Sequencing of the MT-CYB gene in 91 Danish hypertrophic cardiomyopathy probands identified 2 rare, putative disease-causing nonsynonymous variants (p.C93Y and p.S246P).
Observational (n=91)
Are MT-CYB mutations present in patients with hypertrophic cardiomyopathy and do they have structural consequences?
Rare nonsynonymous variants in the MT-CYB gene can be identified in HCM patients and may contribute to progressive mitochondrial dysfunction.
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.
Hagen et al. (Fri,) conducted a observational in Hypertrophic cardiomyopathy (n=91). MT-CYB gene sequencing was evaluated on Identification of nonsynonymous variants in MT-CYB. Sequencing of the MT-CYB gene in 91 Danish hypertrophic cardiomyopathy probands identified 2 rare, putative disease-causing nonsynonymous variants (p.C93Y and p.S246P).