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，以严重和难治性腹泻为特征，并存在循环中的蚂蚁-肠细胞自身抗体。我们已确定自身免疫性肠病相关75 kDa抗原(AIE-75)是该病的候选自身抗原，它分布在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位置，提示其表达受细胞周期或成熟依赖的方式调节。为了探讨这一点，我们用荧光素酶分析了AIIE-75基因启动子区域的顺式元件，发现转录起始点上游的-9到-63个碱基参与了基因表达的负调控。此外，我们还发现肌动蛋白结合蛋白Villin是与这种疾病相关的另一种自身抗原。AIE-75被发现是导致以耳聋和视网膜病变为特征的Usher综合征IC型的一个负责基因。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-75参与了视网膜光感受器与钙粘蛋白23和肌球蛋白VII的组装，但AIE-75的表达不依赖于这两种蛋白的表达。一些自身免疫性肠病是以X连锁的方式遗传的，称为免疫调节失调、多内分泌疾病、肠病、X连锁综合征(IPEX)，其原因是叉头翼状螺旋转录因子FOXP3的突变。我们在一例轻度IPEX中发现了一种新的FOXP3突变T1117G。

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.