Molecular Pathogenesis of Nephrogenic Diabetes Insipidus

Abstract

Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by inability to concentrate the urine in spite of the presence of vasopressin. Most of the patients, if early diagnosis and proper management are delayed, suffer from recurrent episodes of hypernatremic dehydration in neonatal or early infant period, which result in growth and developmental retardations. The mode of transmission is X-linked recessive in about 90% of the patients [arginine vasopressin V2 receptor gene (AVPR2) mutation] and autosomal recessive or dominant in less than 10% of the patients [aquaporin 2 (AQP2) gene mutation]. Part of AVPR2 missense mutations are known to translate mutant receptors which can not be translocated to the cell membrane normally (intracellular mistrafficking) and retained in the endoplasmic reticulum (ER) due to misfolding. These mutant proteins can be functionally rescued by using so-called chemical chaperones. In this study, the genetic analysis of the AVPR2 and AQP2 genes were performed in patients with clinical diagnosis of NDI. In addition, the functional rescue of the some mutant AVPR2 molecules using chemical chaperones was tried. Considering the limited effectiveness of the current pharmacological management of NDI and the practical difficulties in applying gene therapies, chemical chaperones can provide a novel and more easily applicable therapeutic strategy.