Human Molecular Genetics Advance Access originally published online on August 27, 2004
Human Molecular Genetics 2004 13(20):2361-2368; doi:10.1093/hmg/ddh273
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved
A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups
1Department of Genetics, University of Leicester, Leicester LE1 7RH, UK, 2St John's Institute of Dermatology, King's College, London SE1 7EH, UK and 3Department of Dermatology, Western Infirmary, Glasgow G11 6NT, UK
Received April 5, 2004; Revised July 8, 2004; Accepted August 19, 2004
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. On the basis of 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 2-fold increase in stability, compared with 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 39 kDa 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.
* To whom correspondence should be addressed at: Department of Genetics, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, UK. Tel: +44 1162522269; Fax: +44 1162523378; Email: rtrembat{at}hgmp.mrc.ac.uk
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