Analysis of the IDS Gene in 38 Patients with Hunter Syndrome: The c.879G>A (p.Gln293Gln) Synonymous Variation in a Female Create Exonic Splicing

Abstract

BackgroundHunter syndrome (mucopolysaccharidosis type II, MPS II) is a rare disease inherited in an X-linked autosomal recessive pattern. It is the prevailing form of the mucopolysaccharidoses in China. Here we investigated mutations of IDS (iduronate 2-sulfatase) gene in 38 unrelated Chinese patients, one of which is a female.MethodsPeripheral leucocytes were collected from the patients and the IDS gene was amplified to looking for the variations. For a female patient, the X chromosome status was analyzed by androgen receptor X-inactivation assay and the mutation impact on RNA level was further performed by reverse transcription polymerase chain reaction.ResultsWe discovered that point mutations constituted the major form while mutations in codon p.R468 defined the largest number of patients in our cohort. Consistent with data from other ethnic groups, exons 9 and 3 had comparatively more mutations, while exon 2 had quite a few mutations unique to Chinese patients. Of the 30 different mutations identified, only 9 were novel: one was a premature termination mutation, i.e., c.196C>T (p.Gln66X); three were missense mutations, i.e., c.200T>C (p.Leu67Pro), c.215T>C (p.Leu72Pro), c.389C>T (p.Thr130Ile); one was a small deletion, i.e., c.1104_1122del19 (p.Ser369ArgfsX16); and one was a deletion that spanned both exons 8 and 9 deletion leading to gross structural changes in the IDS gene. In addition, a synonymous mutation c.879G>A (p.Gln293Gln) was identified in a female Hunter disease patient, which resulted in loss of the original splicing site, activated a cryptic splicing site upstream, leading to a 28 bp deletion and a premature termination at p. Tyr285GlufsX47. Together with concurrent skewed X-inactivation this was believed to facilitate the development of Hunter disease in this girl.ConclusionsIn conclusion, the molecular analysis of IDS gene in Chinese patients confirmed the Hunter disease diagnosis and expanded the mutation and clinical spectrum of this devastating disorder.

Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome

“…The severe phenotypes found in the patients who presented with the following mutations, p.P86L, p.R88H, p.R468Q, and p. R468W, are in agreement with those reported in literature [3, 18–24]. Specifically, the above mutations have also been found in the Asian population such as in Chinese and Japanese patients [4, 25, 26] presenting with the severe phenotype. The published nonsense mutations, p.Q75*, p.W109*, and p.R172*, were found in our patients with severe phenotypes and were in agreement with previous literature reports among Caucasian and Asian patients with Hunter syndrome in terms of their effects on phenotype [19, 20, 27–29].…”

Mucopolysaccharidosis Type II and the G374sp Mutation

“…This extensive gene variability may be explained by the presence of several transcripts which favors a complex system of intron splicing that makes the IDS gene susceptible to splicing mutations. This is compounded by a pseudogene, located 80 kb downstream of the transcribed IDS, that seems to be responsible for various of the IDS gene mutations and gene rearrangements [Froissart et al, 2007;Zhang et al, 2011]. These data further confirm the extreme heterogeneity of IDS gene alterations and explain the high degree of the clinical presentations.…”

“…In a study of 155 unrelated individuals with MPS II, Froissart et al [2007] identified 27 large and 128 small IDS gene alterations of which 96 were different. Meanwhile, Zhang et al [2011] found in 38 Chinese patients with Hunter syndrome that point mutations constituted the major form, while mutations in codon p.R468 defined the largest number of patients in their cohort. Otherwise, Gort et al [1998] revealed in a study that included 31 Spanish families with MPS II that the most frequent mutation, seen in 10% of the cases, was the G374sp and that this mutation was related with a milder phenotype.…”

Epidemiology of mucopolysaccharidoses

“…The birth prevalence of MPS II in Brazil is lower (0.38), similar to Czech Republic, Denmark, Norway, Sweden, Switzerland, and Tunisia. In general, East Asian countries including China, Japan, and Taiwan have a high incidence of MPS II that could be due to common mutation R468 in IDS gene [24, 49–51]. In contrast, in South Korea, IDS-IDS2 recombination mutations were most frequently found in Korean patients with a severe phenotype [23].…”

“…In contrast, only 6% of mutant alleles in MPS II patients in South America had R468 mutations [52]. It is noteworthy that the mutated codon for R468 is considered as “hot spot” for IDS gene mutation and different mutations have been identified in distinct populations [49–51, 53–56]. Kosuga et al found 8 recombination events involving IDS-IDS2 in the Japanese population [57].…”