A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups
A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups
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DOI：
10.1093/hmg/ddh273
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发表时间：
2004-10-15
影响因子：
3.5
通讯作者：
Trembath, RC
中科院分区：
文献类型：
--
作者：
Capon, F;Allen, MH;Trembath, RC
银屑病是一种多因素病因的慢性皮肤病。全基因组扫描为染色体6p21 （PSORS1）上的一个主要疾病易感位点提供了明确的证据。最小PSORS1区间包含三个携带银屑病相关snp的基因（HLA-C、HCR和CDSN）。在此遗传证据的基础上，我们对CDSN等位基因功能影响进行了评估。CDSN基因内单倍型的比较表明，疾病相关染色体特有的snp位于与RNA转录物稳定有关的区域。由于CDSN在银屑病病变中过度表达，我们假设疾病相关的基因内snp可能改变其mRNA衰变的速率。在这里，我们证明，与从中性单倍型转录的mrna相比，从CDSN风险单倍型转录的mrna的稳定性增加了2倍（t检验P=0.004）。位点定向突变表明，单个同义SNP （CDSN*971T）导致观察到的RNA稳定性增加。CDSN*971T映射到一个RNA稳定性基序，紫外交联分析表明，该SNP影响39 kDa RNA结合蛋白的转录产物亲和力。关联分析表明，携带CDSN*971T的单倍型在广泛的种族群体中具有银屑病易感性。这些结果证明了同义变异对等位基因特异性基因表达的影响，这一发现与未来研究常见和复杂性状的发病机制有关。
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.