Dataset Information

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

ABSTRACT: 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 an 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. To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model. Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilatation 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. We observed similar ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG. We found decreased mitochondrial function in the heart of Pgm2 cKO mice. Transcriptomic analysis of hearts from Pgm2 cKO mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of Pgm2 cKO mice, a glycoproteomic analysis revealed an overall decreased protein glycosylation with significant glycosylation defects in sarcolemmal proteins including different subunits of laminin protein. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD036271 | Pride | 2023-08-18

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	061322_RB_PGM1_KO_Heart_TMT_TP.pdResult	Other
	061322_RB_PGM1_KO_Heart_TMT_TP_1.raw	Raw
	061322_RB_PGM1_KO_Heart_TMT_TP_10.raw	Raw
	061322_RB_PGM1_KO_Heart_TMT_TP_11.raw	Raw
	061322_RB_PGM1_KO_Heart_TMT_TP_12.raw	Raw

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

Balakrishnan Bijina B Altassan Ruqaiah R Budhraja Rohit R Liou Willisa W Lupo Arielle A Bryant Sarah S Mankouski Anastasiya A Radenkovic Silvia S Preston Graeme J GJ Pandey Akhilesh A Boudina Sihem S Kozicz Tamas T Morava Eva E Lai Kent K

Translational research : the journal of laboratory and clinical medicine 20230126

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 ca ...[more]

PMID: 36709920

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