MUCOPOLYSACCHARIDOSIS TYPE-II (HUNTER SYNDROME) - MUTATION HOT-SPOTS IN THE IDURONATE-2-SULFATASE GENE

Mucopolysaccharidosis type II (MPS II, Hunter syndrome)) is an X-chrom osomal storage disorder due to deficiency of the lysosomal enzyme idur onate-2-sulfatase (IDS). We have identified IDS mutations in a total o f 31 families/patients with MPS II, of which 20 are novel and unique a nd a further 1 is novel but has been found in 3 unrelated patients. On e of the mutations detected is of special interest as an A-->G substit ution in an intron, far apart from the coding region, is deleterious b y creating a new 5'-splice-donor site that results in the inclusion of a 78-bp intronic sequence. While the distribution of gene rearrangeme nts (deletions, insertions, and duplications) of <20 bp seems to be ra ndom over the IDS gene, the analysis of a total of 101 point mutations lying within the coding region shows that they tend to be more freque nt in exons III, VIII, and IX. Forty-seven percent of the point mutati ons are at CpG dinucleotides, of which G:C-to-A:T transitions constitu te nearly 80%. Almost all recurrent point mutations involve CpG sites. Analysis of a collective of 50 families studied in our laboratory, to date, revealed that mutations occur more frequently in male meioses ( estimated male-to-female ratio between 3.76 and 6.3).