AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG).

Autor: Balakrishnan B; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Altassan R; Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Budhraja R; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Liou W; Electron Microscopy Core Facility, University of Utah, Salt Lake City, Utah, USA., Lupo A; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Bryant S; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Mankouski A; Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Radenkovic S; Department of Clinical Genomics, Center of Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA., Preston GJ; Department of Clinical Genomics, Center of Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA., Pandey A; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India., Boudina S; Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah, USA., Kozicz T; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; Department of Clinical Genomics, Center of Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Anatomy, University of Pecs School of Medicine, Pecs, Hungary., Morava E; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; Department of Clinical Genomics, Center of Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Medical Genetics, University of Pecs, School of Medicine, Pecs, Hungary., Lai K; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA; Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah, USA. Electronic address: kent.lai@hsc.utah.edu.
Jazyk: angličtina
Zdroj: Translational research : the journal of laboratory and clinical medicine [Transl Res] 2023 Jul; Vol. 257, pp. 1-14. Date of Electronic Publication: 2023 Jan 26.
DOI: 10.1016/j.trsl.2023.01.004
Abstrakt: Phosphoglucomutase 1 (PGM1) deficiency is recognized as the third most common N-linked congenital disorders of glycosylation (CDG) in humans. Affected individuals present with liver, musculoskeletal, endocrine, and coagulation symptoms; however, the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved liver disease, endocrine, and coagulation abnormalities, but does not alleviate the fatal cardiomyopathy and the associated myopathy. Here we report on left ventricular ejection fraction (LVEF) in 6 individuals with PGM1-CDG. LVEF was pathologically low in most of these individuals and varied between 10% and 65%. To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model. Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in individuals with PGM1-CDG. Histological studies demonstrated excess glycogen accumulation and fibrosis, while ultrastructural analysis revealed Z-disk disarray and swollen/fragmented mitochondria, which was similar to the ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG. In addition, we found decreased mitochondrial function in the heart of KO mice. Transcriptomic analysis of hearts from mutant mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of mutant mice, a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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