Abstract
We performed screening of β-galactosidase-deficient fibroblasts for possible chemical
chaperone therapy using N-octyl-4-epi-β-valienamine (NOEV) in patients with GM1-gangliosidosis and Morquio B disease (β-galactosidosis). Fibroblasts were cultured
with NOEV for 4 days and β-galactosidase activity was measured. Mutation analysis
was performed simultaneously. Two separate criteria were set for evaluation of the
chaperone effect: a relative increase of enzyme activity (more than 3-fold), and an
increase up to more than 10% normal enzyme activity. Among the 50 fibroblast strains
tested, more than 3-fold increase was achieved in 17 cell strains (34%), and more
than 10% normal activity in 10 (20%). Both criteria were satisfied in 6 (12%), and
either of them in 21 (42%). Juvenile GM1-gangliosidosis was most responsive, and then infantile GM1-gangliosidosis. This enhancement was mutation-specific. We estimate that the NOEV
chaperone therapy will be effective in 20–40% of the patients, mainly in juvenile
and infantile GM1-gangliosidosis patients. A molecular design may produce mutation-specific chaperone
compounds for the other disease phenotypes. This cellular screening will be useful
for identification of human patients with β-galactosidase deficiency for chaperone
therapy to be started in the near future.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Brain and DevelopmentAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- β-Galactosidase deficiency (β-galactosidosis): GM1-gangliosidosis and Morquio B disease.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. Childs B. Kinzler K.W. Vogelstein B. The metabolic and molecular bases of inherited disease. 8th ed. McGraw-Hill, New York2001: 3775-3809
- Bone marrow transplantation in canine GM1 gangliosidosis.Clin Genet. 1990; 38: 274-280
- Amniotic tissue transplantation as a trial of treatment in some lysosomal storage diseases.J Inherited Metab Dis. 1985; 8: 101-104
- Galactose stabilizes various missense mutants of α-galactosidase in Fabry disease.Biochem Biophys Res Commun. 1995; 214: 1219-1224
- Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor.Nat Med. 1999; 5: 112-115
- α-Galactosidase transgenic mouse: heterogeneous gene expression and posttranslational glycosylation in tissues.Glycoconj J. 1998; 15: 591-594
- α-Galactosidase gene mutations in Fabry disease: heterogeneous expressions of mutant enzyme proteins.Hum Genet. 1995; 95: 557-561
- Aggregation of the inactive form of human α-galactosidase in the endoplasmic reticulum.Biochem Bophys Res Commun. 1996; 220: 812-815
- Chemical chaperone therapy for brain pathology in GM1-gangliosidosis.Proc Natl Acad Sci USA. 2003; 100: 15912-15917
- Chemical modification of the β-glucocerebrosidase inhibitor N-octyl-β-valienamine: synthesis and biological evaluation of 4-epimeric and 4-O-(β-d-galactopyransyl) derivatives.Bioorg Med Chem. 2002; 10: 1967-1972
- Galactosialidosis (β-galactosidase-neuraminidase deficiency): a possible role of serine-thiol proteases in the degradation of β-galactosidase molecules.Clin Chim Acta. 1982; 125: 275-282
- Galactonojirimycin derivatives restore mutant human β-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse.Brain Dev. 2001; 23: 284-287
- Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.J Hum Genet. 1999; 44: 391-396
- N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease.Biochim Biophys Acta. 2004; 1689: 219-228
- Characterization of β-galactosidase mutations Asp332 → Asn and Arg148 → Ser, and a polymorphism, Ser532 → Gly, in a case of GM1 gangliosidosis.Biochem J. 2000; 348: 621-632
- Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy.N Engl J Med. 2001; 345: 25-32
- Human β-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases.Am J Hum Genet. 1991; 49: 435-442
- Human β-galactosidase gene mutations in Morquio B disease.Am J Hum Genet. 1991; 49: 1091-1093
- A homozygous missense arginine to histidine substitution at position 482 of the β-galactosidase in an Italian infantile GM1-ganglosidosis patient.Hum Genet. 1992; 90: 247-250
- Low-dose N-butyldeoxynojirimycin (OGT 918) for type I Gaucher disease.Blood Cells Mol Dis. 2002; 28: 127-133
- Substrate reduction reduces gangliosides in postnatal cerebrum–brainstem and cerebellum in GM1 gangliosidosis mice.J Lipid Res. 2005; 46: 744-751
Article info
Publication history
Accepted:
February 3,
2006
Received in revised form:
January 31,
2006
Received:
December 22,
2005
Identification
Copyright
© 2006 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
