Diversity of Nephrogenic Diabetes Insipidus Mutations and Importance of Early Recognition and Treatment

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Title: Diversity of Nephrogenic Diabetes Insipidus Mutations and Importance of Early Recognition and Treatment
Authors: Bichet, Daniel G.; Fujiwara, T. Mary
Publisher: Clinical and Experimental Nephrology
Date Published: 1998
Reference Number: 489
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In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine, despite normal or elevated concentrations of the antidiuretic hormone, arginine vasopressin. In congenital nephrogenic diabetes insipidus, the obvious clinical manifestations of the disease, polyuria and polydipsia, are present at birth, and need to be immediately recognized to avoid severe episodes of dehydration. Most (>90%) patients with congenital nephrogenic diabetes insipidus have mutations in the AVPR2 gene that codes for the vasopressin V2 (antidiuretic) receptor and is located in chromosome region Xq28. In less than 10% of the families studied, congenital nephrogenic diabetes insipidus has an autosomal recessive mode of inheritance, and mutations have been identified in the aquaporin-2 gene (AQP2) located in chromosome region 12q13, that codes for the vasopressin-sensitive water channel.

Reports of 85 different putative disease-causing mutations in the AVPR2 gene, in 123 unrelated families with X-linked nephrogenic diabetes insipidus, have now been published. Of these, 19 disease-causing mutations were identified in ancestrally independent Japanese families. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellulary, and that are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface, but are unable to bind arginine vasopressin, or to trigger an intracellular cyclic adenosine monophosphate (cAMP) signal. Similarly, AQP2 mutant proteins are trapped intracellularly, and cannot be expressed at the luminal membrane. This APQ2 trafficking defect is correctable, at least in vitro, by chemical chaperones.