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Nephrogenic diabetes insipidus (NDI) usually shows an X-linked recessive mode of inheritance caused by mutations in the vasopressin type 2 receptor gene (AVPR2). In the present study, three NDI families are described in which females show clinical features resembling the phenotype in males. Maximal urine osmolality in three female patients did not exceed 200 mosmol/kg and the absence of extra-renal responses to 1-desamino-8-D-arginine vasopressin was demonstrated in two of them. All affected females and two asymptomatic female family members were shown to be heterozygous for an AVPR2 mutation. Skewed X-inactivation is the most likely explanation for the clinical manifestation of NDI in female carriers of an AVPR2 mutation. It is concluded that, in female NDI patients, the possibility of heterozygosity for an AVPR2 gene mutation has to be considered in addition to homozygosity for mutations in the aquaporin 2 gene.

Nephrogenic diabetes insipidus (NDI) is characterized by insensitivity of the distal renal nephron to the antidiuretic effect of the neurohypophyseal hormone arginine vasopressin. In the last 2 years, two different genetic defects causing the NDI phenotype have been identified. The genes involved encode proteins that reside at both ends of the cellular vasopressin signaling cascade, namely the vasopressin V(2) receptor and the aquaporin-2 water channel. Analysis of naturally occurring mutations in the V(2) receptor and the aquaporin-2 water channel will facilitate the study of structure-function correlates of both proteins, which will lead to substantial progress in elucidating the cellular mechanisms involved in the antidiuretic effect of vasopressin.

Inheritance of mutations in the V2 receptor gene in thirteen families with nephrogenic diabetes insipidus. Congenital nephrogenic diabetes insipidus (NDI) is an X-linked recessive disease characterized by insensitivity of the distal nephron to the antidiuretic effect of arginine vasopressin. The hypothesis that the defect underlying NDI might be a dysfunctional renal vasopressin V2 receptor has recently been proven by the identification of mutations in the V2 receptor gene in NDI patients. We examined thirteen unrelated Dutch NDI families and identified thirteen distinct and unique mutations. These included nine missense mutations, two nonsense mutations and two small deletions and were found in the extracellular domains II, III and IV, the intracellular domains II and IV and in the transmembrane loops I, II, IV and V of the vasopressin type 2 receptor. In the families with multiple NDI patients the mutated gene cosegregated with the disease. Our data suggest a higher mutation frequency in male than in female gametes. No discrepancies between carrier detection by means of DNA analysis with closely linked polymorphic markers and the definite diagnosis based on sequencing data were found.

Congenital nephrogenic diabetes insipidus (NDI) is an X-linked inherited disorder characterized by renal resistance to the antidiuretic hormonal action of arginine vasopressin. The disease gene has been assigned to the subtelomeric region of the X chromosome long arm by demonstrating close linkage between NDI and several X-chromosomal DNA markers. The finding of closely linked genetic markers is useful in the diagnosis of NDI. Receptor studies in patients have indicated that NDI might be due to the absence or an abnormality of the adenylate cyclase-bound vasopressin type 2 receptor. This assumption was supported by the discovery of functional vasopressin V2 receptor activity in somatic cell hybrid cell lines that carried at least the distal part of the human X chromosome long arm. Definite evidence for a V2 receptor defect being the cause of NDI was found in a recent study demonstrating point mutations in the V2 receptor gene from affected individuals. Direct mutation analysis is now applicable for accurate carrier detection and early (prenatal) diagnosis.

Nephrogenic diabetes insipidus (DIR) is an X-linked disorder characterized by insensitivity of the distal nephron for the pituitary hormone, vasopressin. The genetic map location of the DIR gene on chromosome Xq28 coincides with the physical map location of the functional vasopressin renal V2-type receptor. Recently, the human and rat cDNAs for the vasopressin V2 receptor (AVPR2) have been identified. We show here that the structural AVPR2 gene is localized between DXS52 and G6PD, which is within the genetic map location of DIR. We also tested eight X-linked DIR probands and their families for mutations in one of the most conserved extracellular regions of AVPR2: in three of them, we have identified point mutations resulting in non-conservative amino acid substitutions which cosegregated with DIR in all families.

In congenital nephrogenic diabetes insipidus (NDI) blunted responses of plasma factor VIII, von Willebrand factor, and plasminogen activator to the synthetic V2 analogue 1-desamino-8-D-arginine vasopressin (DDAVP) have been reported. In addition, vasodilatory responses to DDAVP appear to be absent in NDI. We describe a boy, who presented shortly after birth with the typical features of NDI, but who showed normal coagulation, fibrinolytic and vasodilatory responses to DDAVP. We conclude that in this patient the defect is confined to the kidney, while in other NDI patients there may be a general V2 receptor abnormality. These findings point to heterogeneity in NDI.

Fibrinolytic responses to infusion of 1-desamino-8-D-arginine-vasopressin (DDAVP) were assessed in 6 males with congenital nephrogenic diabetes insipidus (NDI), 6 carriers of the NDI gene and 6 normal control subjects. Tissue-type plasminogen activator (t-PA) activity and antigen increased significantly in normal subjects, while plasminogen activator inhibitor (PAI) activity decreased. None of these changes were observed in patients with NDI. In 2 female carriers, normal fibrinolytic responses were seen, while in the other carriers responses were delayed. These findings are consistent with the concept of a general V2-receptor defect in congenital NDI. DDAVP tests are of limited use in NDI carrier detection.

The binding of tritium-labelled arginine vasopressin to human platelet vasopressin receptors was investigated in patients with congenital nephrogenic diabetes insipidus. Binding characteristics, that is receptor affinity and the maximum number of binding sites, were not significantly different from those found in normal control individuals. The findings confirm the concept of intact V1 receptors in congenital nephrogenic diabetes insipidus. The defect in nephrogenic diabetes insipidus apparently only affects the cyclic adenosine monophosphate dependent V2 receptors.

This review summarizes various aspects of the inherited kidney disorder nephrogenic diabetes insipidus (NDI). The clinical manifestations of the disease are presented. The important role of the genetic localization of the NDI gene to the X-chromosome long arm, in region Xq28, for carrier detection and early (prenatal) diagnosis of the disorder is emphasized. Following an overview of the cellular physiology involved in the antidiuretic action of vasopressin, possible mechanisms in the pathogenesis of NDI are discussed. We hypothesize that NDI is most probably due to the absence or abnormality of the renal V2 receptor. This assumption is strengthened by recent findings in receptor studies, which indicate a general V2 receptor defect in NDI, and in experiments with somatic cell hybrid cell lines, which are consistent with a co-localization of the genes for NDI and for the V2 receptor in the Xq28 region. Finally, the efficacy of the combination amiloride-hydrochlorothiazide, compared with the indomethacin-hydrochlorothiazide regimen, in the treatment of NDI is presented and the advantages of the former combination are discussed.

In five families with X-linked nephrogenic diabetes insipidus (NDI), linkage studies with the DNA marker DXS52, defined by probe St14, have shown no recombination with a maximum combined lod score of 6.40. These results assign the NDI gene to the subtelomeric region of the X chromosome long arm. This finding should facilitate identification of carriers and should also be helpful in finding the NDI gene itself.

Ten families with nephrogenic diabetes insipidus (NDI) have been analysed for restriction fragment length polymorphisms (RFLPs). A search for linkage was performed using various chromosome-specific single-copy DNA probes of known regional assignment to the human X chromosome. Close linkage was found between the disease locus and the markers DXS52, DXS15, DXS134 and the F8 gene. This result assigns the NDI gene to the subtelomeric region of the long arm of the X chromosome. The regional localization of the gene by the identification of closely linked markers should have repercussions for genetic counselling and prevention in NDI families.

The gene for X-linked nephrogenic diabetes insipidus (NDI), a disorder which, if untreated, causes severe dehydration, mental retardation, and possibly death in affected males, has been mapped recently to the Xq28 band through demonstration of linkage to the DX552 locus and other DNA markers (N. Knoers et al., 1987, Cytogenet. Cell Genet. 46:640; M. Kambouris et al., 1987, Cytogenet. Cell Genet. 46:636). Linkage studies in 11 families with NDI have enabled us to map the NDI gene between closely linked flanking markers in the Xq28 region and to obtain the following gene order: centromere-F9-DXS98-F8/CBD,CBP-DXS52/NDI-DXS134- telomere. These results have implications for presymptomatic and prenatal diagnosis of NDI and should also improve the prospects for identifying the fundamental gene defect underlying this disorder.