Published Online
on December 31, 2008

A more recent version of this article appeared on January 20, 2009

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Submitted on June 15, 2008
Accepted on October 14, 2008

Disruption of Striated Preferentially Expressed Gene Locus Leads to Dilated Cardiomyopathy in Mice

Xiaoli Liu MD, PhD, Tripurasundari Ramjiganesh PhD, Yen-Hsu Chen MD, PhD, Su Wol Chung PhD, Sean R. Hall PhD, Scott L. Schissel MD, PhD, Robert F. Padera Jr MD, PhD, Ronglih Liao PhD, Kate G. Ackerman MD, Jan Kajstura PhD, Annarosa Leri MD, Piero Anversa MD, Shaw-Fang Yet PhD, Matthew D. Layne PhD, and Mark A. Perrella MD^*

From Pulmonary and Critical Care Medicine (X.L., T.R., S.W.C., S.R.H., S.L.S., M.A.P.), Newborn Medicine (M.A.P.), Department of Pathology (R.F.P.), Department of Anesthesia (J.K., A.L., P.A.) and Cardiovascular Division (R.L., J.K., A.L., P.A.), Brigham and Women's Hospital, and Harvard Medical School (X.L., T.R., S.W.C., S.R.H., S.L.S., M.A.P., R.L., J.K., A.L., P.A.), Boston, Mass; Division of Health Sciences and Technology (R.F.P.), Harvard-MIT, Boston, Mass; Division of Infectious Diseases (Y.-H.C.), Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Biological Science and Technology (S.W.C.), College of Natural Sciences, University of Ulsan, Ulsan, South Korea; Department of Pediatrics (K.G.A.), University of Rochester, Rochester, NY; Cardiovascular and Blood Medical Research Center (S.-F.Y.), National Health Research Institutes, Zhunan Town, Taiwan; and Boston University School of Medicine (M.D.L.), Department of Biochemistry, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: mperrella{at}rics.bwh.harvard.edu.

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. -Galactosidase activity was detected in cardiomyocytes of the developing heart starting at day 11.5 days post coitum (dpc). -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 Speg and Speg 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.

Key words: cardiomyopathy • hypertrophy • myocytes • genes

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