Detection of four novel mutations in the iduronate‐2‐sulfatase gene

Abstract

Hunter disease (mucopolysaccharidosis type II or MPS II) is an X-linked recessive disorder caused by the deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS) (E.C.3.1.6.13.) involved in the catabolism of mucopolysaccharides dermatan sulfate and heparan sulfate. A large variety of alterations have been detected at the IDS locus. We report here the identification, in 7 unrelated Italian patients, of IDS gene mutations, four of which are novel and have been confirmed by amplification refractory system (ARMS) or restriction analysis. Our findings include: the missense mutation P86L found in a severe phenotype, the splicing mutation G374G and the nonsense mutation W475X, both associated with mild phenotypes. The four novel mutations were: the missense mutations R88P and R88H, associated with severe phenotypes, concerning a position found to be a mutational "hot-spot" for the IDS gene due to a mutation-prone CpG dinucleotide; mutations T1181 and P266H, both in mild patients. Interestingly, four of our mutations are located on exon III of IDS gene, confirming the high mutation frequency of this exon. After this manuscript was submitted, Rathman et al (Am. J.Hum.Genet.59,1202,1996) reported a total of 101 mutations including one R88H which is one of the novel mutations in this report.

Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II

“…Missense mutations at R88 (R88C, R88G, R88H, R88L, and R88P) have been commonly reported in Europe and Russia (Rathmann et al 1996;Froissart et al 1998;Karsten et al 1998;Balzano et al 1998;Filocamo et al 2001). These R88 mutations related to the severe phenotype.…”

“…The P86L was identified in Japan, Europe, and South Africa and was related to the severe phenotype (Isogai et al 1998;Froissart et al 1998;Vafiadaki et al 1998;Balzano et al 1998). One of the authors speculated that this missense mutation activated a cryptic splice acceptor site and produced a truncated mRNA.…”

“…In addition to these missense mutations, a unique point mutation, c.1122C>T (G374G), has been found in many other ethnicities, European countries, Russia, and Korea (Bunge et al 1993;Rathmann et al 1996;Gort et al 1998;Balzano et al 1998;Vafiadaki et al 1998;Karsten et al 1998;Hartog et al 1999;Filocamo et al 2001). This common mutation appears to relate mainly to the attenuated phenotype, as indicated in our structural analysis, but some patients showed severe manifestations.…”

Molecular analysis of 40 Italian patients with mucopolysaccharidosis type II: New mutations in the iduronate-2-sulfatase (IDS) gene

“…A total of 40 unrelated Italian patients were examined. Results of the examinations of 8 of these have however already been published (Carrozzo et al, 1996;Balzano et al, 1997;Villani et al, 1997;Bonuccelli et al, 1998;Bonuccelli et al, 2000). All 40 patients were diagnosed with Hunter syndrome based on biochemical abnormalities and IDS activity deficiency.…”

“…For genomic DNA amplification, sets of primers flanking each exon were designed. Specific oligonucleotide primers were used for selective amplification of IDS exons II and III from IDS2 homologous exons (Flomen et al, 1993;Bondeson et al, 1995b;Rathmann et al, 1995;Balzano et al, 1997). The PCR amplification conditions were those reported elsewhere (Bonuccelli et al, 1998).…”