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 produce cardiac and skeletal muscle dysfunction referred to as Emery Dreifuss muscular dystrophy. Lamins A and C 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 C-terminus of nesprin-1 was 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 exhibit lethality with approximately half dying at or near birth from respiratory failure. Surviving mice display hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology and cardiac conduction defects develop. The protein components of the LINC complex, including mutant nesprin-1alpha, lamin A/C and SUN2, are localized at the nuclear membrane in this model. However, the LINC components do not normally associate since coimmunoprecipitation experiments with SUN2 and nesprin reveal that mutant nesprin-1 protein no longer interacts with SUN2. These findings demonstrate the role of the LINC complex, and nesprin-1, in neuromuscular and cardiac disease.
Puckelwartz
Megan J
MJ
Department of Human Genetics, Washington University, St Louis, MO, USA.
Kessler
Eric
E
Zhang
Yuan
Y
Hodzic
Didier
D
Randles
K Natalie
KN
Morris
Glenn
G
Earley
Judy U
JU
Hadhazy
Michele
M
Holaska
James M
JM
Mewborn
Stephanie K
SK
Pytel
Peter
P
McNally
Elizabeth M
EM
D000818:Animals; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D003598:Cytoskeletal Proteins; D034882:Lamins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C485901:Syne1 protein, mouse