A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype

✍ Scribed by Hamish S. Scott; Tom Litjens; John J. Hopwood; C. Phillip Morris

• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 612 KB
• Volume: 1
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.1380010204

✦ Synopsis

Communicated by William S. Sly Mucopolysaccharidosis type I (MI'S-I) is an autosomal recessive genetic disease caused by a deficiency of the glycosidase a-L-iduronidase which is required for the lysosomal degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. Patients with MI'S-I store these partially degraded glycosaminoglycans in their lysosomes. MI'S-I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counselling and also impedes the selection and evaluation of patients undergoing therapy such as bone marrow transplantation. We report the presence of a common mutation accounting for 3 1% of MI'S-I alleles in a study of 64 MI'S-I patients, The mutation was originally detected by chemical cleavage and then direct I'CR sequencing. The mutation is a single base substitution that introduces a stop codon at position 402 (W,,,X) of the a-L-iduronidase protein and is associated with an extremely severe clinical phenotype in homozygotes. Patients who are compound heterozygotes having one allele carrying the W,,,X mutation have a wide range of clinical phenotypes. Based on polymorphisms within the a-L-iduronidase gene, W402X is associated with three different haplotypes, implying that there is more than one origin for the mutation or that intragenic recombination has occurred. W,,,X introduces a Mae1 restriction endonuclease site into MI'S-I alleles enabling its simple detection, which should make possible the assessment of the efficacy of bone marrow transplantation in MI'S-I patients homozygous for W40zX.