A canine model of human alpha-L-iduronidase deficiency.
A disease discovered in three Plott Hound littermates was found to be associated with a profound and specific deficiency of alpha-L-iduronidase (mucopolysaccharide alpha-L-iduronohydrolase; EC 3.2.1.76) in fibroblasts and leukocytes. The pedigree was consistent with autosomal recessive inheritance. A markedly increased amount of dermatan sulfate and heparan sulfate was excreted in urine. Fibroblasts cultured from the skin of the affected dogs accumulated excessive 35S-labeled mucopolysaccharide; this accumulation could be decreased to a normal level by exogenous human high-uptake alpha-L-iduronidase (Hurler corrective factor) as well as by secretions of normal human or canine fibroblasts. The correction was inhibited by mannose 6-phosphate. Maturation of alpha-L-iduronidase in normal canine fibroblasts followed the pathway previously observed in human fibroblasts; no cross-reactive material was observed in the cells or in secretions from the fibroblasts of the affected dogs. The canine disorder thus resembles mucopolysaccharidosis I in all biochemical parameters tested; the clinical appearance of the animals is closest to Hurler-Scheie syndrome, a form of alpha-L-iduronidase deficiency of intermediate severity. The animal model should prove valuable for therapeutic experiments.
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000201:enzymology* / Q000235:genetics; D004285:Dogs; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006026:Glycoside Hydrolases / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000172:deficiency*; D007962:Leukocytes / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000235:genetics / Q000662:veterinary*; D010375:Pedigree; D012867:Skin / Q000201:enzymology*
D006026:Glycoside Hydrolases; D007068:Iduronidase