Large Proteoglycan Complexes and Disturbed Collagen Architecture in the Corneal Extracellular Matrix of Mucopolysaccharidosis Type VII (Sly Syndrome)

Young, Robert D.; Lišková, Petra; Pinali, Christian; Palka, Barbara P.; Palos, Michalis; Jirsová, Kateřina; Hrdlickova, Enkela; Tesařová, Markéta; Elleder, M; Zeman, Jiřı́; Meek, Keith Michael Andrew; Knupp, Carlo; Quantock, Andrew J.

doi:10.1167/iovs.11-7377

Cited by 21 publications

(15 citation statements)

References 40 publications

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“…This suggests that the higher order collagen structure is disrupted in the MPS VII MV, which is a likely explanation for the abnormal signal with picrosirius red. This is consistent with the finding that the collagen structure was abnormal in the cornea of animals and patients with MPS [35-36]. …”

Section: Discussionsupporting

confidence: 92%

Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs

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et al. 2013

Molecular Genetics and Metabolism

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Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiavascular 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.

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Section: Discussionsupporting

confidence: 92%

Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs

Bigg

Baldo

Sleeper

et al. 2013

Molecular Genetics and Metabolism

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“…The secondary consequences of interruption of recycling of dermatan and dermatan sul fate revealed in corneas of patients with MPS I and cats with MPS I and VI are probably the cause of prominent alterations in size and arrangement of collagen molecules that result in cloudy cornea [131]. Large complexes of proteases disturb the collagen architecture in corneal extracellular matrix in MPS VII [132]. Corneal trans parency depends on uniform diameter and regular spac ing and arrangement of collagen fibrils within the stroma [133].…”

Section: Interruption Of Glycoprotein and Glycosaminoglycan Metabolismentioning

confidence: 99%

Secondary biochemical and morphological consequences in lysosomal storage diseases

Alroy

Garganta

Wiederschain

2014

Biochemistry Moscow

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More than 50 hereditary lysosomal storage disorders (LSDs) are currently described. Most of these disorders are due to a deficiency of certain hydrolases/glycosidases and subsequent accumulation of nonhydrolyzable carbohydrate-containing compounds in lysosomes. Such accumulation causing hypertrophy of the lysosomal compartment is a characteristic feature of affected cells in LSDs. The investigation of biochemical and cellular parameters is of particular interest for understanding "life" of lysosomes in the normal state and in LSDs. This review highlights the wide spectrum of biochemical and morphological changes during developing LSDs that are extremely critical for many metabolic processes inside the various cells and tissues of affected persons. The data presented will help establish new complex strategies for metabolic correction of LSDs.

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“…Finally, numerous studies concerning PG molecules have been conducted in order to explain corneal opacification which can result from abnormal GAG accumulation and dysregulation of the fibrillar order in this tissue. A significant elongation of PG filaments in addition to their various size changed their architecture and arrangement in MPS I [97,98], IVA [100] and VII [76], in relation to the findings of a normal cornea. Increased amounts of these molecules were also found in the cornea of a 16-year-old patient with MPS VI [117] and in the interphotoreceptor matrix of MPS VII affected animals [118].…”

Section: Pg Expression In Lsdsmentioning

confidence: 88%

Extracellular matrix components: An intricate network of possible biomarkers for lysosomal storage disorders?

2013

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Edied by Wilhelm JustKeywords: Mucopolysaccharidoses Lysosomal storage disorders Biomarker Extracellular matrix molecule a b s t r a c t Biomarkers are extremely important in the case of multisystemic diseases, such as lysosomal storage disorders (LSDs), which are often difficult to assess in clinical practice. Several studies demonstrated significant alterations in the expression of extracellular matrix (ECM) components in LSD patients, raising important questions in relation to their possible involvement in disease pathogenesis and providing evidence for their possible utility as disease biomarkers. This article provides an overview of the possible pathogenic correlations between LSDs and ECM. Data regarding the expression of these molecules are discussed. Finally, the possible implication of ECM components as therapeutic targets in this group of diseases along with the impact of the differential expression of these components in current LSD treatment will be critically addressed.

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Large Proteoglycan Complexes and Disturbed Collagen Architecture in the Corneal Extracellular Matrix of Mucopolysaccharidosis Type VII (Sly Syndrome)

Cited by 21 publications

References 40 publications

Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs

Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs

Secondary biochemical and morphological consequences in lysosomal storage diseases

Extracellular matrix components: An intricate network of possible biomarkers for lysosomal storage disorders?

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