Abstract 1431: Disruption of Nesprin-1 Produces an Emery Dreifuss Muscular Dystrophy-like Phenotype in Mice
Mutations in the gene encoding the inner nuclear membrane proteins lamins A and C, LMNA, produce cardiac and skeletal muscle dysfunction. LMNA mutations most commonly produce cardiomyopathy with cardiac conduction system defects and muscle weakness. Cardiac and skeletal involvement is progressive and together, the phenotype is referred to as Emery Dreifuss muscular dystrophy. Lamins A and C are intermediate filament proteins that participate in the LINC complex that, along with the nesprin and SUN proteins, LInk the Nucleoskeleton with the Cytoskeleton. Nesprins 1 and 2 are giant spectrin-repeat containing proteins that have large and small forms. The nesprins contain a transmembrane anchor that tethers to the nuclear membrane followed by a short domain that resides within the lumen between the inner and outer nuclear membrane. Nesprin’s luminal domain binds directly to SUN proteins. We generated mice where the carboxyl terminus of nesprin-1 had been deleted. This strategy produced a protein lacking the transmembrane and luminal domains that together are referred to as the KASH domain. Mice homozygous for this mutation are born in non-Mendelian ratios with approximately half dying at birth from respiratory failure. Surviving female mice are smaller than their littermates (p<0.0001) and display hindlimb weakness and an abnormal gate that is evident on rotorod testing. With age, kyphoscoliosis and cardiac conduction defects develop. Of note, the protein components of the LINC complex remain at the nuclear membrane in this model similar to what is seen in Emery Dreifuss muscular dystrophy. Specifically, lamin A/C, SUN2 and LAP2 are found normally localized at the inner nuclear membrane. Nesprin-1α lacking the KASH domain is also normally localized at the nuclear membrane. We conclude that KASH-less nesprin-1 retains normal lamin interaction and prohibits nesprin-2 from substituting. Specifically, the nesprin-1 interaction with SUN is disrupted given the absence of the KASH domain. These findings demonstrate the role of the LINC complex, and nesprin-1, in cardiac and muscle disease.