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  1. Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria, with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease.

  2. About 90 percent of patients with congenital NDI are males with X-linked recessive NDI (MIM 304800) who have mutations in the arginine-vasopressin receptor 2 (AVPR2) gene that codes for the vasopressin V2 receptor. The gene is located in chromosome region Xq28.

  3. In less than 10 percent of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance (MIM 222000 and 125800). Mutations have been identified in the aquaporin-2 gene (AQP2), which is located in chromosome region 12q13 and codes for the vasopressin-sensitive water channel.

  4. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A few mutant receptors reach the cell surface but are unable to bind AVP or to properly trigger an intracellular cAMP signal. Similarly, AQP2 mutant proteins are misrouted and cannot be expressed at the luminal membrane.

  5. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value because early diagnosis and treatment can avert the physical and mental retardation associated with repeated episodes of dehydration.

  6. NDI is clinically distinguishable from neurogenic diabetes insipidus (MIM 125700) by a lack of response to exogenous AVP and by plasma levels of AVP that rise normally with increase in plasma osmolality. Neurogenic diabetes insipidus is secondary to mutations in the prepro-arginine-vasopressin-neurophysin II (prepro-AVP-NPII) gene. Neurogenic diabetes insipidus is also a component of Wolfram syndrome (MIM 222300), an autosomal recessive disorder.

  7. Other inherited disorders with mild to moderate inability to concentrate urine include Bartter syndrome (MIM 601678) and cystinosis (MIM 219800), while long-term lithium administration is the main cause of acquired NDI.

GenBank accession numbers: AQP2 (D31846, S73196, Z29491); AVPR2 (L22206, U04357, U52112, Z11687); prepro-AVP-NPII (M11166, M25647).

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