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A novel form of angiokeratoma corporis diffusum: Elucidatim of abnormal metabolites in urine and enzyme defect.

弥漫性体血管角化瘤的一种新形式：尿液中异常代谢物和酶缺陷的阐明。

基本信息

批准号：
02454279
负责人：
KANZAKI Tamotsu
金额：
$ 3.78万
依托单位：
Kagoshima University (1992)Nagoya City University (1990-1991)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

A novel form of angiokeratoma corporis diffusum was discovered in a Japanese female. Abnormal metabolites were detected in the patient's urine and those were reveald to be O-limked glycoaminoacids. From these chemical formula, this novel lysosomal storage disease, now termed Kanzaki disease, was revealed to be caused by an enzyme deficit, ie, alpha-N-acetylgalactosaminidase. ALL these were elucidated in the past a few years in this project. We tried to elucidate a possible defect in the gene encoding this enzyme protein in the last one year.As a result, it was found that a base at the 985th was switched C to T resulting in a change of amino acid of arginine to tryptophane at 329th. This gene was transfected to COS-1 cell and a new protein was observed to be produced by COS-1 cell. This protein reacted with an antibody to the enzyme but did not show an enzymatic activity. Secondly, a computer-assisted two-dimensional molecular structure was studied and it showed that an change of amino acid induced a secondary change from beta-pleated sheet to random coil. this was quit different from the change observed in Schindler disease, i,e., alpha-helix formation. This change was thought to be the cause of susceptibility of these resultant abnormal enzyme proteines to proteases in lysosomes. This will explain the great differences in the phenotypical expression in the patients with Kanzaki disease and Schindler disease (Wang, A,M. Kanzaki, T. and Desnick,R.J.). These results obtained in this year will be published in Archives of Dermatology (in press,1993) and were submitted to other journals.Thus, all research works, from the discovery to the molecular analysis of a noval lysosomal storase disease with angiokeratoma corporis diffusum (Kanzaki), planned in this project were successfully accomplished in these years.

在一名日本女性身上发现了一种新的体部弥漫性血管角化瘤。在患者的尿液中检测到异常代谢物，并发现这些代谢物是O-LIME糖氨基酸。根据这些化学式，这种新的溶酶体储存病，现在被称为Kanzaki病，被发现是由一种酶缺陷引起的，即α-N-乙酰半乳糖胺酶。所有这些都在过去的几年里在这个项目中得到了阐述。在过去的一年里，我们试图阐明该酶蛋白编码基因的一个可能的缺陷。结果发现，第985位的碱基被C切换为T，导致第329位的精氨酸氨基酸变为色氨酸。将该基因导入COS-1细胞，观察到COS-1细胞产生一种新的蛋白质。该蛋白与该酶的抗体发生反应，但不显示出酶活性。其次，对计算机辅助的二维分子结构进行了研究，结果表明，氨基酸的变化导致了从β-折叠片状到无规卷曲的二次变化。这与在辛德勒病中观察到的变化完全不同，即阿尔法螺旋形成。这种变化被认为是这些产生的异常酶蛋白对溶酶体中的蛋白酶易感性的原因。这将解释Kanzaki病和Schindler病(Wang，A，M.Kanzaki，T.和Desnick，R.J.)患者表型表达的巨大差异。这一年的研究成果将发表在《皮肤病文献》(出版中，1993)上，并提交给其他期刊。因此，本项目计划的所有研究工作，从发现到分子分析一种新的溶酶体病合并弥漫性血管角化病(Kanzaki)，都在这些年成功完成。