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.
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