| First Author | Heydemann A | Year | 2007 |
| Journal | Hum Mol Genet | Volume | 16 |
| Issue | 4 | Pages | 355-63 |
| PubMed ID | 17164264 | Mgi Jnum | J:117855 |
| Mgi Id | MGI:3697807 | Doi | 10.1093/hmg/ddl453 |
| Citation | Heydemann A, et al. (2007) Nuclear sequestration of {delta}-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes. Hum Mol Genet 16(4):355-63 |
| abstractText | 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. |
