Abstract
Background and Objectives We report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene.
Methods To address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNACys was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons.
Results The sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele.
Discussion In addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.
Glossary
- CADD=
- Combined Annotation-Dependent Depletion;
- COX=
- cytochrome c oxidase;
- CS=
- citrate synthase;
- MRC=
- Medical Research Council;
- mtDNA=
- mitochondrial DNA;
- NARP=
- neuropathy, ataxia, and retinitis pigmentosa;
- NCS=
- nerve conduction study;
- RFLP=
- restriction fragment length polymorphisms;
- SDH=
- succinate dehydrogenase;
- SDS=
- sodium dodecyl sulfate;
- WES=
- whole-exome sequencing
Footnotes
Go to Neurology.org/NG for full disclosures. Full information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
- Received December 8, 2021.
- Accepted in final form January 10, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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