ArticleHuman genetics2010
Allele-specific recognition of the 3' splice site of INS intron 1.
Article in Human genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 24 citations in OpenAlex.
- The splicing auxiliary factor OsU2AF35a enhances thermotolerance via protein separation and promoting proper splicing of OsHSA32 pre-mRNA in rice.Plant biotechnology journal · 2025Article
- Understanding Insulin in the Age of Precision Medicine and Big Data: Under-Explored Nature of Genomics.Biomolecules · 2023Review
- Restriction of an intron size en route to endothermy.Nucleic acids research · 2021Article
- Article
- Thioflavin T Monitoring of Guanine Quadruplex Formation in the rs689-Dependent INS Intron 1.Molecular therapy. Nucleic acids · 2019Article
- PUF60-activated exons uncover altered 3' splice-site selection by germline missense mutations in a single RRM.Nucleic acids research · 2018Article
- Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes.Genome research · 2017Article
- Stoichiometries of U2AF35, U2AF65 and U2 snRNP reveal new early spliceosome assembly pathways.Nucleic acids research · 2017Article
- Alternative splicing of U2AF1 reveals a shared repression mechanism for duplicated exons.Nucleic acids research · 2017Article
- Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival.PLoS genetics · 2016Article
- Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting.Scientific reports · 2016Article
- Identification of U2AF(35)-dependent exons by RNA-Seq reveals a link between 3' splice-site organization and activity of U2AF-related proteins.Nucleic acids research · 2015Article
- The role of short RNA loops in recognition of a single-hairpin exon derived from a mammalian-wide interspersed repeat.RNA biology · 2015Article
- Optimal antisense target reducing INS intron 1 retention is adjacent to a parallel G quadruplex.Nucleic acids research · 2014Article
- BRCA1 exon 11 a model of long exon splicing regulation.RNA biology · 2014Article
- Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes.Nature genetics · 2011Article
- Compensatory signals associated with the activation of human GC 5' splice sites.Nucleic acids research · 2011Article
- AG-dependent 3'-splice sites are predisposed to aberrant splicing due to a mutation at the first nucleotide of an exon.Nucleic acids research · 2011Article
- Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic predisposition to type 1 diabetes (T1D) has been associated with a chromosome 11 locus centered on the proinsulin gene (INS) and with differential steady-state levels of INS RNA from T1D-predisposing and -protective haplotypes. Here, we show that the haplotype-specific expression is determined by INS variants that control the splicing efficiency of intron 1. The adenine allele at IVS1-6 (rs689), which rapidly expanded in modern humans, renders the 3' splice site of this intron more dependent on the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF). This interaction required both zinc fingers of the 35-kD U2AF subunit (U2AF35) and was associated with repression of a competing 3' splice site in INS exon 2. Systematic mutagenesis of reporter constructs showed that intron 1 removal was facilitated by conserved guanosine-rich enhancers and identified additional splicing regulatory motifs in exon 2. Sequencing of intron 1 in primates revealed that relaxation of its 3' splice site in Hominidae coevolved with the introduction of a short upstream open reading frame, providing a more efficient coupled splicing and translation control. Depletion of SR proteins 9G8 and transformer-2 by RNA interference was associated with exon 2 skipping whereas depletion of SRp20 with increased representation of transcripts containing a cryptic 3' splice site in the last exon. Together, these findings reveal critical interactions underlying the allele-dependent INS expression and INS-mediated risk of T1D and suggest that the increased requirement for U2AF35 in higher primates may hinder thymic presentation of autoantigens encoded by transcripts with weak 3' splice sites.
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