MT‐CYB mutations in hypertrophic cardiomyopathy

Abstract

Mitochondrial dysfunction is a characteristic of heart failure. Mutations in mitochondrial DNA, particularly in MT-CYB coding for cytochrome B in complex III (CIII), have been associated with isolated hypertrophic cardiomyopathy (HCM). We hypothesized that MT-CYB mutations might play an important causal or modifying role in HCM. The MT-CYB gene was sequenced from DNA isolated from blood from 91 Danish HCM probands. Nonsynonymous variants were analyzed by bioinformatics, molecular modeling and simulation. Two germline-inherited, putative disease-causing, nonsynonymous variants: m.15024G>A; p.C93Y and m.15482T>C; p.S246P were identified. Modeling showed that the p.C93Y mutation leads to disruption of the tertiary structure of Cytb by helix displacement, interfering with protein–heme interaction. The p.S246P mutation induces a diproline structure, which alters local secondary structure and induces a kink in the protein backbone, interfering with macromolecular interactions. These molecular effects are compatible with a leaky phenotype, that is, limited but progressive mitochondrial dysfunction. In conclusion, we find that rare, putative leaky mtDNA variants in MT-CYB can be identified in a cohort of HCM patients. We propose that further patients with HCM should be examined for mutations in MT-CYB in order to clarify the role of these variants.

Metabolic Alterations in Inherited Cardiomyopathies

“…One of the least common OXPHOS defects is complex III deficiency. Patients carrying different mutations in the MTCYB gene, encoding for cytochrome b, showed HCM or histiocytoid cardiomyopathy [113][114][115][116]. Moreover, cardiac manifestations may occur in case of defects in complex IV, also known as cytochrome c oxidase (COX).…”

Private Mitochondrial DNA Variants in Danish Patients with Hypertrophic Cardiomyopathy

“…All of the mRNA variants, except one MT-CYB : m.15024G>A, p. C93Y, were assessed to be of no clinical significance ( Table 3 ). MT-CYB : m.15024G>A has previously been described both as a potential modifying mutation, based on molecular modelling, in this cohort, and as a potential DEAF modifier [ 36 , 52 ].…”

“…Thus, the mitochondrial genome is still under strong selective pressure.Thus, mtDNA mutations can act as primary disease causing mutations or as modifiers in combination with either pathological genetic variants or environmental factors. In consequence, it is challenging to predict whether a new or rare mtDNA variant is disease associated [ 31 – 36 ]. This is underscored by the many erroneous conclusions regarding the classification of specific variants that have appeared over time [ 37 – 39 ].…”

Mitochondrial DNA Mutations and Rheumatic Heart Diseases

“…Genomic DNA was extracted using the DNase Blood Kit (Qiagen, South Korea) in accordance with the manufacturer's instructions. Polymerase chain reaction (PCR) was carried out to amplify MT-CYB, since it is reportedly involved in cardiovascular pathologies [12,[15][16][17][18][19]. PCR amplification of MT-CYB was carried out at a reaction volume of 50 µL containing 2 µL of concentrated DNA and 48 µL of the PCR mix comprising 29.8 µL of MilliQ water, 5 µL of buffer, 1 µL of supplementary MgCl 2 , 2 µL of dATP, dCTP, dGTP, and dTTP, 5 µL of H15915, 5 µL of L14723, and 0.2 µL of Tap polymerase.…”

“…These mutations generally show a deficit of enzymatic activity and a decrease in the number of certain subunits of complex III [13]. Mitochondrial dysfunction is characteristic of heart failure [15].…”