MUTATION ANALYSIS OF 19 NORTH-AMERICAN MUCOPOLYSACCHARIDOSIS TYPE-I PATIENTS - IDENTIFICATION OF 2 ADDITIONAL FREQUENT MUTATIONS

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive genetic disorder caused by deficiency of the lysosomal glycosidase alpha-L-id uronidase. Patients with this disorder present with varied clinical ph enotypes ranging from early severe onset of disease and death in early childhood to mild manifestations compatible with adult life, An under standing of the molecular basis of iduronidase deficiency and its corr elation to clinical phenotype will improve prognostic prediction at di agnosis, aid in genetic counselling of families, and provide a framewo rk to more accurately assess experimental treatment protocols. We have used the approach of single-strand conformational polymorphism analys is and direct sequencing of the alpha-L-iduronidase gene in an attempt to define the molecular basis of iduronidase deficiency in affected i ndividuals. An initial series of 19 patients representing 35 independe ntly seg regating mutant alleles were studied. In addition to five pre viously identified mutations (W402X, Q70X, E274X, H82P, and P533R) two novel mutations (A75T and 474-2a-->g) were found. These seven mutatio ns account for 71% of the mutant alleles and 53% of the genotypes in t his group of patients. Analysis of a larger independently ascertained group of 103 MPS I patients, mainly of Northern European origin, revea led that together the two novel mutations account for 7% of mutant all eles and are associated with severe clinical phenotypes, These mutatio ns are the most frequent MPS I mutations detected so far after W402X a nd Q70X. With the definition of these two mutations, a clear picture o f the molecular heterogeneity of MPS I is emerging. (C) 1994 Wiley-Lis s, Inc.