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, Elizabeth M. McNally*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)355-363
Number of pages9
JournalHuman molecular genetics
Issue number4
StatePublished - Feb 15 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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