Mucopolysaccharidosis type I: Characterization of novel mutations affecting α‐ l‐iduronidase activity

Abstract

alpha-L-Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I, MPS I) involves a broad spectrum of clinical severity ranging from a severe Hurler 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 Hurler syndrome, but only a few in Hurler Scheie or Scheie syndrome. The characterization of novel mutations in two patients with the Hurler-Scheie syndrome is reported on. The novel R619G mutation (C-G transversion in codon 619) was apparently homozygous. In transfected COS-7 cells, R619G caused significant reduction in enzyme activity (1.5% of normal activity), although it did not cause significant reduction in IDUA mRNA or protein level. Conversely, the previously described homozygous T364M mutation (C-T transition in codon 364) caused a decrease in the level of IDUA mRNA. Studies inhibiting RNA synthesis with actinomycin D or inhibiting protein synthesis with cycloheximide demonstrate that the decrease in the latter mutation is attributable to an increased rate of mRNA decay. By examining the stability of IDUA mRNA and protein, studies provide better insight into the effect of mutation on IDUA activity.

Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis

“…1). Three mutations previously reported in Taiwan [p.A79V, (12) c.300-3C>G, (13) p.L346R (13)] were also observed in our study. The IDUA protein sequences of 11 species were aligned using Clustal W2, which was used to judge the pathogenicity of a missense mutation.…”

Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations

“…The novel mutation S633L is only 20 amino acids from the C-terminus of the protein and was found in homozygous form in a Scheie patient (Table 7). The only other two missense mutations previously reported in exon 14, R619G and W626R, are both responsible for the intermediate phenotype (Lee-Chen et al 1999;Bunge et al 1995). No missense mutations responsible for the severe phenotype have been reported in this region, although several nonsense mutations in exon 14 (R619X, R621X, R628X) are severe.…”

Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human α-l-iduronidase (IDUA) gene

“…IDUA gene mutations identified from Japanese, 7 Arab, 22 and Chinese patients 20,23 show a different mutational spectrum from those detected in Caucasians. 6,24 The relative frequency of common mutations and frequent recurrent mutations show obvious geographic heterogeneity.…”