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Disruption of striated preferentially expressed gene locus leads to dilated cardiomyopathy in mice.

BACKGROUND: The striated preferentially expressed gene (Speg) generates 4 different isoforms through alternative promoter use and tissue-specific splicing. Depending on the cell type, Speg isoforms may serve as markers of striated or smooth muscle differentiation. METHODS AND RESULTS: To elucidate function of Speg gene isoforms, we disrupted the Speg gene locus in mice by replacing common exons 8, 9, and 10 with a lacZ gene. beta-Galactosidase activity was detected in cardiomyocytes of the developing heart starting at day 11.5 days post coitum (dpc). beta-Galactosidase activity in other cell types, including vascular smooth muscle cells, did not begin until 18.5 dpc. In the developing heart, protein expression of only Spegalpha and Spegbeta isoforms was present in cardiomyocytes. Homozygous Speg mutant hearts began to enlarge by 16.5 dpc, and by 18.5 dpc, they demonstrated dilation of right and left atria and ventricles. These cardiac abnormalities in the absence of Speg were associated with a cellular hypertrophic response, myofibril degeneration, and a marked decrease in cardiac function. Moreover, Speg mutant mice exhibited significant neonatal mortality, with increased death occurring by 2 days after birth. CONCLUSIONS: These findings demonstrate that mutation of the Speg locus leads to cardiac dysfunction and a phenotype consistent with a dilated cardiomyopathy.

Pubmed ID: 19118250

Authors

  • Liu X
  • Ramjiganesh T
  • Chen YH
  • Chung SW
  • Hall SR
  • Schissel SL
  • Padera RF
  • Liao R
  • Ackerman KG
  • Kajstura J
  • Leri A
  • Anversa P
  • Yet SF
  • Layne MD
  • Perrella MA

Journal

Circulation

Publication Data

January 20, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM53249
  • Agency: NHLBI NIH HHS, Id: HL60788
  • Agency: NHLBI NIH HHS, Id: HL65639
  • Agency: NHLBI NIH HHS, Id: K08 HL076286
  • Agency: NIGMS NIH HHS, Id: R01 GM053249
  • Agency: NIGMS NIH HHS, Id: R01 GM053249-10
  • Agency: NIGMS NIH HHS, Id: R01 GM053249-11
  • Agency: NIGMS NIH HHS, Id: R01 GM053249-12
  • Agency: NHLBI NIH HHS, Id: R01 HL060788
  • Agency: NHLBI NIH HHS, Id: R01 HL060788-09
  • Agency: NHLBI NIH HHS, Id: R01 HL060788-10
  • Agency: NHLBI NIH HHS, Id: R01 HL060788-11
  • Agency: NHLBI NIH HHS, Id: R01 HL065639
  • Agency: NHLBI NIH HHS, Id: R01 HL065639-03
  • Agency: NHLBI NIH HHS, Id: R01 HL065639-04
  • Agency: NHLBI NIH HHS, Id: R01 HL065639-05
  • Agency: NHLBI NIH HHS, Id: R01 HL102897

Mesh Terms

  • Animals
  • Animals, Newborn
  • Cardiomyopathy, Dilated
  • Gene Targeting
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muscle Proteins
  • Mutagenesis, Site-Directed
  • Myosin-Light-Chain Kinase