Expanding the landscape of tRNA pathogenic variants in mitochondrial DNA
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ID: 314198
2026
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Abstract
Abstract We present a comprehensive molecular and histopathological characterization of nine patients with mitochondrial myopathy, predominantly manifesting progressive external ophthalmoplegia (PEO), associated with heteroplasmic variants in mitochondrial tRNA genes (mt-tRNA). Among the ten variants identified, four were novel and previously unreported in MITOMAP. Using laser capture microdissection and deep next-generation sequencing, we quantified heteroplasmy at the single-muscle-fiber level, demonstrating that cytochrome c oxidase (COX)–deficient fibers consistently reached near-homoplasmic mutant loads, whereas COX-positive fibers remained heteroplasmic with lower variant fractions. These findings firmly support the pathogenic role of all variants. Furthermore, digital droplet PCR revealed an increased mitochondrial DNA (mtDNA) content in COX-deficient fibers, indicating compensatory mitochondrial biogenesis. Of particular note, one patient harbored two novel heteroplasmic variants, m.10009G>A and m.15961G>A, for which long-read sequencing identified mitogenomes carrying both variants also in cis, suggesting the occurrence of mtDNA recombination in human tissue. By applying refined American College of Medical Genetics and Genomics (ACMG) criteria specific for mt-tRNA, we reclassified several variants as pathogenic or likely pathogenic, including three previously deemed of uncertain significance. Overall, our integrative approach—combining single-fiber molecular dissection, mtDNA quantification, and long-read sequencing—broadens the mutational spectrum of pathogenic mt-tRNA variants, highlights the diagnostic value of single-fiber analyses in confirming pathogenicity, and provides new insights into mitochondrial genome dynamics and compensatory responses in mitochondrial disease.
| Reference Key |
openalex_W7161793199
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| Authors | Salvatore Loris Siragusa, Santino Blando, Claudio Fiorini, Alberto Pietro Pasti, Danara Ormanbekova, Francesco Casadei, Luca Morandi, Elena Pegoraro, Rocco Liguori, Valerio Carelli, Chiara La Morgia, Leonardo Caporali, Maria Lucia Valentino |
| Journal | Brain communications |
| Year | 2026 |
| DOI |
10.1093/braincomms/fcag178
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| URL | |
| Keywords | Keywords not found |
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