Condac Eduard, Silasi-Mansat Robert, Kosanke Stanley, Schoeb Trenton, Towner Rheal, Lupu Florea, Cummings Richard D, Hinsdale Myron E
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, USA.
Proc Natl Acad Sci U S A. 2007 May 29;104(22):9416-21. doi: 10.1073/pnas.0700908104. Epub 2007 May 21.
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 approximately 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 (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.
尽管有证据表明大多数遗传性人类多囊疾病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，但许多遗传性人类多囊疾病背后的基本生化机制仍不清楚。遗传性多囊肾病是最常见的多囊疾病，目前在美国约有50万人受其影响。在患有常染色体显性多囊肾病患者的组织和培养细胞中发现蛋白聚糖（PGs）减少，并且这种PG减少被认为是囊肿形成的原因。这是可能的，因为预计PG浓度的改变会破坏生长、发育和代谢的许多稳态机制。为了验证这一假设，我们培育出了缺乏木糖基转移酶2（XylT2）的小鼠，XylT2是一种参与PG生物合成的酶。在此我们表明，XylT2的失活导致PGs大幅减少，并出现多囊肝和多囊肾病许多方面的特征性表型，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XylT2的缺失会导致PG浓度改变，并且PG减少会诱导囊肿发展。
