Molecular basis of lysosomal storage disease and the possibility of a new therapeutic approach
| Project/Area Number |
10672178
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Laboratory medicine
|
|---|
| Research Institution | Kochi Medical School |
|---|
Principal Investigator |
OKUMIYA Toshika Kochi Medical School, Faculty of Medicine, Research Associate, 医学部, 助手 (50284435)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SAKURABA Hitoshi The Tokyo Metropolitan Institute of Medical Science, Clinical Genetics Chief Researcher, 臨床遺伝学研究部門, 室長 (60114493)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,300,000 (Direct Cost: ¥2,300,000)
|
|---|
| Keywords | Iysosomal storage disease / Fabry disease / GMィイD21ィエD2-gangliosidosis / Morquio B disease / gene mutation / α-galactosidase / β-galactosidase / substrate analog / Morquio disease |
|---|
| Research Abstract |
(1) Tissue-specific posttranslational modification of human α-galactosidase
Heterogeneous gene expression and posttranslational glycosylation were examined in human α-galactosidase (α-Gal) transgenic mouse. The heart and liver of the mouse expressed a high amount of transcript as well as high α-Gal activity. Its gene products in the heart and kidney were sensitive to endoglycosidase H digestion, but those in the spleen and liver were largely resistant. Glycopeptidase F treatment confirmed an identical molecular mass for the peptide moiety of the enzyme. We conclude that heterogeneous molecular mass of the gene products is caused by different degree of posttranslational glycosylation in murine tissues.
(2) Altered substrate specificity of mutant β-galactosidase in patients with Morquio B disease
β-Galactosidodosis is a lysosomal storage disease caused by a deficiency of acid β-galactosidase (β-Gal) consisting of two different clinical phenotypes, GM1-gangliosidosis and Morquio B disease. T
… More
he former has central nervous system lesions, whereas the latter has skeletal lesions with no central nervous system lesions. To clarify the molecular evidence to account for clinical difference between both diseases, we investigated substrate specificity of mutant β-Gal derived from patients with GM1-gangliosidosis and Morquio B disease using artificial substrate analogs. Mutant β-Gal (W237L/W237L, Y83H/R482C) from Morquio B disease exhibited relatively low affinity to Galβl-4Glc NAc , an analog of keratan sulfate, as compared with Galβ1-3GalNAc, an analog of GM1-gangliosid, but there was not such difference in both normal β-Gal and mutant β-Gal (R201C/R201C, 151T/151T) from GM1-gangliosidosis. Furthermore, Morquio B mutants showed considerable decrease in hydrolysis ratio for the analogs (Galβ1-4GlcNAc/Galβ1-3GalNAc), yet GM1-gangliosidosis mutants had similar hydrolysis ratio to normal β-Gal. We conclude that distinct clinical phenotypes between GM1-gangliosidosis and Moquio B disease are caused by altered substrate specificity of mutant P-Gal resulting from unique gene mutations in patients with Morquio B disease. Less
|
Report
(3 results)
Research Products
(4 results)
