Human Molecular Genetics Advance Access originally published online on December 12, 2006
Human Molecular Genetics 2007 16(4):355-363; doi:10.1093/hmg/ddl453
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Nuclear sequestration of 
-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes
1 Department of Medicine, Section of Cardiology, 2 Committee on Developmental Biology and 3 Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
* To whom correspondence should be addressed at: 5841 S. Maryland, MC6088, Chicago, IL 60637, USA. Tel: +1 7737022672; Fax: +1 7737022681; Email: emcnally{at}medicine.bsd.uchicago.edu
Received October 4, 2006; Accepted November 29, 2006
Sarcoglycan is a membrane-associated protein complex found at the plasma membrane of cardiomyocytes and skeletal myofibers. Recessive mutations of 
-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 -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 -sarcoglycan mutation in the heart using the 
-myosin heavy-chain gene promoter. Similar to the human -sarcoglycan gene mutation, S151A -sarcoglycan transgenic mice developed dilated cardiomyopathy at a young age with enhanced lethality. Instead of placement at the plasma membrane, -sarcoglycan was found in the nucleus of S151A -sarcoglycan cardiomyocytes. Retention of -sarcoglycan in the nucleus was accompanied by partial nuclear sequestration of ß- and 
-sarcoglycan. Additionally, the nuclear-membrane-associated proteins, lamin A/C and emerin, were mislocalized throughout the nucleoplasm. Therefore, the S151A -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.
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