Human Molecular Genetics Advance Access originally published online on July 13, 2005
Human Molecular Genetics 2005 14(16):2459-2468; doi:10.1093/hmg/ddi246
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Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN
1Clinical Cancer Genetics Program, Human Cancer Genetics Program, Comprehensive Cancer Center, 2Department of Molecular Virology, Immunology and Medical Genetics and 3Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA, 4Genomic Medicine Institute, Cleveland Clinic Lerner College of Medicine, Department of Genetics, Case Western Reserve University, Cleveland, OH, USA and 5Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK
* To whom correspondence should be addressed at: Genomic Medicine Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, No. NE-40, Cleveland, OH 44195, USA. Tel: +1 216 444 3440; Email: engc{at}ccf.org or spsmce{at}netscape.net
Received May 17, 2005; Accepted July 5, 2005
PTEN, encoding a dual phosphatase tumor suppressor, is mutated in 85 and 65% of individuals with Cowden syndrome (CS) and Bannayan–Riley–Ruvalcaba syndrome (BRRS), respectively. Approximately 23 germline mutations in putative splice sites have been published, but resulting downstream outcome data are limited. We determined splicing defects in PTEN in 40 germline PTEN mutation positive cases and 33 mutation negative cases with classic CS, BRRS and CS- or BRRS-like features. Altered splicing was observed in 4/40 mutation positive probands and 2/33 mutation negative probands. We then sought to characterize the transcriptional and biochemical outcomes of the five distinct splice-site mutations, which led to the skipping of exon 3, 4 or 6. Two mutation negative BRRS patients also showed exon 3 skipping, and later, genomic sequencing revealed a mutation deep in intron 2. The splice-site mutations leading to the deletions of exon 3, 4 or 6 resulted in reduced dual phosphatase activities of PTEN. Deletion of exon 4 was associated with severely reduced lipid phosphatase activity, whereas exon 3 skipping resulted in markedly reduced protein phosphatase activity. In addition, exon 3 deleted transcript and protein were stable and localized to the nucleus more efficiently than the wild-type PTEN. In contrast, exon 4 skipping resulted in unstable transcripts and severely truncated unstable PTEN protein lacking its phosphatase domain. We have not only described for the first time, the effect of a deep intronic/branch-site mutation on exon skipping in PTEN but also found that different splice-site mutations resulting in the deletion of different exons lead to distinct outcomes.
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