Mucopolysaccharidosis type I: Characterization of novel mutations affecting alpha-L-iduronidase activity

alpha-L-Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I, MPS I) involves a broad spectrum of clinical severity ranging from a severe Hurle r syndrome through an intermediate Hurler-Scheie syndrome to a mild Scheie syndrome. To date, a number of mutations of the IDUA gene are known in Hurl er syndrome, but only a few in Hurler-Scheie or Scheie syndrome. The charac terization of novel mutations in two patients with the Hurler-Scheie syndro me is reported on. The novel R619G mutation (C-G transversion in codon 619) was apparently homozygous. In transfected COS-7 cells, R619G caused signif icant reduction in enzyme activity (1.5% of normal activity), although it d id not cause significant reduction in IDUA mRNA or protein level. Conversel y, the previously described homozygous T364M mutation (C-T transition in co don 364) caused a decrease in the level of IDUA mRNA. Studies inhibiting RN A synthesis with actinomycin D or inhibiting protein synthesis with cyclohe ximide demonstrate that the decrease in the latter mutation is attributable to an increased rate of mRNA decay. By examining the stability of IDUA mRN A and protein, studies provide better insight into the effect of mutation o n IDUA activity.