MT-CYB mutations in hypertrophic cardiomyopathy

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Christian M Hagen
  • Frederik H Aidt
  • Ole Havndrup
  • Paula L Hedley
  • Cathrine Jespersgaard
  • Morten Jensen
  • Kanters, Jørgen K.
  • Johanna C Moolman-Smook
  • Daniel V Møller
  • Bundgård, Henning
  • 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.
TidsskriftMolecular genetics & genomic medicine
Udgave nummer1
Sider (fra-til)54-65
Antal sider12
StatusUdgivet - maj 2013

ID: 101010339