Human Molecular Genetics Advance Access published online on April 7, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn098
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Bladder tumour derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms
Cancer Research UK Clinical Centre in Leeds, Leeds Institute for Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom
* To whom correspondence should be addressed at: Cancer Research UK Clinical Centre in Leeds, Leeds Institute for Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, United Kingdom Tel. +44 (0)113 206 4913; Fax: +44(0)1132429886; E-mail m.a.knowles{at}leeds.ac.uk
Received February 4, 2008; Revised March 25, 2008; Accepted March 25, 2008
More than 50% of transitional cell carcinomas of the bladder show loss of heterozygosity (LOH) of a region spanning the TSC1 locus at 9q34 and mutations of TSC1 have been identified in 14.5% of tumours. These comprise nonsense mutations, splicing mutations, small-deletions and missense mutations. Missense mutations are only rarely found in the germline in TSC disease. Therefore we have examined 6 somatic missense mutations found in bladder cancer to determine whether these result in loss of function. We describe loss of function via distinct mechanisms. Five mutations caused mutually exclusive defects at mRNA and protein levels. Of these, two mutations caused pre-mRNA splicing errors that were predicted to result in premature protein truncation and three resulted in markedly reduced stability of exogenous TSC1 protein. Primary tumours with aberrant TSC1 pre-mRNA splicing were confirmed as negative for TSC1 expression by immunohistochemistry. Expression was also significantly reduced in a tumour with a TSC1 missense mutation resulting in diminished protein half-life. A single TSC1 missense mutation identified in a tumour with retained heterozygosity of the TSC1 region on chromosome 9 caused an apparently TSC2- and mTOR-independent localisation defect of the mutant protein. We conclude that although TSC1 missense mutations do not play a major role in causation of TSC disease, they represent a significant proportion of somatic loss of function mutations in bladder cancer.
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