title: Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation.
abstract: BACKGROUND
  Mutations in LMNA gene cause cardiomyopathy, for which mechanistic insights are lacking.
  
  
  RESULTS
  Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy.
  
  
  CONCLUSIONS
  Dusp4 causes cardiac dysfunction and may contribute to the development of LMNA cardiomyopathy.
  
  
  CONCLUSIONS
  Revealing pathogenic mechanisms of LMNA cardiomyopathy is essential for the development of mechanism-based therapies. Mutations in the lamin A/C gene (LMNA) cause a diverse spectrum of diseases, the most common of which is dilated cardiomyopathy often with skeletal muscular dystrophy. Lamin A and C are fundamental components of the nuclear lamina, a dynamic meshwork of intermediate filaments lining the nuclear envelope inner membrane. Prevailing evidence suggests that the nuclear envelope functions as a signaling node and that abnormality in the nuclear lamina leads to dysregulated signaling pathways that underlie disease pathogenesis. We previously showed that activated ERK1/2 in hearts of a mouse model of LMNA cardiomyopathy (Lmna(H222P/H222P) mice) contributes to disease, but the complete molecular pathogenesis remains poorly understood. Here we uncover a pathogenic role of dual specificity phosphatase 4 (Dusp4), which is transcriptionally induced by ERK1/2. Dusp4 is highly expressed in the hearts of Lmna(H222P/H222P) mice, and transgenic mice with cardiac-selective overexpression of Dusp4 display heart dysfunction similar to LMNA cardiomyopathy. In both primary tissue and cell culture models, overexpression of Dusp4 positively regulates AKT-mTOR signaling, resulting in impaired autophagy. These findings identify a pathogenic role of Dusp4 in LMNA cardiomyopathy.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Choi
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.forename: Shinichi
authors.initials: S
authors.lastname: Iwata
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000818:Animals; D001343:Autophagy; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000503:physiopathology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases