(15) Gene Expression Insights into Cardiovascular Pathology of Morquio a Disease

Background: Mucopolysaccharidosis IVA (Morquio A syndrome) is a lysosomal storage disease characterized by deficient N-acetylgalactosamine-6-sulfate sulfatase (GALNS) and subsequently increased glycosaminoglycans (GAGs), specifically keratan sulfate (KS) and chondroitin-6 sulfate (C6S), throughout the body. This results in a highly variable clinical presentation involving skeletal, vision, hearing, and cardiovascular abnormalities. Cardiovascular disease in Morquio A includes valvular disease and cardiac hypertrophy and remains the second leading cause of death in this patient population despite newer enzyme replacement and stem cell therapies.

Objectives: Consequently, the goal of this research is to better understand the pathophysiology of Morquio A on the cardiovascular (CVD) system as it is essential in determining further management and therapies for these patients.

Design/Methods: To study this process, we isolated RNA from the aortas of 18 mice evenly split between wild-type (WT) and Galns-/- (MKC) at 3, 6, and 9 months of age. Transcriptomic analyses between groups were performed to elucidate the most differentially expressed genes (DEGs).

Results: The number of DEGs both upregulated and downregulated varied dramatically between MKC and WT mice with relatively fewer DEGs in the 3- and 9-month groups compared to the 6-month-old mice. There was immense variation in DEGs when comparing the mice across age groups. Analysis of the pathways involved in the DEGs when accounting for age, demonstrated downregulation in catabolic and metabolic processes involving GAGs as well as upregulation in processes involving phosphatidylinositol and G-protein coupled receptors (GPCRs).

Conclusions: These findings seem to confirm that GALNS and GAGs play an important role in the cardiovascular pathophysiology and emphasize the complexity of DEGs in Morquio A. These results serve as an important step to develop future treatment strategies to address CVD in Morquio A patients.