Mutations in the urocanase gene UROC1 are associated with urocanic aciduria.

Urocanase is an enzyme in the histidine pathway encoded by the UROC1 gene. This report describes the first putative mutations, p.L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria presenting with mental retardation and intermittent ataxia. Computed (in silico) predictions, protein expression studies and enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme. The p.L70P substitution, which probably implies the disruption of an alpha-helix in the N-terminus, would alter its properties and therefore, its function. The p.R450C change would render impossible any interaction between urocanase and its substrate and would loss its enzyme activity. Consequently, these studies suggest that both mutations could alter the correct activity of urocanase, which would explain the clinical and biochemical findings described in this patient.

Disturbances in histidine metabolism in children with speech abnormalities.

Catabolism of histidine was investigated in 24 patients with different speech and language disorders and with significantly low histidase activity in stratum corneum. No classical histidinemia was found. Biochemical investigation of these patients after loading with L-histidine led to the conclusions that low histidase activity in stratum corneum was connected with: disturbances in folic acid metabolism (2 cases); "atypical histidinemia" (1 case); heterozygotes of histidinemia (2 cases); normal liver histidine metabolism but abnormal in other tissues (18 cases); previously unknown error of histidine metabolism (1 case).

Biochemical study of malnutrition. Part VI: Histidine and its metabolites.

The present study, as a part of a broader investigation on protein-energy-malnutrition (PEM) in rural Zaire, was undertaken in order to clarify varying aspects of histidine metabolism in patients suffering from protein-energy malnutrition (PEM). Measurement of histidine and its derivatives was performed on blood samples, in urine and in stool ultrafiltrates of healthy rural controls, of PEM mothers and PEM children, before and during dietary treatment, and after histidine oral overloading. In stool ultrafiltrates, unusually high concentration of histidine and of three major catabolites (imidazoleacetic acid, imidazolelactic acid and imidazolepropionic acid) were identified, contrasting with undetectable levels of urocanic acid. On the contrary, very large amounts of urocanic acid may be recovered in the urine of PEM patients, especially in those characterized by very poor life expectancy. Urinary urocanic acid level thus appears as a very sensitive indicator of liver malfunction, in a manner similar to low plasma prealbumin and/or high A-alpha 1-gamma-glutamyltranspeptidase values. These findings point to the severe impairment of histidase and urocanase, two enzymes regulating the histidine catabolic pathway. Under appropriate refeeding, all biochemical abnormalities described in surviving PEM patients are reversible. The persistence of high urinary urocanic acid excretion indicates a worsening of the patient's condition.

A liver urocanase deficiency.

Two sisters with a rare inborn error of histidine metabolism resulting from urocanase deficiency are being presented. The more common form of familial histidinemia due to histidase deficiency is excluded. The urocanase deficiency is proven by demonstrating increased excretion of metabolites of the product of the urocanase enzyme action. Further, the strongest evidence for the urocanase defect rests on the demonstration of urocanase deficiency and normal histidase activity in liver.