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α‐L‐iduronidase mutations (Q 70 X and P 533 R) associate with a severe Hurler phenotype
Author(s) -
Scott Hamish S.,
Litjens Tom,
Nelson Paul V.,
Brooks Doug A.,
Hopwood John J.,
Morris C. Phillip
Publication year - 1992
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1380010412
Subject(s) - mucopolysaccharidosis type i , hurler syndrome , mucopolysaccharidosis i , biology , phenotype , allele , genetics , mucopolysaccharidosis , mutation , lysosomal storage disease , point mutation , genotype , microbiology and biotechnology , gene , enzyme replacement therapy , disease , biochemistry , medicine , enzyme
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 (Q 70 X), and the other that alters the proline at position 533 to an arginine (P 533 R) 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 Q 70 X was found to account for 15% of all MPS‐I alleles and P 533 R 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, W 402 X (Scott et al., 1992c), Q 70 X, and P 533 R totalling 53% of MPS‐I alleles which together define 28% of MPS‐I genotypes. © 1992 Wiley‐Liss, Inc.