Perturbation of NCOA6 Leads to Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a progressive heart disease characterized by left ventricular dilation and contractile dysfunction. Although many candidate genes have been identified with mouse models, few of them have been shown to be associated with DCM in humans. Germline depletion of Ncoa6, a nuclear hormone receptor coactivator, leads to embryonic lethality and heart defects. However, it is unclear whether Ncoa6 mutations cause heart diseases in adults. Here, we report that two independent mouse models of NCOA6 dysfunction develop severe DCM with impaired mitochondrial function and reduced activity of peroxisome proliferator-activated receptor δ (PPARδ), an NCOA6 target critical for normal heart function. Sequencing of NCOA6-coding regions revealed three independent nonsynonymous mutations present in 5 of 50 (10%) patients with idiopathic DCM (iDCM). These data suggest that malfunction of NCOA6 can cause DCM in humans. [Display omitted] •Depletion or functional inactivation of NCOA6 leads to dilated cardiomyopathy in mice•NCOA6 is required for cardiac mitochondrial function•NCOA6 mediates optimal transcriptional activity of PPARδ•Of patients with iDCM tested, 10% encode mutations in NCOA6 Dilated cardiomyopathy (DCM) is a type of heart muscle disease and one cause of congestive heart failure. Because approximately 40% of DCM patients exhibit evidence of autosomal inheritance, the search for susceptibility loci is a major challenge in DCM research. Here, Roh et al. show that depletion of NCOA6 leads to DCM accompanied by impaired mitochondrial function and reduced peroxisome proliferator-activated receptor δ activity. NCOA6 genetic mutations found in patients with DCM suggest a role in normal heart function.