title: Perturbation of NCOA6 leads to dilated cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Yonsei Laboratory Animal Research Center, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Roh
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Institut de Recherches Cliniques de Montréal, Montréal QC H2W 1R7, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal QC H3T 1J4, Canada.
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Yonsei Laboratory Animal Research Center, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Sung
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Yonsei Laboratory Animal Research Center, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Jeehyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Cardiology Division, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 120-752, South Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Oh
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea.
authors.forename: Beom Seob
authors.initials: BS
authors.lastname: Lee
authors.affiliation: DNA Link, Inc., Songpa-Gu, Seoul 138-736, South Korea.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Gyeongbuk 790-784, South Korea.
authors.forename: Yong Song
authors.initials: YS
authors.lastname: Gho
authors.affiliation: Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, South Korea.
authors.forename: Duk-Kyung
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 443-380, South Korea.
authors.forename: Chan Bae
authors.initials: CB
authors.lastname: Park
authors.affiliation: Department of Oral Biology, College of Dentistry, Yonsei University, Seoul 120-752, South Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Jae Woon
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Cardiology Division, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 120-752, South Korea; Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea. Electronic address: smkang@yuhs.ac.
authors.forename: Seok-Min
authors.initials: SM
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Yonsei Laboratory Animal Research Center, Yonsei University, Seoul 120-749, South Korea. Electronic address: hwl@yonsei.ac.kr.
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D006801:Humans; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D056918:Nuclear Receptor Coactivators / Q000235:genetics* / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators; D047494:PPAR delta