Human Molecular Genetics Advance Access originally published online on December 15, 2004
Human Molecular Genetics 2005 14(3):429-435; doi:10.1093/hmg/ddi039
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved
A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes
1Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, 2Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA, 3Department of Cardiology, Children's Hospital; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA and 4Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital and Children's Hospital, Boston, MA 02115, USA
* To whom correspondence should be addressed at: Genetics Laboratory, Hematology, BWH, One Blackfan Circle, 6th Floor, Room 216, Boston, MA 02115, USA. Tel: +1 6173559005; Fax: +1 6173559016; Email: dk{at}rics.bwh.harvard.edu
Received September 24, 2004; Revised November 29, 2004; Accepted December 6, 2004
Tuberous sclerosis is a hamartoma syndrome due to mutations in TSC1 or TSC2 in which cardiac rhabdomyomas are seen in 
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 with humans, during which progestational hormones may accentuate the growth of patient rhabdomyomas.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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