title: Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations.
abstract: OBJECTIVE
  Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM.
  
  
  RESULTS
  A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples from the LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice.
  
  
  CONCLUSIONS
  These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.
authors: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Bunkyo-Ku, Tokyo 113-8510, Japan.
authors: Takuro
authors: T
authors: Arimura
authors: Kenji
authors: K
authors: Onoue
authors: Yumiko
authors: Y
authors: Takahashi-Tanaka
authors: Taisuke
authors: T
authors: Ishikawa
authors: Masayoshi
authors: M
authors: Kuwahara
authors: Mitsutoshi
authors: M
authors: Setou
authors: Shuji
authors: S
authors: Shigenobu
authors: Katsushi
authors: K
authors: Yamaguchi
authors: Anne T
authors: AT
authors: Bertrand
authors: Noboru
authors: N
authors: Machida
authors: Kazumi
authors: K
authors: Takayama
authors: Masayuki
authors: M
authors: Fukusato
authors: Ryo
authors: R
authors: Tanaka
authors: Satoshi
authors: S
authors: Somekawa
authors: Tomoya
authors: T
authors: Nakano
authors: Yoshihisa
authors: Y
authors: Yamane
authors: Keiji
authors: K
authors: Kuba
authors: Yumiko
authors: Y
authors: Imai
authors: Yoshihiko
authors: Y
authors: Saito
authors: Gisèle
authors: G
authors: Bonne
authors: Akinori
authors: A
authors: Kimura
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D009919:Orchiectomy; D010052:Ovariectomy; D010375:Pedigree; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*; D012727:Sex Characteristics; D014162:Transfection
chemical_list: C410798:AR protein, human; C494847:LMNA protein, human; D034904:Lamin Type A; C576142:Lmna protein, mouse; D011944:Receptors, Androgen
keywords: Androgen receptor; Dilated cardiomyopathy; Gender difference; Lamin A/C; Testosterone