 The most common mutations lead to a defective protein folding and processing, resulting in endoplasmic reticulum retention of the mutant protein for further degradation by the proteasome.Two independent ClC-5 knock-out mice, the so called Jentsch and Guggino models, provided critical insights into the mechanisms of proximal tubular dysfunction in Dent disease 1.These two murine models recapitulated the major features of Dent disease (low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis) and demonstrated that ClC-5 inactivation is associated with severe impairment of both fluid phase and receptor-mediated endocytosis, as well as trafficking defects leading to the loss of megalin and cubilin at the brush border of proximal tubules.