| Autor: |
Perdomo-Ramírez A; Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), 38010 Santa Cruz de Tenerife, Spain., Ramos-Trujillo E; Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), 38010 Santa Cruz de Tenerife, Spain.; Seccion Medicina, Departamento de Medicina Fisica y Farmacologia, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain., Machado JD; Seccion Medicina, Departamento de Medicina Fisica y Farmacologia, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38200 Santa Cruz de Tenerife, Spain., García-Nieto V; Unidad de Nefrologia Pediatrica, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain., Mura-Escorche G; Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), 38010 Santa Cruz de Tenerife, Spain., Claverie-Martin F; Unidad de Investigacion, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigacion Sanitaria de Canarias (IISC), 38010 Santa Cruz de Tenerife, Spain. |
| Abstrakt: |
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. |
