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

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. Hum Mutat 32:843–852, 2011. © 2011 Wiley‐Liss, Inc.