Page 75 - GPD-4-2

Gene & Protein in Disease

REVIEW ARTICLE
Revisiting Alport syndrome: Genetic

background, phenotypic variability, and
therapeutic approaches

1†
1†
João Venda * , Beatriz Ferreira , Andreia Henriques 1 , Rita Leal 1,2 ,
1,2
Ana Galvão , and Rui Alves 1,2
1 Department of Nephrology, Hospitais da Universidade de Coimbra, Unidade Local de Saúde de
Coimbra, Coimbra, Portugal
2 Nephrology University Clinic, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

Abstract

Nearly a century has passed since Cecil A. Alport first described the triad of
nephritis, hearing loss, and ocular abnormalities that would later be recognized
as the second most common inherited nephropathy and a significant cause of
end-stage kidney disease. Pathogenic variants in COL4A3, COL4A4, and COL4A5
† These authors contributed equally genes lead to compromised synthesis, assembly, and/or function of α3, α4,
to this work. and α5 chains of type IV collagen (COL4). This disruption leads to an abnormal
*Corresponding author: trimerization of COL4 into a stable network, impairing the integrity and function
João Venda of glomerular, cochlear, and ocular basement membranes. The gold standard for
(12098@ulscoimbra.min-saude.pt) Alport syndrome diagnosis is molecular genetic testing, which provides a non-
Citation: Venda J, Ferreira B, invasive and highly specific approach. In settings with limited access to genetic
Henriques A, Leal R, Galvão testing, kidney biopsy with electron microscopy remains essential, revealing
A, Alves R. Revisiting Alport
syndrome: Genetic background, characteristic glomerular basement membrane abnormalities. Despite significant
phenotypic variability, and advancements in understanding its genetic and molecular basis, Alport syndrome
therapeutic approaches. Gene remains a relentlessly progressive disorder, often culminating in end-stage kidney
Protein Dis. 2025;4(2):7656.
doi: 10.36922/gpd.7656 disease during early adulthood. While no disease-specific therapy exists, early
initiation of renin-angiotensin-aldosterone system blockade is the cornerstone
Received: December 16, 2024 of AS management, delaying disease progression. Emerging therapies, including
Revised: March 19, 2025 sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor
Accepted: March 25, 2025 antagonists, are being investigated for their nephroprotective potential. In
addition, recent breakthroughs in therapeutic research – including gene- and cell-
Published online: April 10, 2025 based treatments – hold the potential to transform disease management. Genetic
Copyright: © 2025 Author(s). factors influence treatment response, reinforcing the need for personalized
This is an Open-Access article therapeutic approaches. In this review, we discuss the genetic background and
distributed under the terms of the
Creative Commons Attribution phenotypic correlations of Alport syndrome, the pathophysiological mechanisms
License, permitting distribution, driving both renal and extrarenal manifestations, and explore diagnostic
and reproduction in any medium, approaches and emerging strategies aimed at modifying the natural course of
provided the original work is
properly cited. this disease.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Alport syndrome; Inherited nephropathy; Glomerular basement membrane;
regard to jurisdictional claims in
published maps and institutional Molecular genetic testing; Nephroprotection
affiliations.

Volume 4 Issue 2 (2025) 1 doi: 10.36922/gpd.7656