Universität zu Köln

Hippen, Marius, Zsurka, Gabor ORCID: 0000-0002-6379-849X, Peeva, Viktoriya, Machts, Judith, Schwiecker, Kati, Debska-Vielhaber, Grazyna, Wiesner, Rudolf J., Vielhaber, Stefan and Kunz, Wolfram S. ORCID: 0000-0003-1113-3493 (2022). Novel Pathogenic Sequence Variation m.5789T > C Causes NARP Syndrome and Promotes Formation of Deletions of the Mitochondrial Genome. Neurol.-Genet., 8 (2). PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 2376-7839

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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 tRNA(Cys) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hippen, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Zsurka, Gabor UNSPECIFIED orcid.org/0000-0002-6379-849X UNSPECIFIED Peeva, Viktoriya UNSPECIFIED UNSPECIFIED UNSPECIFIED Machts, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwiecker, Kati UNSPECIFIED UNSPECIFIED UNSPECIFIED Debska-Vielhaber, Grazyna UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesner, Rudolf J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vielhaber, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kunz, Wolfram S. UNSPECIFIED orcid.org/0000-0003-1113-3493 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-677162
DOI:	10.1212/NXG.0000000000000660
Journal or Publication Title:	Neurol.-Genet.
Volume:	8
Number:	2
Date:	2022
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	2376-7839
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSFER-RNA; MUTATION; MTDNA Multiple languages Genetics & Heredity; Clinical Neurology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67716