Mitochondrial DNA: Hotspot for potential gene modifiers regulating hypertrophic cardiomyopathy

Kargaran, Parisa K., Evans, Jared M., Bodbin, Sara E., Smith, James G. W. ORCID:, Nelson, Timothy J., Denning, Chris and Mosqueira, Diogo (2020) Mitochondrial DNA: Hotspot for potential gene modifiers regulating hypertrophic cardiomyopathy. Journal of Clinical Medicine, 9 (8). ISSN 2077-0383

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Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in mitochondrial DNA (mtDNA) present cardiac phenotypes, the mitochondrial genome is a promising candidate to harbor gene modifiers of HCM. Herein, we sequenced the mtDNA of isogenic pluripotent stem cell-cardiomyocyte models of HCM focusing on two sarcomeric mutations. This approach was extended to unrelated patient families totaling 52 cell lines. By correlating cellular and clinical phenotypes with mtDNA sequencing, potentially HCM-protective or -aggravator mtDNA variants were identified. These novel mutations were mostly located in the non-coding control region of the mtDNA and did not overlap with those of other mitochondrial diseases. Analysis of unrelated patients highlighted family-specific mtDNA variants, while others were common in particular population haplogroups. Further validation of mtDNA variants as gene modifiers is warranted but limited by the technically challenging methods of editing the mitochondrial genome. Future molecular characterization of these mtDNA variants in the context of HCM may identify novel treatments and facilitate genetic screening in cardiomyopathy patients towards more efficient treatment options.

Item Type: Article
Uncontrolled Keywords: disease modeling,gene modifiers,haplogroups,hypertrophic cardiomyopathy,isogenic human pluripotent stem cell-derived cardiomyocytes,mitochondrial dna,medicine(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 13 Aug 2020 23:59
Last Modified: 19 Oct 2023 02:44
DOI: 10.3390/jcm9082349

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