α-L-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype

Abstract

Mucopolysaccharidosis type I (MPS‐I) is an autosomal recessive genetic disease caused by a deficiency of the glycosidase α‐L‐iduronidase which is required for the lysosomal degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. Patients with MPS‐I store forms of these partially degraded glycosaminoglycans in their lysosomes. MPS‐I patients present with a wide range of clinical phenotypes, which makes prognostic predictions and genetic counselling difficult, therefore impeding the selection and evaluation of patients undergoing experimental therapy, such as bone marrow transplantation. We report the presence of two mutations, one that introduces a stop codon at position 70 (Q₇₀X), and the other that alters the proline at position 533 to an arginine (P₅₃₃R) in the 653 amino acid α‐L‐iduronidase protein. These mutations were originally detected by chemical cleavage and then by direct PCR sequencing. Allele specific oligonucleotides were used to detect the mutations in a group of 73 MPS‐I patients and Q₇₀X was found to account for 15% of all MPS‐I alleles and P₅₃₃R for 3% of MPS‐I alleles. Both mutations are associated with an extremely severe clinical phenotype in homozygotes. MPS‐I patients heterozygous for either mutation may have a wide range of clinical phenotypes. We have now described three mutations, W₄₀₂X (Scott et al., 1992c), Q₇₀X, and P₅₃₃R totalling 53% of MPS‐I alleles which together define 28% of MPS‐I genotypes.