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Autosomal Recessive Nephrogenic Diabetes Insipidus Caused by an Aquaporin-2 Mutation*

Departments of Pediatrics (Z.H.) and Hematology (B.B., N.L.), Rambam Medical Center; Department of Pediatrics (L.E.), Bnai-Zion Medical Center, Haifa Israel; Departments of Pediatrics (A.v.L.) and Human Genetics (A.v.L., B.A.v.O., N.V.A.M.K.), University Hospital Nijmegen, The Netherlands

Address correspondence and requests for reprints to: Dr. Z. Hochberg, Department of Pediatrics, POB 9649, Haifa 31096, Israel.

Vasopressin V₂ receptors, expressed from an x-chromosomal gene, are involved in antidiuresis, but also in release of coagulation factor VIII and von Willebrand factor (vWF). The present study describes autosomal recessive nephrogenic diabetes insipidus (NDI) in a large cluster of patients in Israel’s Lower-Galilee. Evidence for an intact V₂ receptor was concluded by their normal increase in factor VIII and vWF after desmopressin infusion. Thus, in these patients a defect in the pathway beyond the V₂ receptor was suspected. The recent cloning of the human Aquaporin-2 gene enabled us to test this gene as a candidate for such a postreceptor defect. Direct sequencing of the Aquaporin-2 gene revealed a G298T substitution causing a Gly100Stop nonsense mutation in the third transmembrane region. Because this putative disease-causing mutation was identified in index patients of different families, we suggest that all patients are descendants of a common ancestor. Thus, this new entity is characterized by an autosomal recessive NDI. The differential response of clotting factors and urine osmolality to desmopressin may provide a simple tool for clinical diagnosis of a V₂-postreceptor defect. The early stop-codon of Aquaporin-2 results in complete resistance to vasopressin antidiuretic effect.

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