The cytosolic B-glucosidase GBA3 does not influence type 1 Gaucher disease manifestation
Dekker, N. ; Voorn-Brouwer, T. ; Verhoek, M. ; Wennekes, T. ; Narayan, R.S. ; Speijer, D. ; Hollak, C.E.M. ; Overkleeft, H.S. ; Boot, R.G. ; Aerts, J.M.F.G. - \ 2011
Blood Cells Molecules and Diseases 46 (2011)1. - ISSN 1079-9796 - p. 19 - 26.
klotho-related protein - human-liver - nonlysosomal glucosylceramidase - marked elevation - specificity - glucocerebrosidase - phenotype - beta-glucosidase-2 - deglycosylation - identification
GBA3, also known as cytosolic ß-glucosidase, is thought to hydrolyze xenobiotic glycosides in man. Deficiency of glucocerebrosidase (GBA), a ß-glucosidase degrading glucosylceramide, underlies Gaucher disease. We examined GBA3, which recently was proposed to degrade glucosylceramide and influence the clinical manifestation of Gaucher disease. Recombinant GBA3 was found to hydrolyze artificial substrates such as 4-methylumbelliferyl-ß-D-glucoside and C6-NBD-glucosylceramide, but hydrolysis of naturally occurring lipids like glucosylceramide and glucosylsphingosine was hardly detected. Consistent with this, inhibition of GBA3 in cultured cells using a novel inhibitor (alpha-1-C-nonyl-DIX) did not result in an additional increase in glucosylceramide as compared to GBA inhibition alone. Examination of the GBA3 gene led to the identification of a common substitution in its open reading frame (1368T¿A), resulting in a truncated GBA3 protein missing the last a-helix of its (ß/a)8 barrel. Both recombinant 1368A GBA3 and 1368A enzyme from spleen of a homozygous individual were found to be inactive. Amongst non-neuronopathic (type 1) Gaucher disease patients, we subsequently identified individuals being wild-type, heterozygous, or homozygous for the GBA3 1368T¿A mutation. No correlation was observed between GBA3 1368A/T haplotypes and severity of type 1 Gaucher disease manifestation. In conclusion, GBA3 does not seem to modify type 1 Gaucher disease manifestation