Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency
✍ Scribed by Katsumi Higaki; Linjing Li; Udin Bahrudin; Soichiro Okuzawa; Ayumi Takamuram; Koichi Yamamoto; Kaori Adachi1; Rubigilda C. Paraguison; Tomoko Takai; Hiroki Ikehata; Lika Tominaga; Ichiro Hisatome; Masami Iida; Seiichiro Ogawa; Junichiro Matsuda; Haruaki Ninomiya; Yasubumi Sakakibara; Kousaku Ohno; Yoshiyuki Suzuki; Eiji Nanba
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 493 KB
- Volume
- 32
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
b-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 b-galactosidase. We have previously reported the chaperone effect of N-octyl-4-epi-b-valienamine (NOEV) on mutant b-galactosidase proteins. In this study, we performed genotype analyses of patients with b-galactosidase deficiency and identified 46 mutation alleles including 9 novel mutations. We then examined the NOEV effect on mutant b-galactosidase proteins by using six strains of patient-derived skin fibroblast. We also performed mutagenesis to identify b-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 b-galactosidase and NOEV. Moreover, we confirmed that NOEV reduced G M1 accumulation and ameliorated the impairments of lipid trafficking and protein degradation in b-galactosidase deficient cells. These results provided further evidence to NOEV as a promising chaperone compound for b-galactosidase deficiency.