Wednesday, April 2, 2025
4/2/2025
Pathobiological mechanisms of cardiac disease in PGM1-CDG - PROJECT SUMMARY / ABSTRACT Phosphoglucomutase 1 (PGM1) catalyzes the interconversion of glucose-1 phosphate (Glc-1P) and glucose-6 phosphate (Glc-6P) and therefore, it plays a fundamental role in glycolysis, glycogenesis, and glycogenolysis. Consequently, inherited deficiency of PGM1 in humans has previously been identified as Glycogen Storage Disorder (GSD) Type 14, but has lately been revealed as a Congenital Disorders of Glycosylation (CDG) with mixed type I and type II glycosylation defects. The liver, the skeletomuscular, endocrine and coagulation systems all get involved over time, but the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved serum transferrin hypoglycosylation, liver function, endocrine abnormalities, and reduces frequency of hypoglycemic episodes, but does not alleviate the fatal cardiomyopathy and most muscle symptoms. To study the pathobiology of cardiac disease in PGM1-CDG patients, we constructed cardiomyocyte- specific conditional Pgm2 (mouse ortholog of human PGM1) knockout mice (Pgm2 cKO) mice. Using echocardiography, we corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in PGM1-CDG patients. Ultrastructural analysis revealed Z-disk disarray, swollen/fragmented mitochondria and macroscopic thickening in the heart of a PGM1-CDG patient. Preliminary transcriptomic analysis of hearts from Pgm2 cKO mice demonstrates a gene signature of DCM. Assessing the glycoproteomic profile of left ventricular tissue of Pgm2 cKO mice, our group showed significant glycosylation defects in sarcolemmal proteins including Laminin-211 (Merosin), sarcoglycans and biglycan. Collectively, not only does our mouse model recapitulate the cardiac phenotypes of PGM1-CDG patients, but our characterization to-date also supports the overarching hypothesis that altered glycosylation alone cannot fully explain the pathobiology of cardiac symptoms in PGM1-CDG patients as other biochemical and metabolic disturbances may also contribute. To test this hypothesis, we will (1) examine for altered energy metabolism, and (2) clarify the role played by aberrant glycosylation of sarcolemmal proteins in the DCM development in the Pgm2 cKO mice. Lastly, we will test the therapeutic potential of PGM1 gene replacement in the Pgm2 cKO mice by assessing whether PGM1 augmentation will restore the energetic deficit and reverse Lamnin-211 glycosylation abnormalities resulting in improved cardiac function and survival in Pgm2 cKO mice.
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