Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders
| Autor: | Aurélien Trimouille, Naïg Gueguen, C. Rouzier, Pascal Reynier, Christophe Verny, Patrizia Amati-Bonneau, Dominique Bonneau, Marie Laure Martin-Negrier, Claude Jardel, Samira Ait-El-Mkadem Saadi, Magalie Barth, Julien Cassereau, Franck Letournel, David Goudenège, Céline Bris, Benoit Rucheton, Estelle Colin, Magot Armelle, Stéphane Allouche, Sylvie Bannwarth, Véronique Paquis-Flucklinger, Abdel Slama, Yann Péréon, Valérie Desquiret-Dumas, Vincent Procaccio, Guy Lenaers, Pauline Gaignard, Marco Spinazzi |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Genetics Mitochondrial DNA Mitochondrial Diseases Nuclear gene Mitochondrial disease Breakpoint Mitochondrial genome maintenance High-Throughput Nucleotide Sequencing Biology medicine.disease DNA Mitochondrial Heteroplasmy Human genetics Mitochondria Genome Mitochondrial medicine Humans Gene Genetics (clinical) Sequence Deletion |
| Zdroj: | Genetics in Medicine. 23:1769-1778 |
| ISSN: | 1098-3600 |
| DOI: | 10.1038/s41436-021-01206-w |
| Popis: | Diseases caused by defects in mitochondrial DNA (mtDNA) maintenance machinery, leading to mtDNA deletions, form a specific group of disorders. However, mtDNA deletions also appear during aging, interfering with those resulting from mitochondrial disorders. Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we established criteria distinguishing age-related mtDNA rearrangements from those due to mtDNA maintenance defects. MtDNA deletion profiles from muscle and urine patient samples carrying pathogenic variants in nuclear genes involved in mtDNA maintenance (n = 40) were compared with age-matched controls (n = 90). Seventeen additional patient samples were used to validate the data mining model. Overall, deletion number, heteroplasmy level, deletion locations, and the presence of repeats at deletion breakpoints were significantly different between patients and controls, especially in muscle samples. The deletion number was significantly relevant in adults, while breakpoint repeat lengths surrounding deletions were discriminant in young subjects. Altogether, eKLIPse analysis is a powerful tool for measuring the accumulation of mtDNA deletions between patients of different ages, as well as in prioritizing novel variants in genes involved in mtDNA stability. |
| Databáze: | OpenAIRE |
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