Nuclear sequestration of delta-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes.
Sarcoglycan is a membrane-associated protein complex found at the plasma membrane of cardiomyocytes and skeletal myofibers. Recessive mutations of delta-sarcoglycan that eliminate expression, and therefore function, lead to cardiomyopathy and muscular dystrophy by producing instability of the plasma membrane. A dominant missense mutation in the gene encoding delta-sarcoglycan was previously shown to associate with dilated cardiomyopathy in humans. To investigate the mechanism of dominantly inherited cardiomyopathy, we generated transgenic mice that express the S151A delta-sarcoglycan mutation in the heart using the alpha-myosin heavy-chain gene promoter. Similar to the human delta-sarcoglycan gene mutation, S151A delta-sarcoglycan transgenic mice developed dilated cardiomyopathy at a young age with enhanced lethality. Instead of placement at the plasma membrane, delta-sarcoglycan was found in the nucleus of S151A delta-sarcoglycan cardiomyocytes. Retention of delta-sarcoglycan in the nucleus was accompanied by partial nuclear sequestration of beta- and gamma-sarcoglycan. Additionally, the nuclear-membrane-associated proteins, lamin A/C and emerin, were mislocalized throughout the nucleoplasm. Therefore, the S151A delta-sarcoglycan gene mutation acts in a dominant negative manner to produce trafficking defects that disrupt nuclear localization of lamin A/C and emerin, thus linking together two common mechanisms of inherited cardiomyopathy.
Heydemann
Ahlke
A
Department of Medicine, Section of Cardiology, The University of Chicago, Chicago, IL 60637, USA.
Demonbreun
Alexis
A
Hadhazy
Michele
M
Earley
Judy U
JU
McNally
Elizabeth M
EM
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D034904:Lamin Type A / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism
D034904:Lamin Type A; D008565:Membrane Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; D049031:Sarcoglycans; C092710:emerin; C440308:lamin C