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

Hastings, M. L., Resta, N., Traum, D., Stella, A., Guanti, G., Krainer, A. R. (January 2005) An LKB1 AT-AC intron mutation causes Peutz-Jeghers syndrome via splicing at noncanonical cryptic splice sites. Nat Struct Mol Biol, 12 (1). pp. 54-9. ISSN 1545-9993 (Print)

DOI: 10.1038/nsmb873


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.

Item Type: Paper
Uncontrolled Keywords: Alternative Splicing genetics Base Sequence Female Humans Introns genetics Male Molecular Sequence Data Mutation genetics Pedigree Peutz-Jeghers Syndrome genetics Protein-Serine-Threonine Kinases genetics RNA Splice Sites genetics RNA Messenger genetics/metabolism RNA, Small Nuclear genetics/metabolism Spliceosomes genetics/metabolism IVS2+1A>G LKB1
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders > mental disorders > genetic disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: CSHL Librarian
Date: January 2005
Date Deposited: 13 Jan 2012 15:44
Last Modified: 09 Apr 2014 16:16
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