Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency

Hum Mutat. 2011 Jul;32(7):843-52. doi: 10.1002/humu.21516.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Enzyme Stability
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Gangliosidosis, GM1 / drug therapy*
  • Gangliosidosis, GM1 / enzymology
  • Gene Expression
  • Genetic Vectors
  • Hexosamines / chemistry
  • Hexosamines / pharmacology*
  • Hexosamines / therapeutic use
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucopolysaccharidosis IV / genetics
  • Mutation, Missense / genetics
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • beta-Galactosidase / chemistry*
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism*


  • Hexosamines
  • N-octyl-beta-valienamine
  • GLB1 protein, human
  • beta-Galactosidase