Tosetto E, Anglani F, Graziotto R, Citron L, D'Angelo A, Gambaro G
Dipartimento di Scienze Mediche e Chirurgiche, Divisione e Cattedra di Nefrologia, Universita' di Padova, Italy.
G Ital Nefrol. 2003 Nov-Dec;20(6):578-88.
Dent's disease, a X-linked hypercalciuric nephrolithiasis, is caused by mutations of the CLCN5 gene. The disease is characterised by low molecular weight proteinuria with variable presence of hypercalciuria, hyperphosphaturia, nephrocalcinosis, and kidney stones. CLCN5 encodes a chloride channel belonging to the voltage-gated chloride channel family, which is predominantly expressed in the endosomes of proximal tubular cells. By shunting the current of electrogenic H+-ATPase, ClC-5 is crucial for efficient acidification of renal endosomes. As shown in knock-out mouse models, the ClC-5 loss of function causes severe impairment of receptor-mediated endocytosis, as well as the endocytotic retrieval of plasma membrane proteins including megalin. In a minority of patients with classical Dent's disease, the analysis of CLCN5 coding sequences failed to identify causative mutations. It is conceivable that mutations in the 5' upstream regulatory regions could impair the correct processing and translation of CLCN5. The complexity of its promoter region seems to support this hypothesis. Molecular diagnosis of Dent's disease is now available; since the risk of developing renal insufficiency in adult life is elevated for this type of nephrolithiasis, the correct diagnosis could potentially modify the natural history of the disease by preventing the evolution towards uraemia.
丹特病是一种X连锁的高钙尿性肾结石病，由CLCN5基因突变引起。该疾病的特征是低分子量蛋白尿，并伴有高钙尿症、高磷尿症、肾钙质沉着症和肾结石的不同程度出现。CLCN5编码一种属于电压门控氯通道家族的氯通道，主要在近端肾小管细胞的内体中表达。通过分流电生H⁺-ATP酶的电流，ClC-5对于肾内体的有效酸化至关重要。如基因敲除小鼠模型所示，ClC-5功能丧失会导致受体介导的内吞作用严重受损，以及包括巨膜蛋白在内的质膜蛋白的内吞回收受损。在少数经典丹特病患者中，对CLCN5编码序列的分析未能鉴定出致病突变。可以想象，5'上游调控区域的突变可能会损害CLCN5的正确加工和翻译。其启动子区域的复杂性似乎支持这一假设。丹特病的分子诊断现已可用；由于这种类型的肾结石病患者成年后患肾功能不全的风险升高，正确的诊断可能通过预防向尿毒症的发展来潜在地改变疾病的自然病程。
