膜転送障害に基づく先天性アミノ酸代謝異常症の病因解析に関する研究

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Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome (HHH) was first reported by Shih et al. (1969). The basic metabolic defect has been suggested to be a defective transport of ornithine by hepatic mitochondria (Shih et al., 1982). The author examined ornithine metabolism in cultured skin fibroblasts from a patient using the double-labeled assay. A liver sample was obtained from this patient by open biopsy and free amino acid contents in the whole tissue and hepatic mitochondria were measured. Familial hyperlysinemia was first described by Woody (1964). Dancis et al. (1976, 1979) demonstrated that the mechanism of familial hyperlysinemia involved enzyme defects of lysine-α-ketoglutarate reductase and saccharopine dehydrogenase. Recently the author encountered two siblings having familial hyperlysinemia in whom the enzyme activities of lysine-α-ketoglutarate reductase and saccharopine dehydrogenase in liver were normal. The lysine and leucine metabolism in cultured skin fibroblasts from these patients were examined. The following results were obtained. 1) Concentrations of ornithine in hepatic mitochondria of the HHH patient were apparently low, compared with concentrations of ornithine in whole liver tissues. 2) Incorporations of the 14C-label of ornithine into protein in cultured skin fibroblasts of the HHH patient were significantly lower than those of controls. 3) In leucine uptake studies, the amounts of 14CO2 obtained by incubation with the hyperlysinemic patients' fibroblasts were similar to the results obtained by controls. 4) In lysine uptake studies, the amounts of 14CO2 obtained by the hyperlysinemic patients' fibroblasts in the low substrate medium were significantly lower than those of controls, but in the high substrate medium amounts of 14CO2 obtained with the patients' fibroblasts were similar to those obtained with the controls' fibroblasts. 5) From these findings, the mechanism of HHH and these patients with hyperlysinemia have a defective transport of ornithine and lysine in hepatic mitochondria.
1986-10-01

膜転送障害に基づく先天性アミノ酸代謝異常症の病因解析に関する研究

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