Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis
Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis
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DOI：
10.1073/pnas.0700908104
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发表时间：
2007-05-29
影响因子：
11.1
通讯作者：
Hinsdale, Myron E.
中科院分区：
文献类型：
--
作者：
Condac, Eduard;Silasi-Mansat, Robert;Hinsdale, Myron E.
许多遗传性人类多囊性疾病的基本生化机制尚不清楚，尽管有证据表明大多数病例是由几个蛋白质家族成员的突变引起的，其中最突出的是多囊蛋白基因家族，其产物存在于初级纤毛上，或者是由于翻译后加工和运输中的突变所致。遗传性多囊肾病是最常见的多囊肾病，目前影响美国约 500,000 人。在患有常染色体显性多囊肾病的患者的组织和培养细胞中发现了蛋白多糖 (PG) 的减少，并且推测这种 PG 的减少是导致囊肿发生的原因。这是可能的，因为 PG 浓度的改变预计会破坏生长、发育和代谢的许多稳态机制。为了验证这一假设，我们培育了缺乏木糖基转移酶 2 (XyIT2) 的小鼠，木糖基转移酶 2 是一种参与 PG 生物合成的酶。在这里，我们发现 XyIT2 失活会导致 PG 大幅减少以及多囊肝和肾病许多方面的表型特征，包括胆管上皮囊肿、肾小管扩张、器官纤维化和基底膜异常。我们的研究结果表明，由于 XyIT2 的缺失，PG 浓度可能会发生变化，并且 PG 的减少会诱导囊肿发育。
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 approximate to 500,000 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 (XyIT2), an enzyme involved in PG biosynthesis. Here we show that inactivation of XyIT2 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 XyIT2, and that reduced PGs can induce cyst development.