title: Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy.
abstract: BACKGROUND
  Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere.
  
  
  OBJECTIVE
  The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM.
  
  
  METHODS
  Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (Mypn(WT/Q526X)) and homozygote mice harboring the human MYPN-Q529X mutation.
  
  
  RESULTS
  Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated Mypn(Q526X) protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers.
  
  
  CONCLUSIONS
  Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence of mutant Mypn(Q526X) protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in Mypn(WT/Q526X) hearts.
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Anne-Cecile
authors.initials: AC
authors.lastname: Huby
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Uzmee
authors.initials: U
authors.lastname: Mendsaikhan
authors.affiliation: Jikei University, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ruben
authors.initials: R
authors.lastname: Martherus
authors.affiliation: Department of Radiology, Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Janaka
authors.initials: J
authors.lastname: Wansapura
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Nan
authors.initials: N
authors.lastname: Gong
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: James
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kristen
authors.initials: K
authors.lastname: Kramer
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.affiliation: Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: enkhsaikhan.purevjav@cchmc.org.
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
mesh_terms: D000818:Animals; D002313:Cardiomyopathy, Restrictive / Q000235:genetics* / Q000503:physiopathology; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D015536:Down-Regulation; D004453:Echoencephalography; D004562:Electrocardiography; D055879:Gene Knock-In Techniques; D054144:Heart Failure, Diastolic / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D018389:Codon, Nonsense; C426225:MYPN protein, human; D009124:Muscle Proteins
keywords: CARP/ANKRD1; ERK1/2; fibrosis; remodeling