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
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Li, C. Long, Y. Yue, and D. Duan Sub-physiological sarcoglycan expression contributes to compensatory muscle protection in mdx mice Hum. Mol. Genet., April 1, 2009; 18(7): 1209 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Luk, E Ahn, G S Soor, and J Butany Dilated cardiomyopathy: a review J. Clin. Pathol., March 1, 2009; 62(3): 219 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Allikian, G. Bhabha, P. Dospoy, A. Heydemann, P. Ryder, J. U. Earley, M. J. Wolf, H. A. Rockman, and E. M. McNally Reduced life span with heart and muscle dysfunction in Drosophila sarcoglycan mutants Hum. Mol. Genet., December 1, 2007; 16(23): 2933 - 2943. [Abstract] [Full Text] [PDF]
|
|