Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

Abstract

The basic biochemical mechanisms underlying many heritable human polycystic diseases are unknown despite evidence that most cases are caused by mutations in members of several protein families, the most prominent being the polycystin gene family, whose products are found on the primary cilia, or due to mutations in posttranslational processing and transport. Inherited polycystic kidney disease, the most prevalent polycystic disease, currently affects Ϸ500,000 people in the United States. Decreases in proteoglycans (PGs) have been found in tissues and cultured cells from patients who suffer from autosomal dominant polycystic kidney disease, and this PG decrease has been hypothesized to be responsible for cystogenesis. This is possible because alterations in PG concentrations would be predicted to disrupt many homeostatic mechanisms of growth, development, and metabolism. To test this hypothesis, we have generated mice lacking xylosyltransferase 2 (XylT2), an enzyme involved in PG biosynthesis. Here we show that inactivation of XylT2 results in a substantial reduction in PGs and a phenotype characteristic of many aspects of polycystic liver and kidney disease, including biliary epithelial cysts, renal tubule dilation, organ fibrosis, and basement membrane abnormalities. Our findings demonstrate that alterations in PG concentrations can occur due to loss of XylT2, and that reduced PGs can induce cyst development.animal model ͉ extracellular matrix ͉ genetics ͉ proteoglycans ͉ cyst

Inactivation of Integrin-β1 Prevents the Development of Polycystic Kidney Disease after the Loss of Polycystin-1

“…1 Distinctive features of ADPKD are the alteration of epithelial extracellular matrix (ECM) 2,3 and the progressive renal fibrosis, which parallels the course of the disease. 4 The involvement of the ECM in the pathogenesis of ADPKD has long been suspected 5,6 and is supported by the observations that the altered expression of the ECM components laminin-a5 and proteoglycans 7,8 or the focal adhesion protein tensin lead to renal cystogenesis. 9 ECM is essential in not only maintaining the normal tubule architecture, but also wound repair and developmental processes as well as the regulation of cell growth, polarity, migration, and differentiation.…”

Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects

“…We examined HSPG assembly levels by using GAG-specific antibody 10E4 performed as previously described. 19 These results showed a qualitative decrease in HS GAG staining in the affected individuals' fibroblasts ( Figure 2D). In all, these results confirm a significant defect in PG assembly due to the XYLT2 mutation.…”

“…) and in our XylT2-deficient (Xylt2 À/À ) mice 19 are also illustrated (n ¼ 3 each) for comparison; error bars represent SD. Total XylT activity was assayed via published protocols 18 and for the study individuals' values, these represent the mean of triplicate measurements.…”

β-d-Xylosides Stimulate GAG Synthesis in Chondrocyte Cultures Due to Elevation of the Extracellular GAG Domains, Accompanied by the Depletion of the Intra–pericellular GAG Pools, with Alterations in the GAG Profiles

“…The soluble glycosyltransferase enzyme, xylosyltransferase, employs uridine diphosphate xylose and incorporates xylose residues. Xylosyltransferase is considered as the pacemaker enzyme of the GAG chain formation [8][9][10]. Xylosyltransferases and the two different galactosyltransferases construct the linkage region.…”