Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN

被引:34
作者
Agrawal, S
Pilarski, R
Eng, C
机构
[1] Univ Cambridge, Canc Res UK Human Canc Genet Res Grp, Cambridge, England
[2] Case Western Reserve Univ, Dept Genet, Cleveland Clin, Lerner Coll Med,Genom Med Inst, Cleveland, OH 44106 USA
[3] Ohio State Univ, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA
[4] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[5] Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Clin Canc Genet Program, Columbus, OH 43210 USA
关键词
D O I
10.1093/hmg/ddi246
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页码:2459 / 2468
页数:10
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