Expression studies of two novel in CIS‐mutations identified in an intermediate case of Hunter syndrome

Abstract

Hunter syndrome (Mucopolysaccharidosis type II) is a rare X-linked recessive lysosomal storage disorder caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS). To date, more than 200 different mutations have been reported in the IDS gene, located on Xq27.3-q28. Here, we report two new mutations (M488I and G489A) identified in hemizygosity in an Italian Hunter patient. Their "in vitro" expression by COS 7 cells was carried out in order to evaluate their functional consequence on enzyme activity as well as their possible cumulative effect on the malfunctioning of the protein. The results obtained enabled us to confirm the G489A mutation as causative. The M488I mutation, however, could not be unequivocally considered as causing disease because of its residual activity. Although a cumulative effect of the two mutations can be excluded "in vitro," we are cautious about drawing a conclusion with regard to the possible role that the two mutations could have played "in vivo" in modulating the phenotype of the patient. Finally, the knowledge of the molecular defect of the patient has enabled us to identify the carriers, providing reliable genetic counselling to the females of the family.

Further cases of “neighbor” mutations in mucopolysaccharidosis type II

“…The deleterious character of I485T is suggested by codon conservation in the murine IDS gene [Daniele et al, 1993] and severe clinical phenotypes associated with I485R and I485K mutations [Schröder et al, 1994;Vafiadaki et al, 1998]. G489 is not a conserved codon; however, the pathogenicity of the G489A mutation has been demonstrated through expression studies [Ricci et al, 2003]. Interestingly, two brothers with MPS II in our cohort (Patients C and D) have a G489D mutation, and they are unrelated to Patient A.…”

“…The ''neighbor'' mutations described here and by Timms et al [1998] and Ricci et al [2003] are located in mutation-rich regions of the IDS gene (exons V, VIII, and IX) involving non-conserved codons with [Daniele et al, 1993] Conserved codon among human sulfatases [Wilson et al, 1990] A nl. TAT AAA GAT CAT GGG CTA; mut.…”

“…According to the HGMD [2006], 309 different mutations in the IDS gene have been described, most of which are point mutations (63%) or small deletions (18%). Only four of those point mutations are considered nondeleterious: T146T [Li et al, 1995], R313C [Gort et al, 1999], D319D [Vellodi et al, 1999], and M488I [Ricci et al, 2003].…”

“…Interestingly, Ricci et al [2003] described the occurrence of two ''neighbor'' point mutations in the IDS gene (M488I and G489A) in a patient with a less severe form of MPS II. The expression of both mutations in COS7 cells confirmed G489A as causative, and the patient's mother was a carrier of both mutations.…”

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

“…By contrast, no wild-type IDS sequence was evident in the genomic DNAs derived from these patients. Whatever the explanation for this phenomenon, it was clear from the outset that it was likely to be infrequent since the IDS gene has previously been studied in at least 65 Hunter syndrome patients at both the genomic and the cDNA level without any other examples of such a discrepancy ever having come to light [Bonuccelli et al, 1998;Filocamo et al, 2001;Ricci et al, 2003a;2003b;Lualdi et al, 2005;2006a;2006b].…”