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Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1839-1850; doi:10.1093/hmg/ddi190
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma

Catherine Wilson1, Shelley Idziaszczyk1, Lee Parry1, Carol Guy1, David F.R. Griffiths2, Edward Lazda2, Rosemary A.L. Bayne3,{dagger}, Andrew J.H. Smith3, Julian R. Sampson1 and Jeremy P. Cheadle1,*

1Department of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK, 2Department of Pathology, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK and 3Gene Targeting Laboratory, Institute for Stem Cell Research, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JQ, UK

* To whom correspondence should be addressed. Tel: +44 2920742652; Fax: +44 2920746551; Email: cheadlejp{at}cardiff.ac.uk

Received March 17, 2005; Accepted May 6, 2005

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or the TSC2 genes and characterized by the development of benign hamartomatous growths in multiple organ systems. We have inactivated Tsc1 in the mouse germ line by gene targeting in ES cells and confirmed that the mutant allele (Tsc1–) has a recessive embryonic lethal phenotype. We found that a significant number (~27%) of heterozygous (Tsc1+/–) mice on the C57BL/6 background died before weaning (P=0.014) and show that these mice die in the post-natal period (P=0.033), normally at 1–2 days, from unknown causes. Forty-four percent (7/16) of Tsc1+/– mice on a C3H background developed macroscopically visible renal lesions as early as 3–6 months, increasing to 95% (37/39) by 15–18 months. Renal lesions progressed from cysts through cystadenomas to solid carcinomas. Eighty percent (16/20) of Tsc1+/– mice on a Balb/c background exhibited solid renal cell carcinomas (RCC) by 15–18 months and in 41%, RCCs were ≥5 mm, resulting in grossly deformed kidneys. Some RCCs had a sarcomatoid morphology of spindle cells in whorled patterns and metastasized to the lungs. We detected loss of the wild-type Tsc1 allele and elevated levels of p-mTOR and p-S6 in lesions from Tsc1+/– mice. This new murine model of hamartin deficiency exhibits a more severe phenotype than existing models.

{dagger} Present address: MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.


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