PATHOGENESIS OF X-LINKED ADRENOLEUKODYSTROPHY

为了阐明x连锁肾上腺脑白质营养不良（ALD）的发病机制，利用大鼠cDNA克隆了ALD缺乏的人甚长链脂肪酰基辅酶a合成酶（VLACS）的互补DNA。人类VLACS基因编码620个与大鼠酶和脂肪酸转运蛋白高度同源的氨基酸，该基因位于染色体15q21.2上。利用体外表达系统表达的纯化蛋白，制备用于蛋白分析的人VLACS多克隆抗体。人VLACS在培养的人细胞中的表达载体正在构建中。通过血浆甚长链脂肪酸（VLCFA）分析和成纤维细胞木质素酸氧化活性，提高了ALD携带者的识别能力，并建立了症状前ALD男孩的筛查方法。发现两种新的ALD蛋白突变，并通过突变分析进行产前诊断。包括ALD在内的过氧化物酶体疾病在日本的发病率得到了澄清。以VLCFA积累为特征的d -双功能蛋白缺乏症首次被发现。针对过氧化物酶体生物发生障碍，鉴定了一种新的致病基因（过氧化物酶体组装因子-2，PAF-2），建立了口腔涂片筛选方法，并研究了二十二碳六烯酸的治疗方法。描述了过氧化物酶体疾病的脑电图特征。

In order to clarify the pathogenesis of X-linked adrenoleukodystrophy (ALD), complementary DNA for human very long chain fatty acyl-CoA synthetase (VLACS), which is deficient in ALD was cloned using rat cDNA.Human VLACS cDNA encodes 620 amino acids with high homology to rat enzyme and fatty acid transport protein and the gene was assinged to chromosome 15q21.2. Polyclonal antibody against human VLACS for protein analysis is raising using purified protein which was expressed by in vitro expression system. Expression vector for human VLACS in cultured human cells is under construction. Carrier identification of ALD was improved by means of plasma very long chain fatty acid (VLCFA) analysis and lignoceric acid oxidation activity in fibroblasts, and the method for the screening of presymptomatic ALD boys was developed. Two novel mutation in ALD protein was identified, and prenatl diagnosis was performed by means of mutation analysis. Incidence of peroxisomal disorders including ALD in Japan was clarified. D-bifunctional protein deficiency, which is characterized by the accumulation of VLCFA,was first identified. As for the peroxisome biogenesis disorders, a novel pathogenic gene (peroxisome assembly factor-2, PAF-2) was identified, screening method using buccal smear was developed, and the treatment with docosahexaenoic acid was investigated. Electroencephalographic characterization of peroxisomal disorders was described.