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

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. 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.

Polymorphisms of Catechol-O-Methyltransferase in Men with Renal Cell Cancer

“…However, gene expression could be affected as a result of a structural change in the RNA due to the variant, and may lead to an alteration in processing or efficiency of translation (49). Several studies have shown evidence that synonymous mutations can affect mRNA secondary structure and result in abnormalities (31)(32)(33). In a study by Duan et al (32), the silent 957 C!T polymorphism of the human dopamine receptor D2 (DRD2) gene has been shown to alter mRNA folding, reduce mRNA stability and translation, as well as alter dopamine-induced DRD2 expression.…”

“…In a study by Duan et al (32), the silent 957 C!T polymorphism of the human dopamine receptor D2 (DRD2) gene has been shown to alter mRNA folding, reduce mRNA stability and translation, as well as alter dopamine-induced DRD2 expression. In another study, Capon et al (33) compared the stability of mRNA transcribed from haplotypes from the psoriasisassociated corneodesmosin (CDSN) gene. They observed that the risk haplotype resulted in a 2-fold increase in mRNA stability compared with the neutral haplotype and was associated with the disease.…”

“…The third polymorphism at codon 62 is silent (His). Although the base change on this codon does not lead to an amino acid change, studies show that synonymous mutations could lead to structural changes in mRNA (31)(32)(33), and as a result, causes altered protein expression (32) as well as disease (33). Furthermore, polymorphisms of COMT have been found to have associations with neurologic/psychological diseases (34,35) and have also been investigated in various cancers such as breast (36), bladder (37), liver (38), endometrial (39), and prostate (40) cancers.…”

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

“…The psoriasis-associated SNPs of CDSN could affect the function of the corresponding proteins. To date, only one study has shown that an intragenic SNP (SNP*971T), present in 3 common haplotypes associated with psoriasis in various ethnic groups, is responsible for an increased stability of the encoded mRNAs [43]. Although these results are in agreement with the known overexpression of CDSN in psoriatic lesions [15,34], they pointed a discrepancy between CDSN haplotypes at the mRNA level only.…”

Association analysis of the skin barrier gene cystatin A at the PSORS5 locus in psoriatic patients: evidence for interaction between PSORS1 and PSORS5

“…39 -41 Also, in the case of the corneodesmosin gene, a synonymous mutation located in an RNA stability motif led to increased stability of the RNA transcript by diminishing the transcript affinity for a 39 kDa RNAbinding protein. 42 More recently, a silent SNP in the multi-drug resistance 1 gene has been reported to change Genetic analysis of CSTA in psoriasis Y Vasilopoulos et al drug and inhibition interactions, suggesting that this synonymous polymorphism may affect co-translational folding of the protein. 43 These results, taken together, provide strong evidence that a synonymous mutation in exon 2 of the human cystatin A gene is strongly associated with psoriasis in both case-control and family-based association studies and act independently from HLA-Cw6.…”