Genetic analysis of nephrogenic diabetes insipidus patients: A study on the Iranian population.

INTRODUCTION: Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body's water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X-linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney. METHODS: Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon-intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines. RESULTS: In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study. DISCUSSION: As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype-phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation.

The ß3-AR agonist BRL37344 ameliorates the main symptoms of X-linked nephrogenic diabetes insipidus in the mouse model of the disease.

X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP-intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the ß3-adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the ß3-AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X-NDI. Here we demonstrate that the ß3-AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X-NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow-release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X-NDI mice. Taken together, these data suggest that human ß3-AR agonists might represent an effective possible treatment strategy for X-NDI.

Targeted long-read sequencing identified a causal structural variant in X-linked nephrogenic diabetes insipidus.

BACKGROUND: X-linked nephrogenic diabetes insipidus (NDI) is a rare genetic renal disease caused by pathogenic variants in the AVPR2 gene. Single nucleotide variants and small insertions/deletions in AVPR2 are reliably detected by routine clinical sequencing. Nevertheless, structural variants involving AVPR2 are challenging to identify accurately by conventional genetic testing. Here, we report a novel deletion of AVPR2 in a Czech family identified for the first time by targeted long-read sequencing (T-LRS). METHODS: A male proband with X-linked NDI underwent clinical sequencing of the AVPR2 gene that failed and thus indicated possible whole-gene deletion. Therefore, PCR mapping and subsequent targeted long-read sequencing (T-LRS) using a Pacific Biosciences sequencer were applied to search for the suspected deletion. To validate the deletion breakpoints and prove variant segregation in the family with X-linked NDI, Sanger sequencing of the deletion junction was performed. Quantitative real-time PCR was further carried out to confirm the carrier status of heterozygous females. RESULTS: By T-LRS, a novel 7.5 kb deletion of AVPR2 causing X-linked NDI in the proband was precisely identified. Sanger sequencing of the deletion junction confirmed the variant breakpoints and detected the deletion in the probands´ mother, maternal aunt, and maternal cousin with X-linked NDI. The carrier status in heterozygous females was further validated by quantitative real-time PCR. CONCLUSIONS: Identifying the 7.5 kb deletion gave a precise molecular diagnosis for the proband, enabled genetic counselling and genetic testing for the family, and further expanded the spectrum of structural variants causing X-linked NDI. Our results also show that T-LRS has significant potential for accurately identifying putative structural variants.

First report on female monozygotic twins discordant for congenital nephrogenic diabetes insipidus.

Ninety percent of congenital nephrogenic diabetes insipidus (NDI) are X-linked inherited and are caused by mutations in the vasopressin type 2 receptor gene (AVPR2). Most affected individuals are males. Only sporadic female cases have been reported. Here, we first reported a female monozygotic twin with discordant phenotypes for NDI carrying a missense variant c.845T>C (p.Leu282Pro) in exon 4 of AVPR2. Intracellular cAMP concentrations in COS7 cells transfected with AVPR2-L282P were significantly decreased by about 60% compared with those in wild-type AVPR2 plasmid transfected cells, suggesting this variation was pathogenic. The X-inactivation pattern was investigated in peripheral leukocytes and urine sediments in both the unaffected and affected pair. Results showed that the affected pair had a skewed X chromosome inactivation (XCI) pattern in urine sediments and a random XCI pattern in leukocytes, while the unaffected pair showed a random XCI pattern both in leukocytes and urine sediments. This was the first report of monozygotic twins who developed different phenotypes of NDI. Our study suggested that the development of NDI symptoms is more closely associated with the XCI pattern in urine sediments compared with the XCI pattern in peripheral leukocytes. Analysis of XCI in peripheral leukocytes may not be enough to explore possible mechanisms.

Tubular Diseases and Stones Seen From Pediatric and Adult Nephrology Perspectives.

The tubular system of the kidneys is a complex series of morphologic and functional units orchestrating the content of tubular fluid as it flows along the nephron and collecting ducts. Renal tubules maintain body water, regulate electrolytes and acid-base balance, reabsorb precious organic solutes, and eliminate specific metabolites, toxins, and drugs. In addition, decisive mechanisms to adjust blood pressure are governed by the renal tubules. Genetic as well as acquired disorders of these tubular functions may cause serious diseases that manifest both in childhood and adulthood. This article addresses a selection of tubulopathies and the underlying pathomechanisms, while highlighting the important differences in pediatric and adult nephrology care. These range from rare monogenic conditions such as nephrogenic diabetes insipidus, cystinosis, and Bartter syndrome that present in childhood, to the genetic and acquired tubular pathologies causing hypertension or nephrolithiasis that are more prevalent in adults. Both pediatric and adult nephrologists must be aware of these conditions and the age-dependent manifestations that warrant close interaction between the two subspecialties.

Structural and functional analysis of aquaporin-2 mutants involved in nephrogenic diabetes insipidus.

Aquaporins are water channels found in the cell membrane, where they allow the passage of water molecules in and out of the cells. In the kidney collecting duct, arginine vasopressin-dependent trafficking of aquaporin-2 (AQP2) fine-tunes reabsorption of water from pre-urine, allowing precise regulation of the final urine volume. Point mutations in the gene for AQP2 may disturb this process and lead to nephrogenic diabetes insipidus (NDI), whereby patients void large volumes of highly hypo-osmotic urine. In recessive NDI, mutants of AQP2 are retained in the endoplasmic reticulum due to misfolding. Here we describe the structural and functional characterization of three AQP2 mutations associated with recessive NDI: T125M and T126M, situated close to a glycosylation site and A147T in the transmembrane region. Using a proteoliposome assay, we show that all three mutants permit the transport of water. The crystal structures of T125M and T126M together with biophysical characterization of all three mutants support that they retain the native structure, but that there is a significant destabilization of A147T. Our work provides unique molecular insights into the mechanisms behind recessive NDI as well as deepens our understanding of how misfolded proteins are recognized by the ER quality control system.

[Clinical and laboratory characteristics of arginine vasopressin resistance, caused by a new homozygous mutation p.R113C in AQP2].

Congenital nephrogenic diabetes insipidus (CNDI, arginine vasopressin resistance) is a rare inherited disorder characterized by insensitivity of the kidney to the antidiuretic effect of vasopressin. NDI is clinically characterized by polyuria with hyposthenuria and nocturia and polydipsia. In the majority of cases, about 90%, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remaining cases, about 10%, the disease is autosomal recessive or dominant and, for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. To date, the nucleotide variants registered in AQP2 were sporadic, there is no data on the presence of «frequent¼ mutations and the prevalence of the disease both among the global population and among individual ethnic groups. In this paper, we describe 12 cases of arginine vasopressin resistance caused by a new homozygous mutation p.R113C in AQP2 presented among the indigenous population of the Republic of Buryatia.

Metabolic reprogramming of renal epithelial cells contributes to lithium-induced nephrogenic diabetes insipidus.

Lithium, mainstay treatment for bipolar disorder, frequently causes nephrogenic diabetes insipidus (NDI) and renal injury. However, the detailed mechanism remains unclear. Here we used the analysis of metabolomics and transcriptomics and metabolic intervention in a lithium-induced NDI model. Mice were treated with lithium chloride (40 mmol/kg chow) and rotenone (ROT, 100 ppm) in diet for 28 days. Transmission electron microscopy showed extensive mitochondrial structural abnormalities in whole nephron. ROT treatment markedly ameliorated lithium-induced NDI and mitochondrial structural abnormalities. Moreover, ROT attenuated the decrease of mitochondrial membrane potential in line with the upregulation of mitochondrial genes in kidney. Metabolomics and transcriptomics data demonstrated that lithium activated galactose metabolism, glycolysis, and amino sugar and nucleotide sugar metabolism. All these events were indicative of metabolic reprogramming in kidney cells. Importantly, ROT ameliorated metabolic reprogramming in NDI model. Based on transcriptomics analysis, we also found the activation of MAPK, mTOR and PI3K-Akt signaling pathways and impaired focal adhesion, ECM-receptor interaction and actin cytoskeleton in Li-NDI model were inhibited or attenuated by ROT treatment. Meanwhile, ROT administration inhibited the increase of Reactive Oxygen Species (ROS) in NDI kidneys along with enhanced SOD2 expression. Finally, we observed that ROT partially restored the reduced AQP2 and enhanced urinary sodium excretion along with the blockade of increased PGE2 output. Taken together, the current study demonstrates that mitochondrial abnormalities and metabolic reprogramming play a key role in lithium-induced NDI, as well as the dysregulated signaling pathways, thereby serving as a novel therapeutic target.

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance).

Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1 per 25,000 population. Central DI (CDI), better now referred to as arginine vasopressin (AVP)-deficiency, is the most common form of DI resulting from deficiency of the hormone AVP from the pituitary. The less common nephrogenic DI (NDI) or AVP-resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP-secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease-causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. Although the cAMP/protein kinase A pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional cAMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurements of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice because of their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, whereas NDI requires the management of any underlying diseases, removal of offending drugs and, in some cases, administration of diuretics. A better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents that are under clinical trial.

Aquaporins in Diabetes Insipidus.

Disruption of water and electrolyte balance is frequently encountered in clinical medicine. Regulating water metabolism is critically important. Diabetes insipidus (DI) presented with excessive water loss from the kidney is a major disorder of water metabolism. To understanding the molecular and cellular mechanisms and pathophysiology of DI and rationales of clinical management of DI is important for both research and clinical practice. This chapter will first review various forms of DI focusing on central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI). This is followed by a discussion of regulatory mechanisms underlying CDI and NDI, with a focus on the regulatory axis of vasopressin, vasopressin receptor 2 (V2R) and the water channel molecule, aquaporin 2 (AQP2). The clinical manifestation, diagnosis, and management of various forms of DI will also be discussed with highlights of some of the latest therapeutic strategies that are developed from in vitro experiments and animal studies.

ß3 Adrenergic Receptor Agonist Mirabegron Increases AQP2 and NKCC2 Urinary Excretion in OAB Patients: A Pleiotropic Effect of Interest for Patients with X-Linked Nephrogenic Diabetes Insipidus.

We previously reported the novel finding that ß3-AR is functionally expressed in the renal tubule and shares its cellular localization with the vasopressin receptor AVPR2, whose physiological stimulation triggers antidiuresis by increasing the plasma membrane expression of the water channel AQP2 and the NKCC2 symporter in renal cells. We also showed that pharmacologic stimulation of ß3-AR is capable of triggering antidiuresis and correcting polyuria, in the knockout mice for the AVPR2 receptor, the animal model of human X-linked nephrogenic diabetes insipidus (XNDI), a rare genetic disease still missing a cure. Here, to demonstrate that the same response can be evoked in humans, we evaluated the effect of treatment with the ß3-AR agonist mirabegron on AQP2 and NKCC2 trafficking, by evaluating their urinary excretion in a cohort of patients with overactive bladder syndrome, for the treatment of which the drug is already approved. Compared to baseline, treatment with mirabegron significantly increased AQP2 and NKCC2 excretion for the 12 weeks of treatment. This data is a step forward in corroborating the hypothesis that in patients with XNDI, treatment with mirabegron could bypass the inactivation of AVPR2, trigger antidiuresis and correct the dramatic polyuria which is the main hallmark of this disease.

Genetic basis of nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus is defined as an inability to concentrate urine due to a complete or partial alteration of the renal tubular response to arginine vasopressin hormone, resulting in excessive diluted urine excretion. Hereditary forms are caused by molecular defects in the genes encoding either of the two main renal effectors of the arginine vasopressin pathway: the AVPR2 gene, which encodes for the type 2 vasopressin receptor, or the AQP2 gene, which encodes for the water channel aquaporin-2. About 90% of cases of nephrogenic diabetes insipidus result from loss-of-function variants in the AVPR2 gene, which are inherited in a X-linked recessive manner. The remaining 10% of cases result from loss-of-function variants in the AQP2 gene, which can be inherited in either a recessive or a dominant manner. The main symptoms of the disease are polyuria, chronic dehydration and hypernatremia. These symptoms usually occur in the first year of life, although some patients present later. Diagnosis is based on abnormal response in urinary osmolality after water restriction and/or administration of exogenous vasopressin. Treatment involves ensuring adequate water intake on demand, possibly combined with thiazide diuretics, non-steroidal anti-inflammatory drugs, and a low-salt and protein diet. In this review, we provide an update on current understanding of the molecular basis of inherited nephrogenic insipidus diabetes.

[Family form of nephrogenic X-linked diabetes indiabetes].

There is a global trend towards an increase in the prevalence of diabetes insipidus. Symptoms of nephrogenic diabetes insipidus with X-linked inheritance appear in men, in women with heterozygous mutations, are characterized by an isolated symptom complex of polyuria, polydipsia, hypostenuria. In children, more often than in adults, with fluid restriction, a clinic of water-deficient dehydration develops with hypernatremia, hyperthermia, and plasma hyperosmolality. This manuscript presents a case of Nephrogenic diabetes insipidus, X-linked familial form in male patients.At the same time, in the family along the female line, the mother and grandmother also had an increased need for water, the use of minirin was ineffective. In the older brother and younger brother, clinical manifestations of diabetes insipidus in the form of severe thirst and polyuria were noted from infancy, after the examination, the diagnosis was made - diabetes insipidus and desmopressin was prescribed.Due to the lack of effect from the use of desmopressin, the analysis of exons and adjacent sections of the introns of the AQP2 and AVPR2 genes was carried out by PCR and subsequent direct sequencing. No mutations were found in the AQP2 gene. The hemizygous substitution S315I was found in the AVPR2 gene. The familial form X was confirmed - linked nephrogenic diabetes insipidus. A hypothiazide was recommended, against the background of constant intake of which only a slight positive trend is observed.

Genetic deletion of the nuclear factor of activated T cells 5 in collecting duct principal cells causes nephrogenic diabetes insipidus.

Water homeostasis is tightly regulated by the kidneys via the process of urine concentration. During reduced water intake, the antidiuretic hormone arginine vasopressin (AVP) binds to the vasopressin receptor type II (V2R) in the kidney to enhance countercurrent multiplication and medullary osmolality, and increase water reabsorption via aquaporin-2 (AQP2) water channels. The importance of this AVP, V2R, and AQP2 axis is highlighted by low urine osmolality and polyuria in people with various water balance disorders, including nephrogenic diabetes insipidus (NDI). ELF5 and nuclear factor of activated T cells 5 (NFAT5) are two transcription factors proposed to regulate Aqp2 expression, but their role is poorly defined. Here we generated two novel mouse lines with principal cell (PC)-specific deletion of ELF5 or NFAT5 and phenotyped them in respect to renal water handling. ELF5-deficient mice (ELF5PC-KO ) had a very mild phenotype, with no clear differences in AQP2 abundance, and mild differences in renal water handling and maximal urinary concentrating capacity. In contrast, NFAT5 (NFAT5PC-KO ) mice had significantly higher water intake and their 24 h urine volume was almost 10-fold greater than controls. After challenging with dDAVP or 8 h water restriction, NFAT5PC-KO mice were unable to concentrate their urine, demonstrating that they suffer from NDI. The abundance of AQP2, other AQPs, and the urea transporter UT-A1 were greatly decreased in NFAT5PC-KO mice. In conclusion, NFAT5 is a major regulator of not only Aqp2 gene transcription, but also other genes important for water homeostasis and its absence leads to the development of NDI.

A Novel Missense Mutation of Arginine Vasopressin Receptor 2 in a Chinese Family with Congenital Nephrogenic Diabetes Insipidus: X-Chromosome Inactivation in Female CNDI Patients with Heterozygote 814A>G Mutation.

Background: To identify novel clinical phenotypic signatures of congenital nephrogenic diabetes insipidus (CNDI). Methods: A Chinese family with CNDI was recruited for participation in this study. The proband and one of his uncles suffered from polydipsia and polyuria since infancy. The results of clinical testing indicated the diagnosis of CNDI. 10 family members had similar symptoms but did not seek medical advice. Genetic testing of mutations in the coding region of the aquaporin 2 (AQP2) gene and the arginine vasopressin receptor 2 (AVPR2) gene were carried out in 11 family members. Somatic DNA from 5 female family members was used to test for methylation of polymorphic CAG repeats in the human androgen receptor (AR) gene, as an index for X-chromosome inactivation pattern (XCIP). Results: AQP2 gene mutations were not found in any family members, but a novel missense mutation (814th base A>G) in exon 2 of the AVPR2 gene was identified in 10 individuals. This mutation leads to a Met 272 Val (GAT-GGT) amino acid substitution. Skewed X-chromosome inactivation patterns of the normal X allele were observed in 4 females with the AVPR2 gene mutation and symptoms of diabetes insipidus, but not in an asymptomatic female with the AVPR2 gene mutation. Conclusions: Met 272 Val mutation of the AVPR2 gene was identified as a novel genetic risk factor for CDNI. The clinical NDI phenotype of female carriers with heterozygous AVPR2 mutation may be caused by X-chromosome inactivation induced by dominant methylation of the normal allele of AVPR2 gene.

Gαs and Gαq/11 protein coupling bias of two AVPR2 mutants (R68W and V162A) that cause nephrogenic diabetes insipidus.

Loss-of-function mutations of the arginine vasopressin receptor 2 gene (AVPR2) cause Nephrogenic diabetes insipidus (NDI). AVPR2 is a kind of G protein coupled receptor (GPCR) and mainly couples with Gαs protein leading to cAMP accumulation in the cell as a secondary messenger. Recent studies showed that some AVPR2 mutations could cause biased Gαq/11 protein coupling rather than Gαs. Investigation into the characterization of biased receptors may give insights into the relationship between the conformational change of the receptor because of the mutation and related downstream signaling. In this study, R68W and V162A were analyzed to whether they show a bias to Gαs or Gαq/11 proteins. Their functionality in terms of cAMP production via Gαs protein coupling was decreased compared to the wild-type receptor. On the other hand, they showed the ability to couple with Gαq/11 protein and make Ca2+ mobilization at different levels in the cell. R68W showed bias to coupling with Gαq/11 protein rather than V162A and wild-type receptor. Studies about the Gα protein coupling bias of mutant AVPR2s may broaden our understanding of the relationship between the changed conformation of the receptor and consequently activated signaling pathways, and also may shed light on the development of more effective new therapeutics.

Renal water transport in health and disease.

Saving body water by optimal reabsorption of water filtered by the kidney leading to excretion of urine with concentrations of solutes largely above that of plasma allowed vertebrate species to leave the aquatic environment to live on solid ground. Filtered water is reabsorbed for 70% and 20% by proximal tubules and thin descending limbs of Henle, respectively. These two nephron segments express the water channel aquaporin-1 located along both apical and basolateral membranes. In the proximal tubule, the paracellular pathway accounts for at least 30% of water reabsorption, and the tight-junction core protein claudin-2 plays a key role in this permeability. The ascending limb of Henle and the distal convoluted tubule are impermeant to water and are responsible for urine dilution. The water balance is adjusted along the collecting system, i.e. connecting tubule and the collecting duct, under the control of arginine-vasopressin (AVP). AVP is synthesized by the hypothalamus and released in response to an increase in extracellular osmolality or stimulation of baroreceptors by decreased blood pressure. In response to AVP, aquaporin-2 water channels stored in subapical intracellular vesicles are translocated to the apical plasma membrane and raise the water permeability of the collecting system. The basolateral step of water reabsorption is mediated by aquaporin-3 and -4, which are constitutively expressed. Drugs targeting water transport include classical diuretics, which primarily inhibit sodium transport; the new class of SGLT2 inhibitors, which promotes osmotic diuresis and the non-peptidic antagonists of the V2 receptor, which are pure aquaretic drugs. Disturbed water balance includes diabetes insipidus and hyponatremias. Diabetes insipidus is characterized by polyuria and polydipsia. It is either related to a deficit in AVP secretion called central diabetes insipidus that can be treated by AVP analogs or to a peripheral defect in AVP response called nephrogenic diabetes insipidus. Diabetes insipidus can be either of genetic origin or acquired. Hyponatremia is a common disorder most often related to free water excess relying on overstimulated or inappropriate AVP secretion. The assessment of blood volume is key for the diagnosis and treatment of hyponatremia, which can be classified as hypo-, eu-, or hypervolemic.

X-Linked Kidney Disorders in Women.

A number of genes that cause inherited kidney disorders reside on the X chromosome. Given that males have only a single active X chromosome, these disorders clinically manifest primarily in men and boys. However, phenotypes in female carriers of X-linked kidney conditions are becoming more and more recognized. This article reviews the biology of X inactivation as well as the kidney phenotype in women and girls with a number of X-linked kidney disorders including Alport syndrome, Fabry disease, nephrogenic diabetes insipidus, X-linked hypophosphatemic rickets, Dent disease, and Lowe syndrome.

A Novel Form of Familial Vasopressin Deficient Diabetes Insipidus Transmitted in an X-linked Recessive Manner.

CONTEXT: Familial pituitary diabetes insipidus has been described only in an autosomal dominant or recessive mode of inheritance. OBJECTIVE: This work aims to determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner. METHODS: Thirteen members from 3 generations of the kindred with familial DI were studied. Water intake, urine volume, urine osmolality, plasma osmolality, and plasma vasopressin were measured under basal conditions, during fluid deprivation, 3% saline infusion, and water loading. Magnetic resonance images of the posterior pituitary also were obtained. In affected males, the effects of desmopressin therapy and linkage of the DI to markers for chromosome Xq28 were determined. In addition, the genes encoding vasopressin, aquaporin-2, the AVPR2 receptor, and its flanking regions were sequenced. RESULTS: This study showed that 4 males from 3 generations of the kindred have DI that is due to a deficiency of vasopressin, is corrected by standard doses of desmopressin, and segregates with markers for the AVPR2 gene in Xq28. However, no mutations were found in AVPR2 or its highly conserved flanking regions. Exome sequencing confirmed these findings and also revealed no deleterious variants in the provasopressin and aquaporin-2 genes. The 4 obligate female carriers osmo-regulated vasopressin in the low normal range. CONCLUSION: X-linked recessive transmission of DI can be due to a defect in either the secretion or the action of vasopressin. Other criteria are necessary to differentiate and manage the 2 disorders correctly.