Journal Article

Nuclear sequestration of δ-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes

Ahlke Heydemann, Alexis Demonbreun, Michele Hadhazy, Judy U. Earley and Elizabeth M. McNally

in Human Molecular Genetics

Volume 16, issue 4, pages 355-363
Published in print February 2007 | ISSN: 0964-6906
Published online December 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl453
Nuclear sequestration of δ-sarcoglycan disrupts the nuclear localization of lamin A/C and emerin in cardiomyocytes

Show Summary Details

Preview

Sarcoglycan is a membrane-associated protein complex found at the plasma membrane of cardiomyocytes and skeletal myofibers. Recessive mutations of δ-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 δ-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 δ-sarcoglycan mutation in the heart using the α-myosin heavy-chain gene promoter. Similar to the human δ-sarcoglycan gene mutation, S151A δ-sarcoglycan transgenic mice developed dilated cardiomyopathy at a young age with enhanced lethality. Instead of placement at the plasma membrane, δ-sarcoglycan was found in the nucleus of S151A δ-sarcoglycan cardiomyocytes. Retention of δ-sarcoglycan in the nucleus was accompanied by partial nuclear sequestration of β- and γ-sarcoglycan. Additionally, the nuclear-membrane-associated proteins, lamin A/C and emerin, were mislocalized throughout the nucleoplasm. Therefore, the S151A δ-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.

Journal Article.  5463 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.