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

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

Volume: 24 Issue: 16

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

Affiliation:

• Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário de Santo António, Porto, Portugal
• Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
• ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal

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.

Cite this article as:

Da Silva Diogo Jorge*, Ribeiro Isaura, Caseiro Carla, Pinto Eugénia, Rocha Sónia, Ribeiro Helena, Ferreira Célia, Silva Elisabete, Laranjeira Francisco, Tkachenko Nataliya, Lacerda Lúcia and Quelhas Dulce, Impact of Structural GLA Protein Changes on Peripheral GLA Activity and Substrate Accumulation in Fabry Disease Patients, Endocrine, Metabolic & Immune Disorders - Drug Targets 2024; 24 (16) . https://dx.doi.org/10.2174/1871530323666230914114414