title: Developmental cardiac hypertrophy in a mouse model of prolidase deficiency.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy, characterized by thickened ventricular walls and reduced ventricular chamber volume, is a common cause of sudden cardiac death in young people. Most inherited forms result from mutations in genes encoding sarcomeric proteins.
  
  
  METHODS
  Histologic analysis identified embryonic cardiac hypertrophy in dark-like mutant mice. BrdU analysis was performed to measure proliferation and cardiomyocytes were isolated to measure cell size. The dark-like mutation was identified by positional cloning.
  
  
  RESULTS
  The dark-like mutation causes cardiomyocyte hypertrophy due to loss-of-function of peptidase d (Pepd), which encodes prolidase, a cytosolic enzyme that recycles proline for collagen re-synthesis. Prolidase deficiency is a rare autosomal recessive disease in humans with a broad phenotypic spectrum not reported to include heart defects, but a conserved role for prolidase in heart development was confirmed by morpholino knockdown in zebrafish. We tested the hypothesis that loss of prolidase function disrupts collagen-mediated integrin signaling and determined that the levels of several key integrin transducers were reduced in the hearts of dark-like mutant embryos.
  
  
  CONCLUSIONS
  This work identifies dark-like mice as a model of prolidase deficiency that will be valuable for studying the role of proline metabolism in normal physiology and disease processes, and suggests that integrin signaling may regulate the onset of hypertrophic cardiac growth.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York.
authors.forename: Seungwoo
authors.initials: S
authors.lastname: Jung
authors.forename: Derek
authors.initials: D
authors.lastname: Silvius
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Nolan
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Borchert
authors.forename: Yoann H
authors.initials: YH
authors.lastname: Millet
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Gunn
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology*; D048429:Cell Size; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology / Q000503:physiopathology; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D009154:Mutation; D032383:Myocytes, Cardiac / Q000473:pathology; D010641:Phenotype; D056732:Prolidase Deficiency / Q000235:genetics*; D011392:Proline / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: D011392:Proline