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

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(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.