title: Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency.
abstract: β-Galactosidase deficiency is a group of lysosomal lipid storage disorders with an autosomal recessive trait. It causes two clinically different diseases, G(M1) -gangliosidosis and Morquio B disease. It is caused by heterogeneous mutations in the GLB1 gene coding for the lysosomal acid β-galactosidase. We have previously reported the chaperone effect of N-octyl-4-epi-β-valienamine (NOEV) on mutant β-galactosidase proteins. In this study, we performed genotype analyses of patients with β-galactosidase deficiency and identified 46 mutation alleles including 9 novel mutations. We then examined the NOEV effect on mutant β-galactosidase proteins by using six strains of patient-derived skin fibroblast. We also performed mutagenesis to identify β-galactosidase mutants that were responsive to NOEV and found that 22 out of 94 mutants were responsive. Computational structural analysis revealed the mode of interaction between human β-galactosidase and NOEV. Moreover, we confirmed that NOEV reduced G(M1) accumulation and ameliorated the impairments of lipid trafficking and protein degradation in β-galactosidase deficient cells. These results provided further evidence to NOEV as a promising chaperone compound for β-galactosidase deficiency.
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago, Japan. kh4060@med.tottori-u.ac.jp
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Linjing
authors.initials: L
authors.lastname: Li
authors.forename: Udin
authors.initials: U
authors.lastname: Bahrudin
authors.forename: Soichiro
authors.initials: S
authors.lastname: Okuzawa
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takamuram
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Kaori
authors.initials: K
authors.lastname: Adachi
authors.forename: Rubigilda C
authors.initials: RC
authors.lastname: Paraguison
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ikehata
authors.forename: Lika
authors.initials: L
authors.lastname: Tominaga
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Masami
authors.initials: M
authors.lastname: Iida
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ogawa
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Yasubumi
authors.initials: Y
authors.lastname: Sakakibara
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004795:Enzyme Stability; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D016537:Gangliosidosis, GM1 / Q000188:drug therapy* / Q000201:enzymology; D015870:Gene Expression; D005822:Genetic Vectors; D006595:Hexosamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009085:Mucopolysaccharidosis IV / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D001616:beta-Galactosidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D006595:Hexosamines; C116532:N-octyl-beta-valienamine; C061901:GLB1 protein, human; D001616:beta-Galactosidase