PDF(Pubmed)
Abstract：
Dent disease-1 (DD-1) is a rare X-linked tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene which encodes the voltage-gated ClC-5 chloride/proton antiporter. Currently, the treatment of DD-1 is only supportive and focused on delaying the progression of the disease. Here, we generated and characterized a Clcn5 knock-in mouse model that carries a pathogenic CLCN5 variant, c. 1566_1568delTGT; p.Val523del, which has been previously detected in several DD-1 unrelated patients, and presents the main clinical manifestations of DD-1 such as high levels of urinary b2-microglobulin, phosphate and calcium. Mutation p.Val523del causes partial ClC-5 retention in the endoplasmic reticulum. Additionally, we assessed the ability of sodium 4-phenylbutyrate, a small chemical chaperone, to ameliorate DD-1 symptoms in this mouse model. The proposed model would be of significant value in the investigation of the fundamental pathological processes underlying DD-1 and in the development of effective therapeutic strategies for this rare condition.
摘要：
Dentdisease-1（DD-1）是一种罕见的X连锁肾小管疾病，其特征是低分子量蛋白尿（LMWP），高钙尿症,肾结石和肾钙化。这种疾病是由编码电压门控ClC-5氯化物/质子反转运蛋白的CLCN5基因中的失活突变引起的。目前,DD-1的治疗仅是支持性的,并且集中于延缓疾病的进展.这里,我们产生并表征了携带致病性CLCN5变体的Clcn5敲入小鼠模型，c.1566_1568delTGT；p.Val523del，先前已在几名DD-1无关患者中检测到，并呈现DD-1的主要临床表现，如高水平的尿b2-微球蛋白，磷酸盐和钙。p.Val523del突变导致部分ClC-5保留在内质网中。此外,我们评估了4-苯基丁酸钠的能力，一个小小的化学伴侣,改善该小鼠模型中的DD-1症状。所提出的模型对于研究DD-1基础的基本病理过程以及开发这种罕见疾病的有效治疗策略具有重要价值。
