Structural Basis of Mucopolysaccharidosis Type II and Construction of a Database of Mutant Iduronate 2-Sulfatases.
Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked genetic disorder caused by a deficiency of iduronate 2-sulfatase (IDS), and missense mutations comprising about 30% of the mutations responsible for MPS II result in heterogeneous phenotypes ranging from the severe to the attenuated form. To elucidate the basis of MPS II from the structural viewpoint, we built structural models of the wild type and mutant IDS proteins resulting from 131 missense mutations (phenotypes: 67 severe and 64 attenuated), and analyzed the influence of each amino acid substitution on the IDS structure by calculating the accessible surface area, the number of atoms affected and the root-mean-square distance. The results revealed that the amino acid substitutions causing MPS II were widely spread over the enzyme molecule and that the structural changes of the enzyme protein were generally larger in the severe group than in the attenuated one. Coloring of the atoms influenced by different amino acid substitutions at the same residue showed that the structural changes influenced the disease progression. Based on these data, we constructed a database of IDS mutations as to the structures of mutant IDS proteins.
Department of Medical Management and Informatics, Hokkaido Information University, 59-2 Nishinopporo, Ebetsu, Hokkaido 069-8585, Japan.
Seiji
S
Saito
Catalyst Inc., 1-5-6 Kudan-minami, Chiyoda-ku, Tokyo 102-0074, Japan.|Education Academy of Computational Life Sciences, Tokyo Institute of Technology, 2-12-1 Ookayama Meguro-ku, Tokyo 152-8552, Japan.
Kazuki
K
Ohno
Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Torayuki
T
Okuyama
Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
Hitoshi
H
Sakuraba
D019943:Amino Acid Substitution; D020134:Catalytic Domain; D030561:Databases, Nucleic Acid; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D016532:Mucopolysaccharidosis II / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D006023:Glycoproteins; C018322:IDS protein, human
Proc Natl Acad Sci U S A. 1990 Nov;87(21):8531-5
2122463
J Hum Genet. 2011 Jun;56(6):467-8
21412250
J Inherit Metab Dis. 2006 Dec;29(6):755-61
17091340
BMC Bioinformatics. 2008 Jan 23;9:40
18215316
Hum Genet. 2005 Aug;117(4):317-28
15924232
J Hum Genet. 2005;50(8):395-402
16133661
Biochem J. 2005 Mar 1;386(Pt 2):395-400
15500445
Orphanet J Rare Dis. 2015 Apr 12;10:43
25887606
Mol Genet Metab. 2013 Mar;108(3):172-7
23375472
Cell. 1995 Jul 28;82(2):271-8
7628016
Hum Genet. 2005 Feb;116(3):160-6
15614569
Proteins. 1995 Dec;23(4):566-79
8749853
Genomics. 1993 Sep;17(3):773-5
8244397
Biochem Genet. 2012 Dec;50(11-12):990-7
22990955
Hum Genet. 1991 Mar;86(5):505-8
1901826
Mol Genet Metab Rep. 2015 Apr 22;3:65-74
26937399
Hum Mutat. 1995;6(2):136-43
7581397
Biochim Biophys Acta. 1998 Mar 5;1406(2):214-8
9573369
Hum Mutat. 2003 Apr;21(4):449-50
12655569
Mol Genet Metab. 2015 Feb;114(2):156-60
25219292
Hum Mol Genet. 1993 Jan;2(1):5-10
8490623
J Chem Theory Comput. 2008 Mar;4(3):435-47
26620784