Molecular basis of mucopolysaccharidosis type II: Mutations in the iduronate-2-sulphatase gene

Abstract

A number of mutations in the X-chromosomal human iduronate-2-sulphatase gene have now been identified as the primary genetic defect leading to the clinical condition known as Hunter syndrome or mucopolysaccharidosis type II. The mutations that are tabulated include different deletions, splice-site and point mutations. From the group of 319 patients thus far studied by Southern analysis, 14 have a full deletion of the gene and 48 have a partial deletion or other gross rearrangements. All patients with full deletions or gross rearrangements have severe clinical presentations. Twenty-nine different "small" mutations have so far been characterised in a total of 32 patients. These include 4 nonsense and 13 missense mutations, 7 different small deletions from 1 to 3 bp, with most leading to a frameshift and premature chain termination, and 5 different splice-site mutations also leading to small insertions or deletions in the mRNA. A 60 bp deletion, that results from a new donor splice-site, has been observed in five unrelated patients with relatively mild clinical phenotypes. This information will not only be useful for MPS II patient and carrier diagnosis, but also will aid in the understanding of the structure and function of iduronate-2-sulphatase, and possibly in correlating genotype with phenotype.

Mutations in the iduronate-2-sulfatase gene in 12 Spanish patients with hunter disease

“…Patient H40 and his brother who show a mild phenotype carry the nonsense mutation R443X also reported in other patients with an intermediate clinical course (Bunge et al, 1992;Sukegawa et al, 1992Sukegawa et al, , 1993Sukegawa et al, , 1995Bunge et al, 1993;Froissart et al, 1993). Patients H10 and H8 and his brother have the aberrant splicing mutation G374sp previously described in other patients with the same clinical course as ours (Flomen et al, 1992;Bunge et al, 1993;Hopwood et al, 1993;Popowska et al, 1995;Goldenfum et al, 1996 Seven other patients have different types of mutations not previously reported. These novel mutations include four missense (H6, H77, H1, and H13), one nonsense (H25), one base pair insertion (H29) and one aberrant splicing (H52).…”

“…Since the cloning and sequencing of the human IDS coding region (Wilson et al, 1990) more than 80 different mutations have been described so far (Crotty et al, 1992;Flomen et al, 1992;Aronovich et al, 1993;Bunge et al, 1993;Goldenfum et al, 1993;Hopwood et al, 1993;Sukegawa et al, 1993;Whitley et al, 1993;Li et al, 1994;Jonsson et al, 1995;Li et al, 1995a;Li et al, 199513;Popowska et al, 1995;Sukegawa et al, 1995;Villani et al, 1995;Goldenfum et al, 1996;Olsen et al, 1996), 47% of these mutations being missense mutations, 11% nonsense mutations, 12% aberrant splicing, and 30% are small deletions or insertions. Moreover, less than 20% of MPS I1 patients have major structural gene alterations, including major gene deletions and rearrangements (Goldenfum et al, 1996).…”

Quantification of X-chromosome inactivation patterns using RT-PCR of the polymorphic iduronate-2-sulphatase gene and correlation of the results obtained with DNA-based techniques

“…13 The two alleles are distinguished by the inclusion of a mismatch nucleotide in one of the primers which introduces a cutting site for the restriction enzyme BclI in T-containing alleles. Screening of 150 DNA samples revealed that 41% were heterozygous for this polymorphism and therefore suitable for further analysis.…”

“…Single base substitutions have been described in three genes so far, G6PD (different from the A/A− variants in African populations), 12 iduronate-2-sulphatase (IDS), 13 and the palmitoylated membrane protein p55. 14 Several different methods of determining an XCIP have been reported, each initially employing reverse transcription of RNA.…”

“…14 The IDS gene encodes a lysosomal enzyme and has been implicated in the mucopolysaccharidosis disorder Hunter's syndrome, where abnormalities include point mutations, as well as large deletions. 13 There is a functionally silent C/T polymorphism at codon 146 and this has been used to determine monoclonality of a cell population. 16 However, quantitative comparison with results from DNA-based assays has not been reported.…”