Dilated Cardiomyopathy due to the Novel MT-CYB Missense Mutation m.14757T>C

Abstract

Mitochondrial DNA (mtDNA) mutations frequently manifest with multisystem disease, including cardiomyopathy (CM). Various studies described mutations in protein-encoding mtDNA genes, such as cytochrome-b, manifesting with CM. A detailed clinical, biochemical, and molecular genetic analysis was performed in a 40-year-old male with dilated CM (DCM) to detect the underlying mtDNA defect. Muscle biopsy showed complex-III deficiency, and sequencing of the cytochrome-b gene revealed the pathogenic variant m.14757T>C in MT-CYB, resulting in the replacement of the hydrophobic methionine by the polar threonine (M4T). By application of the PolyPhen algorithm the variant was predicted as pathogenic. The mutation was not found in 100 healthy controls and never reported as a neutral polymorphism despite extensive sequencing of the cytochrome-b gene in 2,704 normal healthy controls from different ethnic backgrounds. In conclusion, the novel variant m.14757T>C in MT-CYB is associated with DCM suggesting a pathophysiologic role of the variant in the development of DCM.

Keywords: Cytochrome-b gene; Dilated cardiomyopathy; Mitochondria; Mitochondrial; Oxidative phosphorylation; Systolic dysfunction; mtDNA.

Figure 1

Upper panel: (a) muscle biopsy section stained for Gomori’s trichrome shows muscle fibers with normal distribution of mitochondria (magnification × 40). (b) Succinate dehydrogenase (SDH) staining shows a similar picture with some low dark blue fibers (magnification × 40) compared to a healthy control (c). Lower panel: automated sequence analysis of the region encompassing the m.14757T>C mutation of the proband’s mtDNA in muscle.