title: An LKB1 AT-AC intron mutation causes Peutz-Jeghers syndrome via splicing at noncanonical cryptic splice sites.
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.
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hastings
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.forename: Daniel
authors.initials: D
authors.lastname: Traum
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stella
authors.forename: Ginevra
authors.initials: G
authors.lastname: Guanti
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010580:Peutz-Jeghers Syndrome / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism
chemical_list: D022821:RNA Splice Sites; D012333:RNA, Messenger; D012342:RNA, Small Nuclear; C096986:U12 small nuclear RNA; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases