AIE-75 gene : with special reference to the differentiation of mucosal epithelial cells and the regulation of gene expression

自身免疫性肠病是一种罕见的疾病，其特征是严重和顽固性腹泻和循环中存在的抗肠细胞自身抗体。我们已经确定了自身免疫性肠病相关的75 kDa抗原（AIE-75）作为疾病的候选自身抗原，其分布于小肠和近端肾小管的刷状缘。AIE-75的分布仅限于绒毛的顶端部位，表明其表达以细胞周期或成熟依赖的方式进行调节。为了探讨这一点，我们用荧光素酶分析了AIIE-75基因启动子区的顺式元件，发现转录起始位点上游-9 ~-63碱基参与了该基因表达的负调控，并与其他研究组合作证实了抗AJE-75抗体在自身免疫性肠病中的特异性和敏感性。此外，我们还发现了一种肌动蛋白结合蛋白villin，它是另一种与该疾病相关的自身抗原。AIE-75被发现是IC型Usher综合征的一个致病基因，该综合征以耳聋和视网膜病变为特征。事实上，AIE-75也在内耳和视网膜的上皮细胞中表达。我们发现ALE-75参与视网膜感光细胞与钙粘蛋白23和肌球蛋白VII的组装，但AIE-75的表达与这两种蛋白的表达无关。X连锁综合征（IPEX），其原因是叉头翅螺旋转录因子FOXP 3突变。我们在一例轻度IPEX患者中发现了FOXP 3的一个新突变T1117 G。

Autoimmune enteropathy is a rare disease characterized by severe and refracrory diarrhea and the presence of circulating ants-enterocyte autoantibody. We have identified autoimmune enteropathy-related 75 kDa antigen (AIE-75) as a candidate autoantigen in the disease, which distributes to the brush border of both the small intestine and proximal renal tubulus. The distribution of AIE-75 is limited to the apical site of the villi, suggesting that the expression is regulated in cell cycle-or maturation-dependent manners. To approach this, we analyzed cis-element of the promotor region of AIIE-75 gene using luciferase assay, and found that -9 to -63 bases upstream of the transcription initiation site is involved in he negative regulation of the gene expression.The specificity and sensitivity of anti-AJE-75 antibody in autoimmune enteropathy were confirmed in collaboration with other groups. Furthermore, we identified an actin-binding protein, villin, as another autoantigen related to the disease.AIE-75 was found to be a responsible gene for Usher's syndrome type IC which is characterized by deafness and retinopathy. Indeed, AIE-75 was also expressed in both epithelial cells of the inner ear and retina. We found that ALE-75 is involved in the assembly of photoreceptor with cadherin 23 and myosin VII in the retina, but that the expression of AIE-75 is independent of the expression of the both proteins.Some cases of autoimmune enteropathy are inherited in an X-linked manner, named immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) of which cause is the mutation of a forkhead winged helix transcription factor, FOXP3. We found a novel mutation of FOXP3, T1117G, in a mild case of IPEX.