Mariko Sase

Enzymatic Analysis of Citrullinemia (12 Cases) in Japan

Citrullinemia, first described by McMurrey et al l, is considered a rare hereditary disorder of the urea cycle caused by a deficient activity of argininosuccinate synthetase(ASS). Shih2reviewed 12 cases in 1975. In Japan, however, more than 40 cases of citrullinemia have been reported. Most of them were characterized by higher age of onset and moderately high level of serum citrulline3in contrast to neonatal onset and extremely high concentration of serum citrulline of classical-or neonatal-type citrullinemia described by McMurrey et al. and others. These findings suggest that there may be some heterogeneities in citrullinemia. So we analyzed the properties of ASS in the liver and other organs of 12 cases of citrullinemia in Japan.

Level of translatable messenger RNA coding for argininosuccinate synthetase in the liver of the patients with quantitative-type citrullinemia

SummaryThe translation activity of mRNA coding for argininosuccinate synthetase in total RNA extracted from the liver of three patients with quantitative-type citrullinemia was determined using a cell-free translation system. In two patients, the hepatic content of the enzyme was about 20% of the control value, whereas translatable mRNA level for the enzyme was similar to or slightly lower than those of control livers. In the third patient, the enzyme content was about 50% of the control value, and mRNA activity for the enzyme was low normal. These results indicate that at least in the first two patients, the decrease in the enzyme protein is due either to increased degradation of the enzyme or to decreased translation in the patients liver.

Arginine Metabolism in Citrullinemic Patients

Arginine is synthesized from citrulline by the catalytic actions of argininosuccinate synthetase (ASS) and argininosuccinase in the kidney1,2, and utilized as a precursor of creatine biosynthesis or supplied to various organs for protein synthesis. The liver performing ureogenesis also synthesizes arginine, which, however, is rapidly split to ornithine and urea by the potent activity of arginase.

Absence of argininosuccinate lyase protein in the liver of two patients with argininosuccinic aciduria

The enzyme defects in two cases of argininosuccinic aciduria were examined at the molecular level by enzymatic and immunological methods. No argininosuccinate lyase activity was detected in the liver or erythrocytes of either patient nor in the kidney or brain of one of the patients even in the presence of high concentrations of the substrate. The titration curve of antiserum to human argininosuccinate lyase with the liver extract from a control subject was not affected by the addition of the liver extracts from one of the patients. Double immunodiffusion analysis revealed a single precipitin line between the purified antiserum and the liver extract from a control, but no precipitin lines between the antisera and the liver extracts from the two patients. These results indicate a complete or almost complete defect of an immunologically cross-reactive material in the liver of the patients.