RGD Reference Report - Genetic control of alternative splicing in the TAP2 gene: possible implication in the genetics of type 1 diabetes. - Rat Genome Database

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Genetic control of alternative splicing in the TAP2 gene: possible implication in the genetics of type 1 diabetes.

Authors: Qu, HQ  Lu, Y  Marchand, L  Bacot, F  Frechette, R  Tessier, MC  Montpetit, A  Polychronakos, C 
Citation: Qu HQ, etal., Diabetes. 2007 Jan;56(1):270-5.
RGD ID: 2312368
Pubmed: PMID:17192492   (View Abstract at PubMed)
DOI: DOI:10.2337/db06-0865   (Journal Full-text)

The transporter 2, ATP-binding cassette, subfamily B (TAP2) is involved in the transport of antigenic peptides to HLA molecules. Coding TAP2 polymorphisms shows a strong association with type 1 diabetes, but it is not clear whether this association may be entirely due to linkage disequilibrium with HLA DR and DQ. Functionally, rat Tap2 nonsynonymous single-nucleotide polymorphisms (nsSNPs) confer differential selectivity for antigenic peptides, but this was not shown to be the case for human TAP2 nsSNPs. In the human, differential peptide selectivity is rather conferred by two splicing isoforms with alternative carboxy terminals. Here, we tested the hypothesis that alleles at the coding SNPs favor different splicing isoforms, thus determining peptide selectivity indirectly. This may be the basis for independent contribution to the type 1 diabetes association. In RNA from heterozygous lymphoblastoid lines, we measured the relative abundance of each SNP haplotype in each isoform. In isoform NM_000544, the G (Ala) allele at 665 Thr>Ala (rs241447) is more than twice as abundant as A (Thr) (GA = 2.2 +/- 0.4, P = 1.5 x 10(-4)), while isoform NM_018833 is derived almost exclusively from chromosomes carrying A (AG = 18.1 +/- 5.6, P = 2.04 x 10(-7)). In 889 Canadian children with type 1 diabetes, differential transmission of parental TAP2 alleles persisted (P = 0.011) when analysis was confined to chromosomes carrying only DQ*02 alleles, which mark a conserved DR-DQ haplotype, thus eliminating most of the variation at DR-DQ. Thus, we present evidence of TAP2 association with type 1 diabetes that is independent of HLA DR-DQ and describe a plausible functional mechanism based on allele dependence of splicing into isoforms known to have differential peptide selectivities.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TAP2Humantype 1 diabetes mellitus  IAGP  RGD 
Tap2Rattype 1 diabetes mellitus  ISOTAP2 (Homo sapiens) RGD 
Tap2Mousetype 1 diabetes mellitus  ISOTAP2 (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tap2  (transporter 2, ATP binding cassette subfamily B member)

Genes (Mus musculus)
Tap2  (transporter 2, ATP-binding cassette, sub-family B (MDR/TAP))

Genes (Homo sapiens)
TAP2  (transporter 2, ATP binding cassette subfamily B member)


Additional Information