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.