Characterization of novel mucopolysaccharidosis IVA GalnsAAVS1 mouse model

Abstract

Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome, is a rare autosomal recessive disorder caused by mutations in the GALNS gene, leading to deficient activity of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). This enzyme is crucial for the degradation of glycosaminoglycans (GAGs), such as keratan sulfate (KS) and chondroitin-6- sulfate (C6S). Accumulation of these GAGs results in severe skeletal dysplasia and other systemic manifestations. We developed a novel murine model, the Galns hAAVS1 mouse, by inserting a natural safe harbor, human AAVS1 sequence into the mouse Galns gene using CRISPR/Cas9 technology. This model mimics the human MPS IVA phenotype, exhibiting no GALNS enzyme activity, elevated KS levels, and significant pathological changes in bone and heart tissues. Histopathological analysis revealed extensive vacuolization in the myocardium and mitral valve, as well as disrupted chondrocyte organization in the growth plates of the femur and tibia. Micro-CT analysis showed increased bone volume fraction, trabecular thickness, and bone mineral density in homozygous mice. These findings were consistent with the lysosomal storage of GAGs and the resultant skeletal abnormalities observed in MPS IVA patients. This model provides a valuable platform for studying the pathophysiology of MPS IVA and testing potential therapeutic interventions. This strategy of making animal models can be applied to many genetic disorders, contributing to the development of gene editing therapy.