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Open AccessArticle

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

1
Department of Cardiovascular Medicine, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN 55905, USA
2
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
3
Division of Cancer and Stem Cells, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
4
Faculty of Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UK
5
Division of General Internal Medicine, Division of Pediatric Cardiology, Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic Center for Regenerative Medicine, Rochester, MN 55905, USA
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(8), 2349; https://doi.org/10.3390/jcm9082349
Received: 22 June 2020 / Revised: 17 July 2020 / Accepted: 21 July 2020 / Published: 23 July 2020
(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)
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. View Full-Text
Keywords: Hypertrophic cardiomyopathy; disease modeling; isogenic human pluripotent stem cell-derived cardiomyocytes; gene modifiers; mitochondrial DNA; haplogroups Hypertrophic cardiomyopathy; disease modeling; isogenic human pluripotent stem cell-derived cardiomyocytes; gene modifiers; mitochondrial DNA; haplogroups
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MDPI and ACS Style

Kargaran, P.K.; Evans, J.M.; Bodbin, S.E.; Smith, J.G.W.; Nelson, T.J.; Denning, C.; Mosqueira, D. Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy. J. Clin. Med. 2020, 9, 2349. https://doi.org/10.3390/jcm9082349

AMA Style

Kargaran PK, Evans JM, Bodbin SE, Smith JGW, Nelson TJ, Denning C, Mosqueira D. Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy. Journal of Clinical Medicine. 2020; 9(8):2349. https://doi.org/10.3390/jcm9082349

Chicago/Turabian Style

Kargaran, Parisa K.; Evans, Jared M.; Bodbin, Sara E.; Smith, James G.W.; Nelson, Timothy J.; Denning, Chris; Mosqueira, Diogo. 2020. "Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy" J. Clin. Med. 9, no. 8: 2349. https://doi.org/10.3390/jcm9082349

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