PATHOGENIC MECHANISM OF CONGENITAL ANOMALY AND LIFE-STYLE RELATED DISEASES BASED ON PEROXISOMAL METABOLISM

(1)我们在日本建立了过氧化物酶体疾病的诊断体系，在日本确诊了40例过氧化物酶体生物发生障碍（PBD）、11例β -氧化酶缺乏症和100多例x连锁肾上腺白质营养不良（ALD）患者。(2)对全国ALD病史进行调查，采用基于问卷调查的全国回顾性研究。145例患者的资料进行了分析，包括46例儿童脑型、39例肾上腺髓神经病变（AMN）、33例成人脑型、14例青少年型和13例橄榄桥小脑型（OPC）。(3)我们证明黄芩素5,6,7-三甲基醚，一种黄酮类衍生物可能是治疗ALD的候选化合物。(4)我们研究了日本过氧化物酶体β -氧化酶缺乏症患者的临床、生化和分子特征，以及过氧化物酶体的形态，包括酰基辅酶a氧化酶（AOX）或d -3-羟基酰基辅酶a脱水酶/ d -3-羟基酰基辅酶a脱氢酶双功能蛋白（D-BP）。(5)为了阐明PBD中温度敏感（TS）表型的分子机制，我们分析了PEX13蛋白的SH3结构域的蛋白质3d结构，其Ile326Thr突变在过氧化物酶体生物发生中表现出TS表型。这些数据表明，Ile326应该是折叠动力学的核心残基，用苏氨酸取代Ile326应该直接改变动力学平衡，这表明当患者发高烧时，未折叠的分子显著增加。

(1) We have established a diagnostic system of peroxisomal diseases in Japan, and have identified 40 Japanese with peroxisomal biogenesis disorders (PBD), 11 patients with beta-oxidation enzyme deficiencies and more than 100 patients with X-linked adrenoleukodystrophy (ALD).(2) The national history of ALD was investigated, using a nation-wide retrospective study based on a questionnaire survey. The data on 145 patients, including 46 patients with the childhood cerebral form, 39 with adrenomyeloneuropathy (AMN), 33 with the adult cerebral form, 14 with the adorescent form and 13 with the olivo-ponto-cerebellar (OPC) form, were analyzed.(3) We demonstrated Baicalein 5,6,7-trimethyl ether, a flavonoid derivative may be a candidate for the therapeutic compound for ALD.(4) We investigated the clinical, biochemical and molecular findings, and morphology of peroxisomes in Japanese patients with peroxisomal beta-oxidation enzymes deficiencies, including acyl-CoA oxidase (AOX) or D-3-hydroxyacyl-CoA dehydratase / D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (D-BP).(5) To clarify the molecular mechanism of a temperature-sensitive (TS) phenotype in PBD, we analyzed the protein 3D-structure of a SH3 domein of PEX13 protein, whose Ile326Thr mutation demonstrated a TS phenotype in peroxisomal biogenesis. These data indicated that the Ile326 should be a core residue for folding kinetics and the substitution of the Ile326 by threonine should directly alter the kinetic equilibrium, suggesting a marked increase of the unfolded molecules when the patient had a high fever.