Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

Kargaran, Parisa K.; Evans, Jared M.; Bodbin, Sara E.; Smith, James G. W.; Nelson, Timothy J.; Denning, Chris; Mosqueira, Diogo

Abstract

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.

Citation

Kargaran, P. K., Evans, J. M., Bodbin, S. E., Smith, J. G. W., Nelson, T. J., Denning, C., & Mosqueira, D. (2020). Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy. Journal of Clinical Medicine, 9(8), Article 2349. https://doi.org/10.3390/jcm9082349

• Journal Article Type: Article
• Acceptance Date: Jul 21, 2020
• Online Publication Date: Jul 23, 2020
• Publication Date: 2020-08
• Deposit Date: Jul 27, 2020
• Publicly Available Date: Jul 27, 2020
• Journal: Journal of Clinical Medicine
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 8
• Article Number: 2349
• DOI: https://doi.org/10.3390/jcm9082349
• Public URL: https://nottingham-repository.worktribe.com/output/4785923
• Publisher URL: https://www.mdpi.com/2077-0383/9/8/2349