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Human Molecular Genetics Advance Access published online on August 27, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh273
© 2004 by Oxford University Press
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Article

A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups

Francesca Capon 1, Michael H Allen 2, Mahreen Ameen 2, A David Burden 3, David Tillman 3, Jonathan N Barker 2, Richard C Trembath 4*

1 Department of Genetics, University of Leicester, Leicester LE1 7RH, UK
2 St John's Institute of Dermatology, King's College, London SE1 7EH, UK
3 Department of Dermatology, Western Infirmary, Glasgow G11 6NT, UK
4 Department of Genetics, Adrian Building, University of Leicester, University road, LE1 7RH, Leicester, UK

* To whom correspondence should be addressed. E-mail: rtrembat{at}hgmp.mrc.ac.uk.


  Abstract

Psoriasis is a chronic skin disorder with multifactorial aetiology. Genome-wide scans have provided unambiguous evidence for a major disease susceptibility locus on chromosome 6p21 (PSORS1). A minimal PSORS1 interval has been defined which encompasses three genes (HLA-C, HCR and CDSN) carrying psoriasis associated SNPs. Based upon this genetic evidence, we have undertaken an assessment of CDSN allele functional impact. A comparison of CDSN intragenic haplotypes showed that SNPs exclusive to disease-associated chromosomes are located in regions implicated in the stabilization of RNA transcripts. As CDSN is over-expressed in psoriatic lesions, we hypothesised that disease-associated intragenic SNPs may alter the rate of its mRNA decay. Here, we demonstrate that mRNAs transcribed from a CDSN risk haplotype present a twofold increase in stability, compared to those transcribed from a neutral haplotype (t-test P=0.004). Site-directed mutagenesis revealed that a single synonymous SNP (CDSN*971T) accounts for the observed increase in RNA stability. CDSN*971T maps to a RNA stability motif and UV cross-linking analysis demonstrated that the SNP affects the transcript affinity for a 39kDa RNA binding protein. Association analyses show that haplotypes bearing CDSN*971T confer psoriasis susceptibility in a wide range of ethnic groups. These results demonstrate the effect of synonymous variation upon allele specific gene expression, a finding of relevance to future studies of the pathogenesis of common and complex traits.


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