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Heteroplasmic Mutant Load Differences in Mitochondrial DNA-Associated Leigh Syndrome

Authors
 Ji-Hoon Na  ;  Young-Mock Lee 
Citation
 PEDIATRIC NEUROLOGY, Vol.138 : 27-32, 2023-01 
Journal Title
PEDIATRIC NEUROLOGY
ISSN
 0887-8994 
Issue Date
2023-01
MeSH
DNA, Mitochondrial / genetics ; Genes, Mitochondrial ; Humans ; Leigh Disease* / genetics ; Leigh Disease* / pathology ; Mutation / genetics ; Phenotype
Keywords
Heteroplasmic mutation ; Heteroplasmy ; Leigh syndrome ; Mitochondrial DNA ; Mitochondrial diseases
Abstract
Background: Mitochondrial DNA (mtDNA)-associated Leigh syndrome is influenced by mutant pathogenicity and corresponding heteroplasmic loads; however, the manner in which heteroplasmic mutant load affects patient phenotypes and the relationship between mutant types and heteroplasmic mutant loads remain unknown. We aimed to investigate the distribution of the mutant load of different mtDNA mutations in a single-center cohort.

Methods: We used next-generation sequencing to confirm mtDNA mutations in 31 patients with Leigh syndrome. Subsequently, we counted the number of mtDNA reads to quantitatively analyze the heteroplasmic mutant load and categorize the patients according to the mtDNA mutations they harbored. Confirmed cases of mtDNA-associated Leigh syndrome were classified according to the mutations observed in six genes and 10 nucleotides.

Results: Of the 31 patients with Leigh syndrome, 27 harbored known pathogenic mutations. We discovered that MT-ATP6 was the most commonly mutated gene (n = 13 patients), followed by MT-ND3 (n = 7) and MT-ND5 (n = 4). MT-ATP6 had a significantly higher mutant load than MT-ND3 and MT-ND5 (P < 0.001, each). By contrast, MT-ND5 had a significantly lower mutant load than MT-ND3 (P = 0.007). Notably, the mutation loads varied significantly among patients carrying the MT-ATP6, MT-ND3, and MT-ND5 mutations.

Conclusions: Our study illustrated the heteroplasmic diversity and phenotypic expression threshold of mutated mitochondrial genes in mtDNA-associated Leigh syndrome. The results provide promising insights into the genotype-phenotype correlation in mtDNA-associated Leigh syndrome that are expected to guide the development of tailored treatments for Leigh syndrome.
Full Text
https://www.sciencedirect.com/science/article/pii/S0887899422002077
DOI
10.1016/j.pediatrneurol.2022.09.006
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Na, Ji Hoon(나지훈) ORCID logo https://orcid.org/0000-0002-3051-2010
Lee, Young Mock(이영목) ORCID logo https://orcid.org/0000-0002-5838-249X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/193507
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