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首页> 外文期刊>Journal of Molecular Biology >Human genome search in celiac disease using gliadin cDNA as probe.
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Human genome search in celiac disease using gliadin cDNA as probe.

机译：使用麦醇溶蛋白cDNA作为探针在乳糜泻中进行人类基因组搜索。

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Celiac disease is a wheat gliadin-promoted disorder that displays a complex genetic susceptibility associated with HLA-DQ2, and one or more unknown factor(s), possibly gliadin-like. The presence of mammalian proteins with partial gliadin similarity was suggested by transglutaminase-independent multi-tissue reactivity of gliadin-immunopurified antibodies from celiac patients. No non-plant sequence, however, was identified in gliadin peptide epitope searches of non-redundant and EST databanks via TBLASTN, BLASTP and FASTA, even at E values as high as 20. Therefore, an alpha-gliadin cDNA screen of human cDNA and genomic libraries was undertaken, an approach in keeping with positive human Northern and Southern analyses with the same probe. Four distinct cDNA clones were obtained, the most stringent of which (3.2 and 5.1 kb) were novel, and featured potential open reading frames with high gliadin domain II and domain IV homologies (BestFit quality scores >/=295 and 322, respectively, versus random value 126-127). Both were also homologous to ESTs. An additional 5' gliadin oligonucleotide screen identified the widely distributed cytoplasmic protein acyl coA hydrolase whose homology was restricted to the oligonucleotide probe (BestFit quality=215 versus 100 for random); and achaete-scute homologous protein, which displays particularly high gliadin domain II homology (BestFit quality 316 versus 111 for random). Genomic screening uncovered 16 positives, one of which was the ALR gene, whose similarity to three of gliadin's five domains (I, II and IV; BestFit quality 322-473 versus 121-154 for random) was remarkable. More extensive was novel genomic clone 2, with fragments hybridizing to cDNA probes approximating gliadin domains I, II+IV, V and the gliadin 5' untranslated region, and mapping by FISH to 19q13.11-13. 12. Two fragments were sequenced; one was exonic, as predicted by four different programs; and test oligonucleotides suggested widespread 4 and/or 2 kb mRNA expression, even at high stringency (t(m)-8.8 deg. C). Taken together, it is apparent that several genes with partial gliadin homology exist in the human genome. Many bear gliadin-like T-cell epitopes, are expressed in intestine and, like transglutaminase, are cytoplasmic. Glutamine to glutamic acid or other mutation within such epitopes followed by injury or infection-related release could explain enhanced disease susceptibility in affected families. Copyright 2000 Academic Press.
机译：腹腔疾病是小麦麦醇溶蛋白促进的疾病，表现出与HLA-DQ2和一个或多个未知因子（可能与麦醇溶蛋白类似）相关的复杂遗传易感性。乳糜泻患者的麦醇溶蛋白免疫纯化抗体的转谷氨酰胺酶非依赖性多组织反应表明存在与麦醇溶蛋白部分相似的哺乳动物蛋白。然而，即使在E值高达20的情况下，通过TBLASTN，BLASTP和FASTA在麦醇溶蛋白肽表位搜索非冗余和EST数据库中也未发现非植物序列，因此，人cDNA和人进行了基因组文库，该方法与同一探针在人类北方和南方的阳性分析中保持一致。获得了四个不同的cDNA克隆，其中最严格的（3.2和5.1 kb）是新颖的，并且具有潜在的开放阅读框，具有高醇溶蛋白II结构域和IV结构同源性（BestFit质量得分分别大于/ = 295和322，与随机值126-127）。两者也与ESTs同源。另外的5'麦醇溶蛋白寡核苷酸筛选确定了广泛分布的胞质蛋白酰基辅酶A水解酶，其同源性限于寡核苷酸探针（BestFit质量= 215，随机为100）;和achaete-scute同源蛋白，它显示出特别高的醇溶蛋白结构域II同源性（BestFit质量316与111随机）。基因组筛选发现16个阳性，其中一个是ALR基因，其与麦醇溶蛋白的五个结构域中的三个（I，II和IV; BestFit质量322-473与121-154的随机性）相似。更广泛的是新型基因组克隆2，其片段与cDNA探针杂交，近似于麦醇溶蛋白结构域I，II + IV，V和麦醇溶蛋白5'非翻译区，并通过FISH定位到19q13.11-13。 12.对两个片段进行了测序。正如四个不同程序所预测的，一个是外显子;并且测试寡核苷酸表明即使在高严格性（t（m）-8.8℃）下也普遍存在4和/或2 kb mRNA表达。两者合计，很明显在人类基因组中存在几个具有部分醇溶蛋白同源性的基因。许多熊麦醇溶蛋白样T细胞表位在肠道中表达，并且像转谷氨酰胺酶一样具有细胞质。谷氨酰胺在这些表位中发生谷氨酸或其他突变，继而受到损伤或与感染相关的释放可能解释了受影响家庭的疾病易感性增强。版权所有2000学术出版社。

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