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

Abstract

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive genetic disease caused by a deficiency of the glycosidase alpha-L-iduronidase which is required for the lysosomal degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. Patients with MPS-I store these partially degraded glycosaminoglycans in their lysosomes. MPS-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 31% of MPS-I alleles in a study of 64 MPS-I patients. The mutation was originally detected by chemical cleavage and then direct PCR sequencing. The mutation is a single base substitution that introduces a stop codon at position 402 (W402X) of the alpha-L-iduronidase protein and is associated with an extremely severe clinical phenotype in homozygotes. Patients who are compound heterozygotes having one allele carrying the W402X mutation have a wide range of clinical phenotypes. Based on polymorphisms within the alpha-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. W402X introduces a MaeI restriction endonuclease site into MPS-I alleles enabling its simple detection, which should make possible the assessment of the efficacy of bone marrow transplantation in MPS-I patients homozygous for W402X.

α-l-Iduronidase Premature Stop Codons and Potential Read-Through in Mucopolysaccharidosis Type I Patients

“…To date, only a TAG codon has been reported for MPS I patients with the W402X mutation, but the mutation to TGA is possible and would be expected to produce more residual a-L-iduronidase and hence generate a slightly attenuated clinical phenotype compared to Hurler syndrome. Interestingly, the report of only a TAG codon for W402X 3,7,9,14 supports the strong founder effect observed for this mutation. In theory, a premature TAA stop codon should generate the most severe clinical phenotype in an MPS I patient, but this is less likely at the Q70 and W402 positions, due to the need for a double base change.…”

“…2 -6 In Caucasians, the two most common IDUA mutations are the premature stop codons Q70X and W402X which are responsible for approximately 70% of disease alleles †. 2,3,7 -9 Both of these mutations produce no detectable a-L-iduronidase protein and activity, 7,8,10 and in the homozygous condition are associated with a very severe clinical presentation. At least 13 other mutations causing premature IDUA stop codons have been identified †, 2,6,11 -15 including the new mutation described here (i.e.…”

Common Mutations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients of Different Origins

“…1C. This is also a known mutational mechanism (14). We describe the first occurrence of 1094-1106del in a Finnish patient and another mutation, X546C, in two Finnish patients.…”

“…Haplotype analyses indicate a minimum of five independent mutational events worldwide for this mutation, but the more likely scenario is that there have been a minimum of nine independent occurrences of R257X. This is not unprecedented as recurring C3T transition mutations in CpG dinucleotides, particularly those in arginine codons, are commonly described mutation events (13)(14)(15). R257X has only been observed with one haplotype in Finnish patients, and the success of linkage disequilibrium studies in Finnish families (10) and the frequency of the disease in Finland point to a single mutational event for the Finnish R257X.…”

Enzyme replacement in a canine model of Hurler syndrome.

“…A milder form of a-Liduronidase deficiency, the Hurler/Scheie syndrome, is compatible with normal intelligence and survival to adulthood although with severe physical handicaps, whereas the Scheie syndrome is milder yet and may permit a normal life. These disorders are caused by recessive mutations in the a-L-iduronidase gene (IDUA), with genetic heterogeneity both within and between the three clinical groups (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”