Autosomal recessive nephrogenic diabetes insipidus caused by an aquaporin-2 mutation.
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.
Hochberg
Z
Z
Department of Pediatrics, Rambam Medical Center, Haifa Israel.
Van Lieburg
A
A
Even
L
L
Brenner
B
B
Lanir
N
N
Van Oost
B A
BA
Knoers
N V
NV
D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D003894:Deamino Arginine Vasopressin; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics*; D005169:Factor VIII / Q000032:analysis; D005808:Genes, Recessive; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D007557:Israel; D009154:Mutation; D010375:Pedigree; D014841:von Willebrand Factor / Q000032:analysis
C496023:AQP2 protein, human; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D007473:Ion Channels; D014841:von Willebrand Factor; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin