Lee Han Woong, Kang Seok Min
Discover NCOA6, a Novel Gene for Dilated Cardiomyopathy Professor Lee Han-Woong and Kang Seok-Min's Research Team
Dilated cardiomyopathy (DCM), characterized by cardiac enlargement and systolic dysfunction, is the most common form of cardiomyopathy, accounting for up to 30–40% of all heart failure cases. Clinical investigations have shown that approximately 40% of idiopathic DCM patients exhibit the patterns of autosomal-dominant inheritance, implying that genes play an important role in DCM pathogenesis. Recently, correlation between genetic mutations and DCM has been reported, while only few candidates are identified. Depletion of one of nuclear hormone receptor, PPARδ, leads to DCM in mice, however relevant to human DCM is still unknown. Using two independent mouse models of NCOA6, a PPARδ coactivator, Prof. Lee and Kang’s lab revealed that cardiac-specific knockout (cKO) of Ncoa6 causes DCM in mice, accompanying impaired PPARδ activity in the mouse heart. Ultra-structural examination of the mouse heart showed disarray and functional impairment of mitochondria in the Ncoa6 cKO mouse. Importantly, by screening of entire NCOA6 coding sequences of the genome, Prof Lee and Kang’s lab identified three patient-specific non-synonymous substitutions (G703E, M766L, and T1176A) in 10 out of 50 idiopathic DCM patients. Additional examinations with those mutant forms showed remarkable reduction of PPARδ activity, compared with wild-type NCOA6. malfunction of Ncoa6 causes DCM with the relevance to human DCM.
A recent study in mice revealed that NCOA6 promotes ubiquitination-mediated degradation of ERa, while Ncoa6 deficiency causes ERa accumulation in uterine stromal cells during the pre-implantation period. Consistent with these findings, we observed that the expression of ERa and its target genes were significantly increased in Ncoa6 cKO mice prior to DCM development. Interestingly, it is common for ERα expression to increase in end-stage DCM patients. Based on these lines of evidence, we hypothesized that the expression and/or function of NCOA6 may be suppressed prior to the onset of DCM, possibly accelerating the progression of the disease. Taken together, Prof. Lee and Kang’s findings will manifest stepping forward to screening and diagnosis of human idiopathic DCM.