Genetic variants of unknown significance in alpha-galactosidase A: Cellular delineation from Fabry disease.

Autor: Klein A; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Klug K; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Breyer M; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Grüner J; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Medala VK; Department of Neurology, University Hospital Würzburg, Würzburg, Germany., Nordbeck P; University Hospital Würzburg, Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), Würzburg, Germany.; Department of Internal Medicine 1, Division of Cardiology, University Hospital Würzburg, Würzburg, Germany., Wanner C; University Hospital Würzburg, Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), Würzburg, Germany.; Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany., Klopocki E; University of Würzburg, Institute for Human Genetics, Würzburg, Germany., Üçeyler N; Department of Neurology, University Hospital Würzburg, Würzburg, Germany.; University Hospital Würzburg, Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), Würzburg, Germany.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2024 Jul; Vol. 47 (4), pp. 805-817. Date of Electronic Publication: 2024 Apr 15.
DOI: 10.1002/jimd.12743
Abstrakt: Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (GLA). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 GLA variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems. We have analyzed four different male subject-derived cell types for alpha-galactosidase A enzyme (GLA) activity and intracellular Gb3 load. Additionally, Gb3 load in skin tissue as well as clinical data were studied for correlates of disease manifestations. A reduction of GLA activity was observed in cells carrying p.A143T compared with controls (p < 0.05). In cells carrying the p.D313Y variant, a reduced GLA activity was found only in endothelial cells (p < 0.01) compared with controls. No pathological changes were observed in cells carrying the p.S126G variant. None of the VUS investigated caused intracellular Gb3 accumulation in any cell type. Our data of aberrant GLA activity in cells of p.A143T hemizygotes and overall normal cellular phenotypes in cells of p.D313Y and p.S126G hemizygotes contribute a basic science perspective to the clinically highly relevant discussion on VUS in GLA.
(© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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