Dai K Z, Harbo H F, Celius E G, Oturai A, Sørensen P S, Ryder L P, Datta P, Svejgaard A, Hillert J, Fredrikson S, Sandberg-Wollheim M, Laaksonen M, Myhr K M, Nyland H, Vartdal F, Spurkland A
Institute of Immunology, The National Hospital, N-0027 Oslo, Norway.
Genes Immun. 2001 Aug;2(5):263-8. doi: 10.1038/sj.gene.6363774.
The T cell specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the control of T cell activation. The gene is located in the 1q21 region, which has been implicated in susceptibility to experimental allergic encephalomyelitis in the mouse. We therefore evaluated whether a polymorphic GA repeat (GA(13)-GA(33)) within the promoter region of the SH2D2A gene shows association to multiple sclerosis (MS). The frequency of the short alleles GA(13-16) was increased among 313 Norwegian MS patients compared to 277 healthy controls (0.332 vs 0.249, OR 1.5, Pc = 0.03). Transmission disequilibrium analysis in 146 Scandinavian families with at least two affected sibs showed increased transmission of GA(16) to MS patients. No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed. After activation of naive CD4(+) T cells, T cells homozygous for MS associated short alleles displayed lower level of TSAd ex vivo than T cells carrying at least one long allele, which were not associated to MS. Since the SH2D2A protein modulates T cell activation, this may be a mechanism for how short SH2D2A alleles confer susceptibility to develop MS.
由SH2D2A基因编码的T细胞特异性衔接蛋白（TSAd）参与T细胞活化的调控。该基因位于1q21区域，该区域与小鼠实验性变应性脑脊髓炎的易感性有关。因此，我们评估了SH2D2A基因启动子区域内的多态性GA重复序列（GA(13)-GA(33)）是否与多发性硬化症（MS）相关。与277名健康对照相比，313名挪威MS患者中短等位基因GA(13-16)的频率增加（0.332对0.249，OR 1.5，Pc = 0.03）。对146个至少有两个患病同胞的斯堪的纳维亚家庭进行的传递不平衡分析显示，GA(16)向MS患者的传递增加。未观察到MS与SH2D2A基因侧翼的四个遗传标记之间存在连锁或关联。在未成熟CD4(+) T细胞活化后，与MS相关的短等位基因纯合的T细胞在体外显示出比携带至少一个与MS无关的长等位基因的T细胞更低水平的TSAd。由于SH2D2A蛋白调节T细胞活化，这可能是短SH2D2A等位基因赋予MS易感性的一种机制。
