MT-CYB mutations in hypertrophic cardiomyopathy.
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.
Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut Copenhagen, Denmark ; Department of Biomedical Sciences, University of Copenhagen Copenhagen, Denmark.
Christian M
CM
Hagen
Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut Copenhagen, Denmark ; Institute of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen Copenhagen, Denmark.
Frederik H
FH
Aidt
Department of Cardiology, Roskilde Sygehus Roskilde, Denmark.
Ole
O
Havndrup
Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut Copenhagen, Denmark ; Department of Biomedical Sciences, Stellenbosch University Cape Town, South Africa.
Paula L
PL
Hedley
Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut Copenhagen, Denmark.
Cathrine
C
Jespersgaard
Department of Medicine B, The Heart Center, Rigshospitalet Copenhagen, Denmark.
Morten
M
Jensen
Department of Biomedical Sciences, University of Copenhagen Copenhagen, Denmark.
Jørgen K
JK
Kanters
Department of Biomedical Sciences, Stellenbosch University Cape Town, South Africa.
Johanna C
JC
Moolman-Smook
Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut Copenhagen, Denmark.
Daniel V
DV
Møller
Department of Medicine B, The Heart Center, Rigshospitalet Copenhagen, Denmark.
Henning
H
Bundgaard
Department of Clinical Biochemistry, Immunology, and Genetics, Statens Serum Institut Copenhagen, Denmark.
Michael
M
Christiansen
Cardiomyopathy; DNA sequencing; genetic disorders; hypertrophy; mitochondria