GLA Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease DOI Creative Commons
Ping Li,

Yuqian Xi,

Yanping Zhang

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(5), P. 437 - 437

Published: March 1, 2024

Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated FD, most notably kidney, heart, and central nervous system. In our previous study, we identified four from independent families with kidney or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) c.801+1G>A (p.L268fsX3). To reveal molecular mechanism underlying predisposition mutations, analyzed effects these on protein structure α-galactosidase using bioinformatics methods. The results showed that have significant impact internal dynamics structures GLA, all altered amino acids close activity center lead significantly reduced activity. Furthermore, led accumulation autophagosomes impairment autophagy cells, which may turn negatively regulate slightly increasing phosphorylation mTOR. Moreover, overexpression mutants promoted expression lysosome-associated membrane 2 (LAMP2), resulting increased number lysosomes. Our study reveals pathogenesis FD provides scientific foundation for accurate diagnosis precise medical intervention FD.

Language: Английский

CRISPR/Cas9-mediated A4GALT suppression rescues Fabry disease phenotypes in a kidney organoid model DOI
Sheng Cui,

Yoo Jin Shin,

Xianying Fang

et al.

Translational research, Journal Year: 2023, Volume and Issue: 258, P. 35 - 46

Published: Feb. 18, 2023

Language: Английский

Citations

13
Status and frontiers of Fabre disease DOI Creative Commons
Wei Chu, Ming Chen,

Xiaoran Lv

et al.

Orphanet Journal of Rare Diseases, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 13, 2025

Abstract Fabry disease is characterized by an X sex chromosome gene mutation caused α-galactosidase A deficiency, resulting in the accumulation of globotriaosylceramide and globotriaosylsphingosine various organs, which induces end-organ lesions. In disease, enzymes with lost or decreased activity body are replaced exogenous supplementation normal-function A. Currently, agalsidase α β widely used for ERT therapy. However, this therapy has limitations such as high cost, short half-life, production neutralizing drug antibodies. The use Migalastat chaperone been approved many countries, it plays a therapeutic role enhancing enzyme activity. companion drugs only suitable patients activity, so scope their application limited. addition, there several development, including new generation therapies, resistant to anti-drug antibody drugs, substrate reduction drugs. Due existing researchers have begun explore pathogenic mechanisms adjuvant continuously discovered, development related will contribute control treatment. This article summarizes potential treating facilitate selection effective

Language: Английский

Citations

0
Commentary on ‘Lentivirus‐mediated gene therapy for Fabry disease: 5‐year end‐of‐study results from the Canadian FACTS trial’ DOI Creative Commons
Alessandro Rossi, Nicola Brunetti‐Pierri

Clinical and Translational Discovery, Journal Year: 2025, Volume and Issue: 5(2)

Published: Feb. 27, 2025

Language: Английский

Citations

0
Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney DOI Creative Commons
Natalya Kaverina, Diana G. Eng, Jeffrey H. Miner

et al.

Aging, Journal Year: 2020, Volume and Issue: 12(17), P. 17601 - 17624

Published: Aug. 28, 2020

Healthy aging is typified by a progressive and absolute loss of podocytes over the lifespan animals humans. To test hypothesis that subset glomerular parietal epithelial cell (PEC) progenitors transition to podocyte fate with aging, dual reporter PEC-rtTA|LC1|tdTomato|Nphs1-FLPo|FRT-EGFP mice were generated. PECs inducibly labeled tdTomato reporter, constitutively an EGFP reporter. With advancing age (14 24 months) glomeruli in juxta-medullary cortex (JMC) more severely injured than those outer (OC). In aged (24m), lower number (41% decrease), showed PEC migration differentiation mildly or healthy glomeruli. differentiated had ultrastructural features co-expressed markers podocin, nephrin, p57 VEGF164, but not mesangial (Perlecan) endothelial (ERG) cells. did express CD44, marker activation. Taken together, we demonstrate subpopulation differentiate predominantly advanced age.

Language: Английский

Citations

32
Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up DOI Open Access
Clara Carnicer-Cáceres,

Jose Antonio Arranz-Amo,

Cristina Cea-Arestin

et al.

Journal of Clinical Medicine, Journal Year: 2021, Volume and Issue: 10(8), P. 1664 - 1664

Published: April 13, 2021

Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations GLA gene, resulting gradual accumulation of globotriaosylceramide and other derivatives different tissues. Substrate promotes pathogenic mechanisms which several mediators could be implicated, inducing multiorgan lesions, mainly kidney, heart nervous system, clinical manifestations disease. Enzyme replacement therapy was shown delay progression, if initiated early. However, diagnosis early stages represents challenge, especially patients with non-classic phenotype, prompts search for biomarkers that help detect predict evolution We have reviewed involved were studied as potential can easily incorporated into practice. Some seem useful forms even improve female patients. The combination such some response biomarkers, may detection organ injury. incorporation practice increase capacity compared currently obtained established diagnostic markers provide more information on progression prognosis

Language: Английский

Citations

25
Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues DOI Creative Commons
Camilla Tøndel,

Beth L. Thurberg,

Pronabesh DasMahapatra

et al.

Molecular Genetics and Metabolism, Journal Year: 2022, Volume and Issue: 137(4), P. 328 - 341

Published: Oct. 30, 2022

Fabry disease (FD) is a rare lysosomal storage disorder, characterized by reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) its metabolites cells various organs. Agalsidase beta, an replacement therapy (ERT), approved for use patients with FD Europe, Canada, Australia, South America, Asia, only ERT United States. In this review, we discuss clinical relevance GL3 accumulation, effect agalsidase beta on target tissues, association between treatment-related tissue clearance long-term structure, function, or outcomes. Accumulation kidney, heart, vasculature, neurons, skin, gastrointestinal tract auditory system correlates to cellular damage irreversible organ damage, as result sclerosis, fibrosis, apoptosis, inflammation, endothelial dysfunction. Damage leads renal dysfunction end-stage disease; myocardial hypertrophy heart failure arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia dysmotility; hearing loss. Treatment effective substantially clearing range from tissues affected FD. has also been shown slow decline lower overall risk progression, demonstrating indirect link stabilization

Language: Английский

Citations

17
Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels DOI
Sanne J. van der Veen, Mohamed El Sayed, Carla E. M. Hollak

et al.

Clinical Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 18(10), P. 1272 - 1282

Published: July 27, 2023

Fabry disease is a very heterogeneous X-linked lysosomal storage disease. Disease manifestations in the kidneys, heart, and brain vary greatly, even between patients of same sex with classification (classical or nonclassical). A biomarker strong association development needed to determine need for Fabry-specific treatment appropriate frequency follow-up because clinical disorder may take decennia develop.

Language: Английский

Citations

10
Longitudinal biomarker evaluation in Fabry disease patients receiving lentivirus-mediated gene therapy DOI Open Access
Christiane Auray‐Blais, Paméla Lavoie, Tristan Martineau

et al.

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(3)

Published: June 27, 2024

Aim: In 2016, a team of Canadian researchers initiated the world’s first gene therapy clinical trial for Fabry disease. The study, aiming to determine safety and toxicity lentivirus α-galactosidase A transduced autologous CD34+ cells in adult males with disease (n = 5), was conducted at three centers. objective present work evaluate profile disease-related biomarkers five participants during 5-year surveillance period, as part evaluation this novel therapy. Methods: Sixteen globotriaosylceramide (Gb3) isoforms eight globotriaosylsphingosine (lyso-Gb3) analogues were measured by LC-MS/MS plasma urine numerous time points before after Plasma peripheral blood leukocyte activity also measured. Results: Levels lyso-Gb3 analogues, Gb3 lower while treated enzyme replacement (ERT) compared baseline (before therapy) ERT only. Three chose cease treatment some point Two these patients had levels baseline, whereas one participant higher baseline. An increase observed when ceased (P < 0.05) all participants. Conclusion: complete glycosphingolipid biomarker useful monitoring biochemical response cohort

Language: Английский

Citations

3
Investigating lysosomal dysfunction in Fabry disease using induced pluripotent stem cell-derived podocytes DOI Open Access

Caitlin Ryan,

Andrea F. Wise,

Elisha Tindoy

et al.

Journal of Translational Genetics and Genomics, Journal Year: 2025, Volume and Issue: 9(1), P. 48 - 51

Published: Feb. 26, 2025

Aims: This study used induced pluripotent stem cell-derived podocytes from a Fabry disease (FD) patient carrying the p.Met284Thr pathogenic variant as an in vitro model to investigate lysosomal abnormalities driving cell pathology. Proteomic analysis was assess changes protein abundance FD compared controls. Additionally, temporal lysosome number were analyzed using automated live-cell imaging. Methods: Label-free mass spectrometry proteomics performed on at day 10 of differentiation For imaging, cultured transfected with CellLight Lysosomes-GFP and Plasma Membrane-CFP, then visualized quantified days 20 post-differentiation Perkin Elmer Phenix High Content Screening Microscope. Results: showed dysregulation glycosphingolipid metabolism proteins, including decreased galactosidase alpha (GLA; P < 0.01) increased galactosylceramidase glucosylceramidase (P podocytes. Lysosomal proteins enriched, significant increase cathepsin B 0.001) decrease lipase A 0.01). Furthermore, involved cycle regulation growth signaling pathways, such polo-like kinase 1 (PLK1; 0.0001) proto-oncogene tyrosine-protein Src (SRC; 0.01), suggested broader impacts cellular processes. Temporal imaging revealed controls Conclusions: These findings collectively suggest that undergo progressive impairment, which may contribute dysfunction progression. proof-of-concept lay foundation for future research targeted therapies high-throughput screening advanced analytical techniques.

Language: Английский

Citations

0
Genetics in Kidney Diseases DOI
Samuel Mon-Wei Yu, Kirk N. Campbell

Advances in Kidney Disease and Health, Journal Year: 2025, Volume and Issue: 32(1), P. 33 - 40

Published: Jan. 1, 2025

Language: Английский

Citations

0