Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

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.

Mitochondrial Medicine: Genetic Underpinnings and Disease Modeling Using Induced Pluripotent Stem Cell Technology

“…This study not only strongly supported causation of HCM by mtDNA mutations, but also overcame limitations associated with clinical studies showing varying tissue-specific heteroplasmy and susceptibilities to specific mtDNA mutations (78). Furthermore, our own studies related different in vitro phenotypic severities between hiPSC-CM lines bearing either the R453C-βMHC or the E99K-ACTC1 sarcomeric mutations with specific variants in mtDNA (79). This approach focused on coupling phenotypes of hiPSC-CMs with mtDNA sequencing is promising to unveil novel variants with potentially HCMprotective or aggravator function.…”

“…Moreover, these approaches can be multiplexed with existing platforms for evaluating mitochondrial respiration profiles in hiPSC-CMs such as the Seahorse assay (82), which is performed in 96-well plate format thereby facilitating high-throughput screening studies, in response to various energy sources or metabolic modulators such as perhexiline (51). This approach may also be incorporated in isogenic sets of patient-derived hiPSC lines with known mitochondrial diseases affected by mtDNA variants (79).…”

Whole mitochondrial genome sequencing of Malaysian patients with cardiomyopathy

“…In recent years, numerous mtDNA variants have been identified and reported to be associated with CMP ( Govindaraj et al, 2014 ; Kargaran et al, 2020 ). However, only limited number of studies were carried out in Asia, and none was conducted in Malaysia.…”

CRISPR/Cas9-mediated generation and analysis of N terminus polymorphic models of β2AR in isogenic hPSC-derived cardiomyocytes

“…A strength of the hPSC-cardiomyocyte system is the potential to investigate polymorphisms that vary in their impact on phenotype and function from overtly disease-causing through to more subtle modifiers, and we have published data at both ends of the spectrum. 59 , 60 While polymorphisms that modify phenotype are often common variations rather than mutations or rare polymorphisms and hence are often undetected in minor allele frequency (MAF)-related searches, 61 they are important. Examples are D/I variant in ACE, associated with the COVID-19 pandemic, 62 or Q41L in GRK5 63 and G16R/E27Q in β 2 AR, associated with altered signaling in the heart.…”