Allele-specific recognition of the 3′ splice site of INS intron 1

• DOI: 10.1007/s00439-010-0860-1
• Publication Date: 2010-07-13T13:05:06Z
• Authors: Jana Kralovicova; Igor Vorechovsky
• Keywords: Splice site mutation; Exon skipping; Exonic splicing enhancer

Genetic predisposition to type 1 diabetes (T1D) has been associated with a chromosome 11 locus centered on the proinsulin gene (INS) and differential steady-state levels of INS RNA from T1D-predisposing -protective haplotypes. Here, we show that haplotype-specific expression is determined by variants control splicing efficiency intron 1. The adenine allele at IVS1-6 (rs689), which rapidly expanded in modern humans, renders 3' splice site this more dependent auxiliary factor U2 small nuclear ribonucleoprotein (U2AF). This interaction required both zinc fingers 35-kD U2AF subunit (U2AF35) was repression competing exon 2. Systematic mutagenesis reporter constructs showed removal facilitated conserved guanosine-rich enhancers identified additional regulatory motifs Sequencing primates revealed relaxation its Hominidae coevolved introduction short upstream open reading frame, providing efficient coupled translation control. Depletion SR proteins 9G8 transformer-2 interference 2 skipping whereas depletion SRp20 increased representation transcripts containing cryptic last exon. Together, these findings reveal critical interactions underlying allele-dependent INS-mediated risk T1D suggest requirement for U2AF35 higher may hinder thymic presentation autoantigens encoded weak sites.