Molecular Analysis of X-Linked Nephrogenic Diabetes Insipidus
| Title: | Molecular Analysis of X-Linked Nephrogenic Diabetes Insipidus |
|---|---|
| Authors: | Fujiwara, T. Mary; Morgan, Kenneth; Bichet, Daniel G. |
| Publisher: | European Journal of Endocrinology |
| Date Published: | June 01, 1996 |
| Reference Number: | 20 |
In congenital nephrogenic diabetes insipidus, the renal collecting ducts are resistant to the antidiuretic action of arginine-vasopressin, or to its antidiuretic analog dDAVP (1, 2). This is a rare, but now well described entity secondary to either mutations in the AVPR2 gene that codes for the vasopressin antidiuretic (V2) receptor or to mutations in the AQP2 gene that codes for the vasopressin-dependent water channel (3, 4). Of 75 families with congenital nephrogenic diabetes insipidus referred to our laboratory in Montreal, 71 famiilies have AVPR2 mutations and four have AQP2 mutations. The AVPR2 gene is located in chromosome region Xq28 and as a consequence males who have an AVPR2 mutation have a phenotype characterized by early dehydration episodes, hypernatremia and hyperthermia as early as the first week of life. The dehydration episodes can be so severe that they lower arterial blood perfusion pressure to a degree that is not sufficient to sustain adequate oxygenation to the brain, kidneys and other organs. Mental and physical retardation and renal failure are the classical "historical" consequences of a late diagnosis and lack of treatment. The AQP2 gene is located in chromosome region 12q13. Males and females affected with congenital nephrogenic diabetes insipidus have been described who are homozygous for a mutation in the AQP2 gene or carry two different mutations (3, 4). The onset and severity of the clinical manifestations of autosomal recessive nephrogenic diabetes insipidus are similar to those of X-linked nephrogenic diabetes insipidus.
Jinnouchi and co-workers are presenting, in this issue, a molecular analysis of three Japanese families with congenital nephrogenic diabetes insipidus; thus, 12 different AVPR2 mutations have now been identified in Japanese families. In family A, deletion of the entire AVPR2 gene was inferred with Southern blot analysis. Four other families are known to have large, partial deletions of AVPR2 (see Fig. 1). In family B a de novo mutations [sic], V88M, was identified. The same V88M mutation has also been found in two unrelated caucasian families (5, 6). The mutation in family C was not identified; however, the disease-causing allele can be identified because the mutation co-segregates with a silent substitution (CTA to CTG, which both code for leucine at codon 309).
The diversity of AVPR2 mutations found in Japanese families is consistent with the broad spectrum of mutations found in many ethnic groups. This diversity of mutations and the rareness of the disease is consistent with an X-linked recessive disease that was lethal in the past for male patients and was balanced by recurrent mutation. Seventy-two different putative disease-causing mutations in the AVPR2 gene have been reported in 102 unrelated families with X-linked nephrogenic diabetes insipidus (Fig. 1).
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V278, Y280C, W284X, A285P, P286L, P286R, L292P, W293X. EIV: 977delG, 982-2A—›The cause of loss of function or dysregulation of 23 different mutant V2 receptors has been studied using in vitro expression systems (8, 9 and references therein). In addition to characterizing the defect, it has been possible to differentiate between mutations that are disease-causing and those that are benign sequence variants. A classification system similar to the classification of LDL receptor mutations based on the phenotypic effects of the protein (10) has been proposed by Tsukaguchi et al. (8) to help understand the molecular pathophysiology of X-linked nephrogenic diabetes insipidus. Type 1 receptors reach the cell surface but have impaired binding, type 2 receptors have defective intracellular transport, and type 3 receptors are ineffectively translated and/or rapidly degraded. More recently, Schoneberg and co-workers (9) pharmacologically rescued truncated V2 receptors by co-expression of a polypeptide consisting of the last 130 amino acids of the V2 receptor. Four of the six truncated receptors (E242X, 804delG, 834delA, and W284X) regained considerable functional activity, as demonstrated by an increase in the number of binding sites and stimulation of adenylate cyclase activity.
There are many other hereditary endocrine and non-endocrine diseases that are caused by mutations which result in a loss of function or dysregulation of G-protein linked receptors: hereditary familial glucocorticoid deficiency (ACTH receptor), familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (calcium sensing receptor), hereditary male precocious puberty (LH receptor), autosomal dominant retinitis pigmentosa (ospin), dominantly inherited bleeding disorder due to a mutation in the thromboxane A2 receptor, hereditary hypergonadotropic ovarian failure (FSH), etc. (Ref. 11). Thus, the V2 receptor may be a model system for developing therapeutic strategies for the treatment of disease caused by mutations in G-protein-linked receptors that contain seven transmembrane domains.
How is this new molecular knowledge transferred to the care of patients with X-linked nephrogenic diabetes insipidus? When the disease-causing mutation has been identified, carrier and perinatal testing can be done by mutation analysis. If a large deletion is observed (family A of Jinnouchi et al.) or if a mutation has not yet been identified (family C), reliable testing can be performed using Southern blot analysis (for large deletions) or haplotype analysis using an informative sequence variant in the AVPR2 gene or closely linked markers (12). We encourage physicians who follow families with X-linked nephrogenic diabetes insipidus to recommend molecular genetic analysis because early diagnosis and treatment of male infants can avert the physical and mental retardation associated with episodes of dehydration. Diagnosis of X-linked nephrogenic diabetes insipidus was accomplished by mutation testing of a sample of cord blood in three of our patients. These patients were immediately treated with abundant water intake, a low sodium diet and hydrochlorothiazide. They never experienced episodes of dehydration and their physical and mental development is normal. They can wait safely for further developments in pharmacotherapeutics and possibly somatic gene therapy.
REFERENCES
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- Knoers N, Monnens LAH. Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment [invited review]. Pediatr Nephrol 1992; 6:476-82
- Deen PMT, Verdijk MAJ, Knoers NVAM, Wieringa B, Monnens LAH, van Os CH, et al. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 1994; 264:92-5
- Van Lieburg AF, Verdijk MAJ, Knoers NVAM, van Essen AJ, Proesmans W, Mallmann R, et al. Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. Am J Hum Genet 1994; 55:648-52
- Knoers NVAM, van den Ouweland AMW, Verdijk M, Monnens LAH, van Oost BA. Inheritance of mutations in the V2 receptor gene in thirteen families with nephrogenic diabetes insipidus. Kidney Int 1994; 46:170-6
- Bichet DG, Birnbaumer M, Lonergan M, Arthus MF, Rosenthal W, Goodyer P, et al. Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet 1994; 55:278-86
- Cooper DN, Krawczak M., Antaonarakis SE. The nature and mechanisms of human gene mutation. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. Vol 1, 7th ed. New York: McGraw-Hill, 1995:259-91
- Tsukaguchi H, Matsubara H, Taketani S, Mori Y, Seido T, Inada M. Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus. J Clin Invest 1995; 96:2043-50
- Schoneberg T, Yun J, Wenkert D, Wess J. Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a coespressed receptor polypeptide. EMBO J 1996; 15:1283-91
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- References available from authors.
- Bichet DG, Arthus MF, Lonergan M, Hendy GN, Paradis AJ, Fujiwara TM, et al. X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest 1993; 92:1262-8
Departments of Human Genetics, Medicine and Pediatrics (T Mary Fujiwara) and Departments of Human Genetics and Medicine (Kenneth Morgan), McGill University, Montreal, Québec, Canada; Unité de recherche clinique (Daniel G. Bichet), Centre de recherche et Service de néphrologie, Département de Médecine, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Quebec, Canada
Received March 5th, 1996; Accepted March 7th; 1996
Address correspondence and reprint requests to Professor Albert Burger, Chief Editor, European Journal of Endocrinology, c/o Hôpital Cantonal Universitaire cp 30, CH1211 Geneva 4, Switzerland
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
NDI is a rare kidney disorder in which the kidneys' collecting ducts do not respond to the antidiuretic hormone. Therefore, the kidneys are unable to concentrate urine or reabsorb water for the body's use. This results in excessive urination resulting in dehydration and attendant complications.
NDI can be acquired, but more often it is congenital. In both instances, NDI is the result of mutations in the V2 receptor (AVPR2) gene, a structure within kidney cells that is supposed to bind the antidiuretic hormone, arginine vasopressin. NDI may also be caused by mutations in the AQP2 gene that codes for the vasopressin-dependent water transporting protein. Of the 75 families with congenital NDI referred to the authors' laboratory, 71 families had AVPR2 mutations and four had AQP2 mutations.
The AVPR2 is located in chromosome region xq28, so this means the mutations of this gene are X-linked and therefore expressed in males. Symptoms of X-linked congenital NDI, which can appear as early as the first week of life, include dehydration, excessive sodium levels in the blood, and high fevers. The dehydration could be so severe as to lower blood pressure so that it cannot supply adequate oxygen to the brain, kidney or other organs. If NDI is not diagnosed and treated early, then mental and physical retardation and kidney failure could result.
The AQP2 gene is located in chromosome region 12ql3. It is not X-linked; both males and females are equally susceptible to this form of NDI. The onset and severity of congenital NDI resulting from mutated AQP2 genes are similar to X-linked NDI.
The AVPR2 gene can be mutated in different ways. The authors mention a study of 12 different AVPR2 mutations in Japanese families. This diversity is consistent with the broad range of mutations in the AVPR2 gene found in many ethnic groups. In fact, 72 different types of disease causing AVPR2 mutations have been recorded in 102 unrelated families with X-linked NDI.
Research into AVPR2 gene dysfunction holds great promise. It has been possible to differentiate between mutations that are disease-causing and those that are benign sequence variants. A classification system for the V2 receptor mutation types has been proposed:
- Type 1 receptors are those that reach the cell surface, but do not bind to it as they should.
- Type 2 receptors can't get to the cell surface.
- Type 3 receptors are ineffectively translated and/or rapidly degraded.
Scientists have even been able to partially restore the functional activity of four truncated V2 receptors by synthesizing a polypeptide consisting of the last 130 amino acids of the V2 receptor.
There are many other diseases caused by mutations of gene receptors, and continued research into the V2 receptor may provide a model system for developing therapeutic strategies for similar diseases. This new molecular knowledge of NDI cause and function enables families who carry the disease-causing mutation to know in advance if their fetus is also carrying the mutated gene. If so, the infant can receive proper treatment, thus averting the physical and mental retardation associated with NDI-induced dehydration.