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

• Published in: PloS one Vol. 6; no. 8; p. e22951
• Main Authors: Zhang, Huiwen, Li, Jing, Zhang, Xinshun, Wang, Yu, Qiu, Wenjuan, Ye, Jun, Han, Lianshu, Gao, Xiaolan, Gu, Xuefan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2011; Public Library of Science (PLoS)
• Subjects: Androgen receptors; Base Sequence; Biology; China; Cohort Studies; Deactivation; Deoxyribonucleic acid; DNA; DNA Primers; DNA, Complementary; Endocrinology; Exons; Female; Gene amplification; Gene deletion; Glycoproteins - genetics; Humans; Inactivation; Intellectual disabilities; Leukocytes; Medicine; Metabolism; Minority & ethnic groups; Missense mutation; Mucopolysaccharidosis; Mucopolysaccharidosis II - genetics; Mutagenesis; Mutation; Patients; Pediatrics; Point Mutation; Polymerase chain reaction; Proteins; Rare diseases; Reverse Transcriptase Polymerase Chain Reaction; Reverse transcription; Ribonucleic acid; RNA; RNA Splicing; Splicing; Urine; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0022951

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. Here we investigated mutations of IDS (iduronate 2-sulfatase) gene in 38 unrelated Chinese patients, one of which is a female. Peripheral 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. We 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. In 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.