title: Molecular pathology of Sandhoff disease with p.Arg505Gln in HEXB: application of simulation analysis.
abstract: Sandhoff disease is a GM2 gangliosidosis caused by mutations in HEXB encoding the β-subunit of β-hexosaminidase A. β-Hexosaminidase A exists as a heterodimer consisting of α- and β-subunits, and requires a GM2 activator protein to hydrolyze GM2. To investigate the molecular pathology in an adult Sandhoff disease patient with an early disease onset, we performed mutation detection, western blot analysis and molecular simulation analysis. The patient had compound heterozygous mutations p.Arg505Gln and p.Ser341ValfsX30. Western blot analysis showed that the amount of mature form of the α- and β-subunits was markedly decreased in the patient. We then performed docking simulation analysis of the α- and β-subunits with p.Arg505Gln, the GM2AP/GM2 complex and β-hexosaminidase A, and GM2 and β-hexosaminidase A. Simulation analysis showed that p.Arg505Gln impaired each step of molecular conformation of the α- and β-subunits heterodimer, the activator protein and GM2. The results indicated that p.Ser341ValfsX30 reduced the amount of β-subunit, and that p.Arg505Gln hampered the maturation of α- and β-subunits, and hindered the catalytic ability of β-hexosaminidase A. In conclusion, various methods including simulation analysis were useful to understand the molecular pathology in Sandhoff disease.
authors.affiliation: Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yasui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takaoka
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
authors.forename: Dian K
authors.initials: DK
authors.lastname: Nurputra
authors.forename: Kenji
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Hamaguchi
authors.forename: Hisatomo
authors.initials: H
authors.lastname: Kowa
authors.forename: Eiichi
authors.initials: E
authors.lastname: Maeda
authors.forename: Aki
authors.initials: A
authors.lastname: Sugano
authors.forename: Kenji
authors.initials: K
authors.lastname: Miura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Fumio
authors.initials: F
authors.lastname: Kanda
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000328:Adult; D005260:Female; D049289:G(M2) Activator Protein / Q000737:chemistry; D054818:Hexosaminidase A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D055503:Protein Multimerization; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012497:Sandhoff Disease / Q000201:enzymology / Q000235:genetics*
chemical_list: D049289:G(M2) Activator Protein; D021122:Protein Subunits; D054818:Hexosaminidase A