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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi190
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 17, 2005
Revised May 6, 2005
Accepted May 6, 2005

Article

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

Catherine Wilson 1, Shelley Idziaszczyk 1, Lee Parry 1, Carol Guy 1, David F.R. Griffiths 2, Edward Lazda 2, Rosemary A.L. Bayne 3, Andrew J.H. Smith 3, Julian R. Sampson 1, and Jeremy P. Cheadle 4*

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

* To whom correspondence should be addressed.
Jeremy P. Cheadle, E-mail: cheadlejp{at}cardiff.ac.uk


  Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutation in either the TSC1 or TSC2 genes and characterised 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.


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