title: Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase.
abstract: Mucopolysaccharidosis type II (MPS II: also called as Hunter syndrome) is an X-linked recessive lysosomal storage disorder characterized by the accumulation of extracellular glycosaminoglycans due to the deficiency of the enzyme iduronate-2-sulfatase (IDS). Previous observations suggested that MPS II can be classified into two distinct disease subtypes: (1) severe type of MPS II involves a decline in the cognitive ability of a patient and (2) attenuated type of MPS II exhibits no such intellectual phenotype. To determine whether such disease subtypes of MPS II could be explained by genetic diagnosis, we analyzed mutations in the IDS gene of 65 patients suffering from MPS II among the Japanese population who were diagnosed with both the accumulation of urinary glycosaminoglycans and a decrease in their IDS enzyme activity between 2004 and 2014. Among the specimens examined, we identified the following mutations: 33 missense, 8 nonsense, 7 frameshift, 4 intronic changes affecting splicing, 8 recombinations involving IDS-IDS2, and 7 other mutations including 4 large deletions. Consistent with the previous data, the results of our study showed that most of the attenuated phenotype was derived from the missense mutations of the IDS gene, whereas mutations associated with a large structural alteration including recombination, splicing, frameshift, and nonsense mutations were linked to the severe phenotype of MPS II. Furthermore, we conducted a homology modeling study of IDS P120R and N534I mutant as representatives of the causative mutation of the severe and attenuated type of MPS II, respectively. We found that the substitution of P120R of the IDS enzyme was predicted to deform the α-helix generated by I119-F123, leading to the major structural alteration of the wild-type IDS enzyme. In sharp contrast, the effect of the structural alteration of N534I was marginal; thus, this mutation was pathogenically predicted to be associated with the attenuated type of MPS II. These results suggest that a combination of the genomic diagnosis of the IDS gene and the structural prediction of the IDS enzyme could enable the prediction of a phenotype more effectively.
authors.affiliation: Center for Lysosomal Storage Diseases, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan; Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan; Division of Medical Genetics, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: kosuga-m@ncchd.go.jp.
authors.forename: Motomichi
authors.initials: M
authors.lastname: Kosuga
authors.affiliation: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: mashima-r@ncchd.go.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Mashima
authors.affiliation: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Hirakiyama
authors.affiliation: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Fuji
authors.affiliation: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Joo-Hyun
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Biobank, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Nikaido
authors.affiliation: Department of Medical Management and Informatics, Hokkaido Information University, 59-2 Nishinopporo, Ebetsu, Hokkaido 069-8585, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Saito
authors.affiliation: Catalyst Inc., 1-5-6 Kudan-minami, Chiyoda-ku, Tokyo 102-0074, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
authors.affiliation: Center for Lysosomal Storage Diseases, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan; Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Torayuki
authors.initials: T
authors.lastname: Okuyama
mesh_terms: D044466:Asian People / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics*; D006025:Glycosaminoglycans / Q000652:urine; D006801:Humans; D007564:Japan; D008297:Male; D008958:Models, Molecular; D016532:Mucopolysaccharidosis II / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D010375:Pedigree; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein
chemical_list: D006023:Glycoproteins; D006025:Glycosaminoglycans; C018322:IDS protein, human
keywords: Genotypephenotype correlation; Homology modeling; Hunter syndrome; Iduronate-2-sulfatase; MPS type II