title: Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice.
abstract: OBJECTIVE
  Cardiac myosin-binding protein C (cMyBP-C) gene mutations are involved in familial hypertrophic cardiomyopathy (FHC). Many of these mutations produce truncated proteins, which are unstable in the cardiac tissue of patients, suggesting that haploinsufficiency could account for the development of the phenotype. However, existing mouse models of cMyBP-C gene mutations have represented hypomorphic alleles without evidence of asymmetric septal hypertrophy, a key FHC phenotypic feature. In the present study, we generated a new model of cMyBP-C null mice and characterized the phenotype in both homozygotes and heterozygotes at different ages.
  
  
  METHODS
  The mouse model was based upon the targeted deletion of exons 1 and 2, which contain the transcription initiation site, and the phenotype was determined by molecular, functional and morphological analyses.
  
  
  RESULTS
  Herein, we demonstrate that inactivation of one or two mouse cMyBP-C alleles leads to different cardiac disorders at different post-natal time windows. The homozygous cMyBP-C null mice do not express the cMyBP-C gene, develop eccentric left ventricular hypertrophy with decreased fractional shortening at 3-4 months of age and a markedly impaired relaxation after 9 months. This is associated with myocardial disarray and an increase of interstitial fibrosis. The heterozygous cMyBP-C null mice present a slight but significant decrease of cMyBP-C amount and develop asymmetric septal hypertrophy associated with fibrosis at 10-11 months of age.
  
  
  CONCLUSIONS
  These data provide evidence that heterozygous cMyBP-C null mice represent the first model with a key feature of human FHC that is asymmetric septal hypertrophy.
authors.affiliation: INSERM U582, Institut de Myologie, Bâtiment Babinski, GH Pitié-Salpêtrière, Paris, France. l.carrier@myologi.chups.jussieu.fr
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignier
authors.forename: Dagmar I
authors.initials: DI
authors.lastname: Keller
authors.forename: Pedro
authors.initials: P
authors.lastname: Bausero
authors.forename: Bernard
authors.initials: B
authors.lastname: Prudhon
authors.forename: Richard
authors.initials: R
authors.lastname: Isnard
authors.forename: Marie-Lory
authors.initials: ML
authors.lastname: Ambroisine
authors.forename: Marc
authors.initials: M
authors.lastname: Fiszman
authors.forename: John
authors.initials: J
authors.lastname: Ross
authors.forename: Ketty
authors.initials: K
authors.lastname: Schwartz
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004452:Echocardiography; D006346:Heart Septum; D006579:Heterozygote; D006720:Homozygote; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C