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An LKB1 AT-AC intron mutation causes Peutz-Jeghers syndrome via splicing at noncanonical cryptic splice sites

Nature Structural & Molecular Biology volume 12, pages 5459 (2005) | Download Citation

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Abstract

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder associated with gastrointestinal polyposis and an increased cancer risk. PJS is caused by germline mutations in the tumor suppressor gene LKB1. One such mutation, IVS2+1A>G, alters the second intron 5′ splice site, which has sequence features of a U12-type AT-AC intron. We report that in patients, LKB1 RNA splicing occurs from the mutated 5′ splice site to several cryptic, noncanonical 3′ splice sites immediately adjacent to the normal 3′ splice site. In vitro splicing analysis demonstrates that this aberrant splicing is mediated by the U12-dependent spliceosome. The results indicate that the minor spliceosome can use a variety of 3′ splice site sequences to pair to a given 5′ splice site, albeit with tight constraints for maintaining the 3′ splice site position. The unusual splicing defect associated with this PJS-causing mutation uncovers differences in splice-site recognition between the major and minor pre-mRNA splicing pathways.

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Acknowledgements

This work was supported by US National Institutes of Health grant GM42699 (A.R.K.) and MIUR-FIRB RBAU01SZHB-001 (G.G.). M.L.H. was supported by an American Cancer Society postdoctoral fellowship. We thank L. Manche and A. Quagliarella for technical assistance.

Author information

Author notes

    • Michelle L Hastings
    •  & Nicoletta Resta

    These authors contributed equally to this work.

Affiliations

  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.

    • Michelle L Hastings
    •  & Adrian R Krainer
  2. Sezione Genetica Medica DIMIMP, Università di Bari, Piazza G. Cesare 11, 70124 Bari, Italy.

    • Nicoletta Resta
    • , Alessandro Stella
    •  & Ginevra Guanti
  3. Stony Brook University, Graduate Program in Genetics, Stony Brook, New York 11794, USA.

    • Daniel Traum

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The authors declare no competing financial interests.

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Correspondence to Adrian R Krainer.

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DOI

https://doi.org/10.1038/nsmb873

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