MT-CYB mutations in hypertrophic cardiomyopathy

Christian Munch Hagen, Frederik Heurlin Aidt, Ole Havndrup, Paula L Hedley, Cathrine Jespersgaard, Morten Jensen, Jørgen K Kanters, Johanna C Moolman-Smook, Daniel V Møller, Henning Bundgaard, Michael Christiansen


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.
Original languageEnglish
JournalMolecular Genetics & Genomic Medicine
Issue number1
Pages (from-to)54-65
Number of pages12
Publication statusPublished - May 2013


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