Mucopolysaccharidosis type I is an autosomal recessive disorder caused by deficiency of α-l-iduronidase, encoded by the IDUA gene. More than 100 disease causing mutations have been reported in the gene, resulting in a wide range of phenotypes. Here we describe a previously unreported IDUA splice site mutation (NG_008103.1:g.21632G>C; NM_000203.3:c.1727+3G>C) causing a Hurler phenotype in a patient heterozygous for the common p.Q70X (NG_008103.1:g.5862C>T) mutation. Sequence analysis of IDUA transcripts demonstrated that the g.21632G>C mutation results in aberrant splicing of intron 12 (NM_000203.3:c.1727_1728insGTCC), introducing a frame shift and premature termination codon (NP_000194.2:p.Cys577SerfsX15). Gene expression studies suggest that the deleterious effect of the mutation is primarily due to a C-terminal truncation of the encoded polypeptide. Furthermore, we observed that both normal and mutant IDUA alleles give rise to alternatively spliced transcripts in leukocytes. Exclusion of exon 4 appeared to be the predominant alternative splicing event, probably resulting in polypeptides lacking iduronidase activity. The Hurler patient demonstrated exon 4 skipping in 5.6% of IDUA transcripts, while exon 4 skipping ranged 25-34% of transcripts among healthy individuals (n=5). Alternative splicing might represent a mechanism for regulation of this enzyme, and the lower level of exon 4 skipping in the patient might be a response to intracellular accumulation of iduronidase substrates. Molecular characterization of IDUA mutations and splicing may assist early prediction of mucopolysaccharidosis type I phenotypes and increase the understanding of disease mechanisms. This is important considering the choice of current treatment options and for the development of future therapies.
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