Mucopolysaccharidosis VII (MPS VII) is due to the deficient activity of β-
glucuronidase (GUSB) and results in the accumulation of
glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiovascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact
collagen in the MV at 6 months of age, when
mitral regurgitation had developed. Electron microscopy demonstrated that
collagen fibrils were of normal diameter, but failed to align into large parallel arrays.
mRNA analysis demonstrated a modest reduction in the expression of genes that encode
collagen or
collagen-associated
proteins such as the
proteoglycan decorin which helps
collagen fibrils assemble, and a marked increase for genes that encode
proteases such as
cathepsins. Indeed,
enzyme activity for
cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal
intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact
collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV
collagen structure. This could be due to upregulation of
enzymes that degrade
collagen or
collagen-associated
proteins, to the accumulation of GAGs that compete with
proteoglycans such as
decorin for binding to
collagen, or to other causes. Further delineation of the etiology of abnormal
collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues.