G.P.122 Heterozygous LmnadelK32 mutant mice showed alterations of the ubiquitin–proteasome system and developed dilated cardiomyopathy

• Published in: Neuromuscular disorders : NMD Vol. 22; no. 9; p. 903
• Main Authors: Cattin, M.E, Schlossarek, S, Decostre, V, Maron, S, Skov Jensen, S, Le Bihan, M.C, Bertand, A.T, Crocini, C, Lainé, J, Mougenot, N, Varnous, S, Fromes, Y, Hansen, A, Eschenhagen, T, Carrier, L, Bonne, G
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2012
• Subjects: Indexing in process; Neurology
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2012.06.328

Abstract Mutations of LMNA gene give rise to a range of muscular dystrophies associated with dilated cardiomyopathy (DCM) and conduction and/or rhythm defects. LMNA encodes lamin A/C, nuclear envelope proteins that form a meshwork beneath the inner nuclear membrane. The pathomechanisms linking LMNA mutations to muscular and cardiac diseases remain to be elucidated. We created the LmnaΔK32 knock-in mouse, mutation associated with congenital muscular dystrophy in humans. The heterozygous LmnaΔK32/+ mice (Het) showed neither skeletal muscle nor rhythm/conduction defects. But they progressively developed cardiac dysfunction and DCM, and died between 35 and 70 weeks of age. Lamin A/C showed similar nuclear rim localization in Het and Wt hearts. The evolution of DCM was associated with a modulation of cardiac lamin A/C protein level. Before the development of DCM, lamin A/C protein level was 50% lower in Het than Wt hearts whereas it did not differ between the two groups thereafter. This difference in lamin A/C cardiac content was due to ΔK32-lamin degradation via the ubiquitin–proteasome system (UPS), leading to very low level of Δ K32-lamin in Het hearts (7.5% of total lamin A/C content). The function of the UPS was assessed in vivo by crossing our mice with UbG76V-GFP transgenic mice, expressing a UPS reporter substrate. Levels of UbG76V-GFP proteins were 2-fold higher in Het than in Wt mice, showing the global impairment of UPS in the heart of Het mice. After gene transfer in rat engineered heart tissue and treatment with proteasome inhibitor, ΔK32-lamin formed nuclear aggregates and impaired contractile function, suggesting a poison peptide effect. The LmnaΔK32/+ mice are the first knock-in Lmna model with a cardiac-specific phenotype at the heterozygous state. They represent a valuable tool for studying dominant LMNA-related DCM. Our data provide evidence that degradation of ΔK32-lamin A/C is a protective process, limiting the dominant negative effect on cardiac function.