The novel mitochondrial tRNAAsn gene mutation m.5709T>C produces ophthalmoparesis and respiratory impairment

Abstract

Although mutations in mitochondrial tRNAs constitute the most common mtDNA defect, the presence of pathological variants in mitochondrial tRNA Asn is extremely rare. We were able to identify a novel mtDNA tRNA Asn gene pathogenic mutation associated with a myopathic phenotype and a previously unreported respiratory impairment. Our proband is an adult woman with ophthalmoparesis and respiratory impairment. Her muscle biopsy presented several cytochrome c oxidase-negative (COXÀ) fibres and signs of mitochondrial proliferation (ragged red fibres). Sequence analysis of the muscle-derived mtDNA revealed an m.5709T4C substitution, affecting mitochondrial tRNA Asn gene. Restriction-fragment length polymorphism analysis of the mutation in isolated muscle fibres showed that a threshold of at least 91.9% mutated mtDNA results in the COX deficiency phenotype. The new phenotype further increases the clinical spectrum of mitochondrial diseases caused by mutations in the tRNA Asn gene.

Progressive external ophthalmoplegia associated with novel MT ‐ TN mutations

“…Nine different point mutations in MT ‐ TN have previously been reported to be associated with mitochondrial disease. Five of these appeared as isolated PEO with mitochondrial myopathy without demonstrated inheritance 2–4,7–10,13 . Together with the two mutations described here, seven out of eleven mutations show this phenotype, which is otherwise associated mainly with large‐scale deletions of mtDNA.…”

“…We identified two mtDNA mutations, m.5669G>A and m.5702delA, in the MT ‐ TN gene, encoding the tRNA Asn and demonstrated their pathogenicity. Nine probably pathogenic mutations have previously been described in the MT ‐ TN gene 2–14 . Five of these were associated with sporadic PEO, which together with the two mutations described here makes the MT ‐ TN gene a hot spot for sporadic PEO associated with mtDNA point mutations.…”

“…Five of these appeared as isolated PEO with mitochondrial myopathy without demonstrated inheritance. [2][3][4][7][8][9][10]13 Together with the two mutations described here, seven out of eleven mutations show this phenotype, which is otherwise associated mainly with large-scale deletions of mtDNA. Although sporadic PEO with mitochondrial myopathy has also been described to be related to other mtDNA tRNA genes, MT-TN seems to be a hot spot for this particular phenotype together with MT-TL2.…”

“…Nine probably pathogenic mutations have previously been described in the MT-TN gene. [2][3][4][5][6][7][8][9][10][11][12][13][14] Five of these were associated with sporadic PEO, which together with the two mutations described here makes the MT-TN gene a hot spot for sporadic PEO associated with mtDNA point mutations.…”

Breaking a single hydrogen bond in the mitochondrial tRNAPhe‐PheRS complex leads to phenotypic pleiotropy of human disease

“…Mitochondrially localized aaRSs (mit-aaRS) have been of considerable clinical interest since mutations have been identified that cause distinctive disease phenotypes dependent on the particular mit-aaRS. The last two decades have accumulated both clinical and diagnostic data, indicating that mutations in either the substrate mit-tRNA or in the mitochondrial aaRS can lead to diverse presentations of mitochondrial disease [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. More than 200 point mutations have been identified in mitochondrial genes, the vast majority of which are associated with diverse forms of neurological diseases [20][21][22].…”