Molecular and Structural Characterization of Five Novel GLA Gene Variants in Fabry Disease.
8 affiliations
- 1Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy.
- 2Department of Pediatrics, University of Torino, 10126 Torino, Italy.
- 3Nephrology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia-ASST Spedali Civili of Brescia, 25100 Brescia, Italy.
- 4Nephrology Unit, Policlinico Le Scotte, 53100 Siena, Italy.
- 5Cardiology Unit, Vittorio Emanuele Hospital, 93012 Gela, Italy.
- 6Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, 56126 Pisa, Italy; [email protected] .
- 7Department of Medical, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy; [email protected] .
- 8Clinical Medicine and Rheumatology Unit, Cattinara University Hospital, 34149 Trieste, Italy.
Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, encoding α-galactosidase A. Enzyme deficiency leads to progressive globotriaosylceramide (Gb3) accumulation and multisystemic involvement. Here, we characterize five previously undescribed GLA variants (p.D109N, p.N215T, p.N192H, p.L166P, and p.F248S) through an integrated approach combining biomolecular and computational analyses to investigate their effects on enzyme structure, catalytic activity, and dimerization. The identified substitutions affect residues located in regions critical for protein folding and active-site integrity. The p.F248S variant may destabilize the hydrophobic core and reduce thermodynamic stability, whereas p.D109N and p.N192H may disrupt hydrogen-bond networks required for proper catalytic geometry. The p.N215T substitution is associated with impaired glycosylation, while p.L166P may induce local conformational changes that compromise correct folding. Biochemical analyses of all samples carrying these variants revealed reduced α-galactosidase A activity and increased the Gb3 levels, but also of uncertain significance (VUS). Overall, these findings support an effect of the five variants on α-galactosidase A structure and function and highlight the value of integrating clinical, genetic, biochemical, and computational data for variant interpretation. Molecular characterization of novel variants may improve genetic diagnosis, inform therapeutic decisions, and support the development of targeted treatment strategies in Fabry disease.
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BibTeX
@article{anania2026molecular,
title = {{Molecular and Structural Characterization of Five Novel GLA Gene Variants in Fabry Disease.}},
author = {Monia Anania and Veronica Pagliardini and Marco Spada and Laura Econimo and Irene Giacalone and Martina Vinci and Paolo Colomba and Francesca Cappelletti and Carmelo Tonelli and Michelangelo Mancuso and Giulia Duro and Emanuela Maria Marsana and Marta Moschetti and Giovanni Duro},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198669},
url = {https://europepmc.org/article/MED/42883914},
note = {CC BY},
}
RIS
TY - JOUR
TI - Molecular and Structural Characterization of Five Novel GLA Gene Variants in Fabry Disease.
AU - Monia Anania
AU - Veronica Pagliardini
AU - Marco Spada
AU - Laura Econimo
AU - Irene Giacalone
AU - Martina Vinci
AU - Paolo Colomba
AU - Francesca Cappelletti
AU - Carmelo Tonelli
AU - Michelangelo Mancuso
AU - Giulia Duro
AU - Emanuela Maria Marsana
AU - Marta Moschetti
AU - Giovanni Duro
PY - 2026
DA - 2026/09/28
JO - International journal of molecular sciences
DO - 10.3390/ijms27198669
UR - https://europepmc.org/article/MED/42883914
AB - Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, encoding α-galactosidase A. Enzyme deficiency leads to progressive globotriaosylceramide (Gb3) accumulation and multisystemic involvement. Here, we characterize five previously undescribed GLA variants (p.D109N, p.N215T, p.N192H, p.L166P, and p.F248S) through an integrated approach combining biomolecular and computational analyses to investigate their effects on enzyme structure, catalytic activity, and dimerization. The identified substitutions affect residues located in regions critical for protein folding and active-site integrity. The p.F248S variant may destabilize the hydrophobic core and reduce thermodynamic stability, whereas p.D109N and p.N192H may disrupt hydrogen-bond networks required for proper catalytic geometry. The p.N215T substitution is associated with impaired glycosylation, while p.L166P may induce local conformational changes that compromise correct folding. Biochemical analyses of all samples carrying these variants revealed reduced α-galactosidase A activity and increased the Gb3 levels, but also of uncertain significance (VUS). Overall, these findings support an effect of the five variants on α-galactosidase A structure and function and highlight the value of integrating clinical, genetic, biochemical, and computational data for variant interpretation. Molecular characterization of novel variants may improve genetic diagnosis, inform therapeutic decisions, and support the development of targeted treatment strategies in Fabry disease.
SN - 1422-0067
ER -