Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene.

Abstract

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder resulting from a deficiency of the lysosomal glycosidase, alpha-L-iduronidase (IDUA). Patients with MPS I present with variable clinical manifestations ranging from severe to mild. To facilitate studies of phenotype-genotype correlation, the authors performed molecular studies to detect mutations in MPS I patients and characterize single nucleotide polymorphism (SNP) in the gene. Twenty-two unrelated MPS I patients were subjects for mutation detection using reverse transcriptional polymerase chain reaction (RT-PCR) and genomic PCR sequencing. Polymorphism analyses were performed on controls by restriction enzyme assays of PCR amplicons flanking nine intragenic single nucleotide polymorphic alleles. Eleven different mutations including two common mutations (Q70X, W402X), five recurrent mutations (D315Y, P533R, R621X, R628X, S633L), and four novel mutations (R162I, G208D, 1352delG, 1952del25bp) were identified from MPS I patients. Multiple SNP alleles coexisting with the disease-causing mutations were detected. Allelic frequencies for nine SNP alleles including A8, A20, Q33H, L118, N181, A314, A361T, T388, and T410 were determined. The results provide further evidence for the mutational heterogeneity among MPS I patients and point out possible common haplotype structures in the gene.