Identification of a new exon 2-skipped TNFR1 transcript: regulation by three functional polymorphisms of the TNFR-associated periodic syndrome (TRAPS) gene.

Ann Rheum Dis 2014 Jan 16;73(1):290-7. Epub 2013 Mar 16.

Génétique des maladies Autoinflammatoires et des ostéoarthropathies chroniques, INSERM U844, Hôpital Saint Eloi, Bâtiment INM, , Montpellier, France.

Background: Mutations in the TNFRSF1A gene encoding the tumour necrosis factor α cell surface receptor, TNFR1, cause TNFR-associated periodic syndrome (TRAPS) and polymorphisms in TNFRSF1A, including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases.

Objectives: To describe a new exon 2-spliced transcript-TNFR1-d2-and the impact of these three single nucleotide polymorphisms on exon 2 splicing, transcriptional activity of TNFRSF1A and TRAPS phenotype.

Methods: Expression of TNFRSF1A transcripts was performed by reverse-transcription-PCR in a range of human cells and tissues. Exon 2 splicing and transcriptional activity were analysed in HEK293T and SW480 cells by in vitro alternative splicing and luciferase assays, respectively. We constructed haplotypes containing rs4149570, rs767455 and rs1800692 in controls (n=72), patients with TRAPS (n=111) and in TRAPS-like patients (n=450) to compare their distribution and association with clinical features of TRAPS.

Results: TNFR1-d2 was expressed in a tissue-specific manner, whereas TNFR1 expression was ubiquitous. Alternative splicing assays showed that the T-A-T haplotype at rs4149570-rs767455-rs1800692 had a significantly higher expression of exon 2-skipping product (p=0.02) compared with the G-G-C haplotype. Transcriptional activity from the T-T haplotype at rs4149570-rs1800692 was increased compared with the G-C haplotype (p=0.03). In patients with TRAPS, rs1800692 T/T homozygotes were excessively rare (p<10(-4)) and TRAPS-like patients with this genotype experienced less fever.

Conclusions: Our study provides a new mechanism of TNFRSF1A regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing. These polymorphisms may affect the phenotype of TRAPS and TRAPS-like patients.

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2012-203023DOI Listing
January 2014
20 Reads

Publication Analysis

Top Keywords

transcriptional activity
12
tnfr-associated periodic
8
rs767455 rs1800692
8
patients traps
8
splicing transcriptional
8
exon splicing
8
alternative splicing
8
rs4149570 rs767455
8
periodic syndrome
8
syndrome traps
8
traps
5
reverse-transcription-pcr range
4
p=002 compared
4
range human
4
cells tissues
4
analysed hek293t
4
hek293t sw480
4
sw480 cells
4
exon 2-skipping
4
2-skipping product
4

References

(Supplied by CrossRef)
The autoinflammatory syndromes
McDermott et al.
Curr Opin Allergy Clin Immunol 2002

Similar Publications