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Human Molecular Genetics Advance Access published online on December 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi039
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Human Molecular Genetics © Oxford University Press 2004; all rights reserved

Article

A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes

Lynsey Meikle 1, Julie R. McMullen 2, Megan C. Sherwood 3, Alan S. Lader 1, Victoria Walker 1, Jennifer A. Chan 4, and David J. Kwiatkowski 5*

1 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
2 Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02215
3 Department of Cardiology, Children's Hospital; Department of Pediatrics, Harvard Medical School, Boston, MA 02115
4 Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital and Children's Hospital, Boston, MA 02115
5 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Genetics Laboratory, Hematology, BWH, One Blackfan Circle, 6th flr, Rm.216, Boston, MA 02115

* To whom correspondence should be addressed.
David J. Kwiatkowski, E-mail: dk{at}rics.bwh.harvard.edu


  Abstract

Tuberous sclerosis is a hamartoma syndrome due to mutations in TSC1 or TSC2 in which cardiac rhabdomyomas are seen in about 60% of patients. These lesions have an unusual natural history as they are usually most prominent immediately after birth, and spontaneously resolve in most cases. To develop a mouse model of this lesion, we used a conditional, floxed allele of Tsc1 and a modified myosin light chain 2v allele in which cre recombinase expression occurs in ventricular myocytes. Mice with ventricular loss of Tsc1 had a median survival of 6 months, and developed a dilated cardiomyopathy with the occurrence of scattered foci of enlarged ventricular myocytes. The enlarged cells were periodic acid-Schiff positive indicating the presence of excess glycogen and expressed elevated levels of phospho-S6, similar to findings in patient rhabdomyoma cells. The observations confirm that rhabdomyomas occur through a two hit mechanism of pathogenesis. However, the mice showed no evidence of fetal/neonatal demise, and there was no evidence of proliferation in the lesions. We propose that these differences are due to the timing of loss of Tsc1 in the ventricular myocytes and/or the truncated gestational period in the mouse compared to humans, during which progestational hormones may accentuate the growth of patient rhabdomyomas.


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