Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Abstract

Impact of Structural GLA Protein Changes on Peripheral GLA Activity and Substrate Accumulation in Fabry Disease Patients

Author(s): Jorge Diogo Da Silva*, Isaura Ribeiro, Carla Caseiro, Eugénia Pinto, Sónia Rocha, Helena Ribeiro, Célia Ferreira, Elisabete Silva, Francisco Laranjeira, Nataliya Tkachenko, Lúcia Lacerda and Dulce Quelhas

Volume 24, Issue 16, 2024

Published on: 25 September, 2023

Page: [3 - 3] Pages: 1

DOI: 10.2174/1871530323666230914114414

conference banner
Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, leading to decreased/absent α-galactosidase activity. In clinical practice, enzyme activity and substrate/byproduct accumulation play a role in diagnosis and disease-monitoring bi-omarkers. However, interpreting biomarker levels is not straightforward and can change according to the underlying GLA protein abnormality.

Objective: Our goals were to understand how disrupting specific protein regions changes biomarker behaviour and to establish specific patterns for individual variants.

Methodology: We analysed data from the Biochemical Genetics Laboratory regarding GLA variants, GLA enzyme activity (in dried blood spots, plasma or white blood cells), plasma LysoGb3 accumu-lation, and urinary Gb3 excretion. We assessed correlations, trends, and potential predictor models of biomarker behaviour.

Results: We assessed 169 hemizygous male and 255 heterozygous female patients. For both groups, substrate accumulation correlates inversely with GLA activity. Variants affecting residues buried within the protein core or the active site were associated with more severe biomarker changes, while those affecting residues that establish disulfide bonds or are glycosylated were similar to other vari-ants. For each non-truncating variant, we also established specific profiles of biomarker behaviour. Finally, we also designed predictor models of biomarker behaviour based on structural variant infor-mation. This study provides the groundwork for the impact of GLA protein variation on GLA activity and substrate accumulation.

Conclusion: This knowledge is of extreme relevance for diagnostic labs and clinicians, as some ge-netic variants are challenging to interpret regarding pathogenicity. Assessing whether biomarker changes are in the expected range for a specific variant may help diagnostic evaluation. This study also contributes to recognising non-disease-causing variants, considering their overall biochemical impact, and providing a comparative reference for biomarker discovery studies. In the future, the correlation of these findings with disease severity may be of great relevance for diagnosis and mon-itoring progression.

Keywords: Fabry disease, GLA, Biomarkers, GLA Structure


© 2024 Bentham Science Publishers | Privacy Policy