title: Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II.
abstract: We investigated mutations of the iduronate-2-sulfatase (I2S) gene and structural characteristics of I2S to clarify genotype/phenotype relationships in 18 Japanese patients with mucopolysaccharidosis type II. The I2S gene was analyzed in five patients with a severe phenotype and in 13 patients with an attenuated phenotype. The tertiary structural model of the human I2S was constructed by homology modeling using the arylsulfatase structure as a template. We identified four missense mutations and a nonsense mutation in the severe phenotype; four missense, two nonsense, three frame shifts, and one each of splice and amino acid deletion in the attenuated phenotype. Seven of them (L73del, Q75X, G140R, C171R, V401 fs, C422 fs, and H441 fs) were novel mutations. Structural analysis indicated that the residues of the mutations found in the severe phenotype would have direct interactions with the active site residues or should break the hydrophobic core domain of I2S, whereas residues of the missense mutations found in the attenuated phenotype were located in the peripheral region. In addition, effects by deletion or frameshift mutations could also be interpreted by the structure. Structural analysis of mutant proteins would help in understanding the genotype/phenotype relationships of Hunter disease.
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan. tomok@cc.gifu-u.ac.jp.|Medical Education Development Center, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan. tomok@cc.gifu-u.ac.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Zenichiro
authors.initials: Z
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kuratsubo
authors.affiliation: Research Center, Japan Chemical Research Pharmaceuticals Co. Ltd., Kobe, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Research Center, Japan Chemical Research Pharmaceuticals Co. Ltd., Kobe, Japan.
authors.forename: Tabito
authors.initials: T
authors.lastname: Ishigami
authors.affiliation: Research Center, Japan Chemical Research Pharmaceuticals Co. Ltd., Kobe, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kajihara
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sukegawa-Hayasaka
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Orii
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Isogai
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
authors.affiliation: Division of Genomic Research, Life Science Research Center, Gifu University, Gifu, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimozawa
authors.affiliation: Chubu Gakuin University, Gifu, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Orii
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.|Medical Education Development Center, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D006801:Humans; D007066:Iduronate Sulfatase / Q000737:chemistry / Q000235:genetics*; D007564:Japan; D008958:Models, Molecular; D016532:Mucopolysaccharidosis II / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D007066:Iduronate Sulfatase