Human Molecular Genetics Advance Access published online on December 12, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl453
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© The Author 2006. Published by Oxford University Press. All rights reserved
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 3 Department of Human Genetics, The University of Chicago, Chicago 60637, USA
* Correspondence: E. M. McNally, M.D., Ph.D. 5841 S. Maryland, MC6088 Chicago, Il 60637 T: 773 702 2672 F: 773 702 2681 Email: emcnally{at}medicine.bsd.uchicago.edu
Received October 4, 2006; Revised November 29, 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 instead found in the nucleus of S151A -sarcoglycan cardiomyocytes. Retention of -sarcoglycan in the nucleus was accompanied by partial nuclear sequestration of ß-sarcoglycan and 
-sarcoglycan. Additionally, the nuclear membrane-associated proteins, emerin and lamin A/C, 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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