Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance.
X-linked Emery-Dreifuss muscular dystrophy is caused by loss of function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy; this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle, and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from littermate controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms.
Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA; Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA.
Ji-Yeon
JY
Shin
Iván
I
Méndez-López
Yuexia
Y
Wang
Arthur P
AP
Hays
Kurenai
K
Tanji
Jay H
JH
Lefkowitch
P Christian
PC
Schulze
Howard J
HJ
Worman
William T
WT
Dauer
D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D048008:TNF Receptor-Associated Factor 3; C486250:TOR1AIP1 protein, human; C092710:emerin