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

[gm1 gangliosidosis]

β-Galactosidase deficiency is a group of lysosomal lipid storage disorders with an autosomal recessive trait . It causes two clinically different diseases , G (M 1 ) -gangliosidosis and Morquio B disease . It is caused by heterogeneous mutations in the GLB 1 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 (M 1 ) 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 .