Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity

TY - JOUR

T1 - Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity

AU - Cattin, Marie-Elodie

AU - Bertrand, Anne T

AU - Schlossarek, Saskia

AU - Le Bihan, Marie-Catherine

AU - Skov Jensen, Søren

AU - Neuber, Christiane

AU - Crocini, Claudia

AU - Maron, Sophia

AU - Lainé, Jeanne

AU - Mougenot, Nathalie

AU - Varnous, Shaïda

AU - Fromes, Yves

AU - Hansen, Arne

AU - Eschenhagen, Thomas

AU - Decostre, Valérie

AU - Carrier, Lucie

AU - Bonne, Gisèle

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cardiomyopathy, Dilated

KW - Cell Nucleus

KW - Disease Models, Animal

KW - Disease Progression

KW - Female

KW - Haploinsufficiency

KW - Heterozygote

KW - Lamin Type A

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Muscle, Skeletal

KW - Mutation

KW - Myocardial Contraction

KW - Myocardium

KW - Myocytes, Cardiac

KW - Phenotype

KW - Proteasome Endopeptidase Complex

KW - Proteolysis

KW - Ubiquitin

U2 - 10.1093/hmg/ddt172

DO - 10.1093/hmg/ddt172

M3 - SCORING: Journal article

C2 - 23575224

VL - 22

SP - 3152

EP - 3164

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 15

ER -