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.
Highlights
Hunter syndrome (MPS II; OMIM 309900), is caused by deficiency of the lysosomal enzyme iduronate 2-sulfatase (IDS, EC 3.1.6.13) which functions in the catabolism of two glycosaminoglycans, dermatan sulphate and heparan sulphate
Mutation spectrum of IDS in Chinese patients Among these 38 unrelated Chinese patients with Hunter syndrome, 37 of them have been identified with IDS gene variations
All the variations were considered to be causative for Hunter disease, since they were not found in 100 alleles from normal people
Summary
Hunter syndrome (MPS II; OMIM 309900), is caused by deficiency of the lysosomal enzyme iduronate 2-sulfatase (IDS, EC 3.1.6.13) which functions in the catabolism of two glycosaminoglycans, dermatan sulphate and heparan sulphate. The presence of several transcripts in normal humans reflects a complex system of intron splicing and strongly suggests that the IDS gene is susceptible to splicing mutations. About 80 kb downstream of the transcribed IDS gene, there is an IDS pseudogene, called IDS2. It is homologous in exons 2 and 3, and introns 2, 3, 7 of transcribed IDS [1], where exon 3 is 100% identical and the other sequences are 96% identical. Hunter 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. We investigated mutations of IDS (iduronate 2-sulfatase) gene in 38 unrelated Chinese patients, one of which is a female
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