Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone.
OBJECTIVE
To examine the relationship between types and locations of mutations of the enzyme alpha-galactosidase (Gal) A in Fabry disease and the response to the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ).


METHODS
T cells grown from normal individuals or from patients with Fabry disease were tested for response to treatment with DGJ by increased activity of alpha-Gal A.


RESULTS
Cells from normal controls responded with a 28% increase in alpha-Gal A activity, whereas response in Fabry individuals was mutation dependent ranging from no increase to fully normal activity. Nine truncation mutations (all nonresponsive) and 31 missense mutations were tested. Three groups of missense mutations were categorized: responders with activity more than 25% of normal, nonresponders, with less than 7% and an intermediate response group. In normal cells and in responders an increase in the mature lysosomal form of alpha-Gal A was observed after DGJ treatment. Nonresponders showed little or no protein with or without DGJ. The intermediate response group showed an increase in band intensity but incomplete processing of the enzyme to the mature form.


CONCLUSIONS
Mapping the missense mutations to the structure of alpha-Gal A identified several factors that may influence response. Mutations in regions that are not in alpha-helix or beta-sheets, neither involved in disulfide bonds nor with an identified functional or structural role were more likely to respond. Predictability is, however, not precise and testing of each mutation for response to pharmacological chaperone therapy is necessary for Fabry disease and related lysosomal storage disorders.
Shin
Sang H
SH
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke/NIH, Bethesda, MD 20892, USA.
Kluepfel-Stahl
Stefanie
S
Cooney
Adele M
AM
Kaneski
Christine R
CR
Quirk
Jane M
JM
Schiffmann
Raphael
R
Brady
Roscoe O
RO
Murray
Gary J
GJ
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D000795:Fabry Disease / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
D017485:1-Deoxynojirimycin; C090092:migalastat; D000519:alpha-Galactosidase