysis revealed a novel variant, m.14677 T > C, in the tRNAGlu gene, with Sanger sequencing indicating 45% heteroplasmy in the muscle tissue. Single-fiber analysis showed a significantly higher mutation load of m.14677 T > C in RRFs (range: 25.3-92.8%; median: 88.1%; n = 6) compared with non-RRFs (range: 3.5-85.9%; median: 17.1%; n = 5) (P = 0.03). Based on the significantly higher mutation load in RRFs than in non-RRFs, pathological evidence of mitochondrial disease, and the mutation’s occurrence at an evolutionarily conserved site, we concluded that m.14677 T > C, a novel variant of the tRNAGlu gene, is the cause of CPEO. Biochemical and histopathological examinations of muscle tissue, combined with single-fiber analysis, are valuable tools for evaluating mtDNA variants, particularly those within tRNA genes.
PMID:40770229 | DOI:10.1038/s10038-025-01381-7
