title: Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity.
abstract: Dilated cardiomyopathy (DCM) associates left ventricular (LV) dilatation and systolic dysfunction and is a major cause of heart failure and cardiac transplantation. LMNA gene encodes lamins A/C, proteins of the nuclear envelope. LMNA mutations cause DCM with conduction and/or rhythm defects. The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(ΔK32/+) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic ΔK32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac remodelling. In older hearts, when DCM has developed, the lamin A/C level was normalized and associated with increased toxic ΔK32-lamin expression. Crossing our mice with the Ub(G76V)-GFP ubiquitin-proteasome system (UPS) reporter mice revealed a heart-specific UPS impairment in Het. While UPS impairment itself has a clear deleterious effect on engineered heart tissue's force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of ΔK32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our data provide evidence that Het cardiomyocytes have to deal with major dilemma: mutant lamin A/C degradation or normalization of lamin level to fight the deleterious effect of lamin haploinsufficiency, both leading to DCM.
authors.affiliation: Inserm, U974, Paris F-75013, France.
authors.forename: Marie-Elodie
authors.initials: ME
authors.lastname: Cattin
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bertrand
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Le Bihan
authors.forename: Søren
authors.initials: S
authors.lastname: Skov Jensen
authors.forename: Christiane
authors.initials: C
authors.lastname: Neuber
authors.forename: Claudia
authors.initials: C
authors.lastname: Crocini
authors.forename: Sophia
authors.initials: S
authors.lastname: Maron
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.forename: Shaïda
authors.initials: S
authors.lastname: Varnous
authors.forename: Yves
authors.initials: Y
authors.lastname: Fromes
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Valérie
authors.initials: V
authors.lastname: Decostre
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D057895:Haploinsufficiency; D006579:Heterozygote; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex