Diabetes Insipidus: A disease that is characterized by frequent urination, excretion of large amounts of dilute URINE, and excessive THIRST. Etiologies of diabetes insipidus include deficiency of antidiuretic hormone (also known as ADH or VASOPRESSIN) secreted by the NEUROHYPOPHYSIS, impaired KIDNEY response to ADH, and impaired hypothalamic regulation of thirst.Diabetes Insipidus, Neurogenic: A genetic or acquired polyuric disorder caused by a deficiency of VASOPRESSINS secreted by the NEUROHYPOPHYSIS. Clinical signs include the excretion of large volumes of dilute URINE; HYPERNATREMIA; THIRST; and polydipsia. Etiologies include HEAD TRAUMA; surgeries and diseases involving the HYPOTHALAMUS and the PITUITARY GLAND. This disorder may also be caused by mutations of genes such as ARVP encoding vasopressin and its corresponding neurophysin (NEUROPHYSINS).Diabetes Insipidus, Nephrogenic: A genetic or acquired polyuric disorder characterized by persistent hypotonic urine and HYPOKALEMIA. This condition is due to renal tubular insensitivity to VASOPRESSIN and failure to reduce urine volume. It may be the result of mutations of genes encoding VASOPRESSIN RECEPTORS or AQUAPORIN-2; KIDNEY DISEASES; adverse drug effects; or complications from PREGNANCY.Polyuria: Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes (DIABETES MELLITUS; DIABETES INSIPIDUS).Deamino Arginine Vasopressin: A synthetic analog of the pituitary hormone, ARGININE VASOPRESSIN. Its action is mediated by the VASOPRESSIN receptor V2. It has prolonged antidiuretic activity, but little pressor effects. It also modulates levels of circulating FACTOR VIII and VON WILLEBRAND FACTOR.Aquaporin 2: Aquaporin 2 is a water-specific channel protein that is expressed in KIDNEY COLLECTING DUCTS. The translocation of aquaporin 2 to the apical PLASMA MEMBRANE is regulated by VASOPRESSIN, and MUTATIONS in AQP2 have been implicated in a variety of kidney disorders including DIABETES INSIPIDUS.Pituitary Diseases: Disorders involving either the ADENOHYPOPHYSIS or the NEUROHYPOPHYSIS. These diseases usually manifest as hypersecretion or hyposecretion of PITUITARY HORMONES. Neoplastic pituitary masses can also cause compression of the OPTIC CHIASM and other adjacent structures.Rats, Brattleboro: A mutant strain of Rattus norvegicus used in research on renal function and hypertension and as a disease model for diabetes insipidus.Receptors, Vasopressin: Specific molecular sites or proteins on or in cells to which VASOPRESSINS bind or interact in order to modify the function of the cells. Two types of vasopressin receptor exist, the V1 receptor in the vascular smooth muscle and the V2 receptor in the kidneys. The V1 receptor can be subdivided into V1a and V1b (formerly V3) receptors.Antidiuretic Agents: Agents that reduce the excretion of URINE, most notably the octapeptide VASOPRESSINS.Neurophysins: Carrier proteins for OXYTOCIN and VASOPRESSIN. They are polypeptides of about 10-kDa, synthesized in the HYPOTHALAMUS. Neurophysin I is associated with oxytocin and neurophysin II is associated with vasopressin in their respective precursors and during transportation down the axons to the neurohypophysis (PITUITARY GLAND, POSTERIOR).Vasopressins: Antidiuretic hormones released by the NEUROHYPOPHYSIS of all vertebrates (structure varies with species) to regulate water balance and OSMOLARITY. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a CYSTINE. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the KIDNEY COLLECTING DUCTS to increase water reabsorption, increase blood volume and blood pressure.Chlorpropamide: A sulfonylurea hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. (From Martindale, The Extra Pharmacopoeia, 30th ed, p277)Hypopituitarism: Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including LH; FOLLICLE STIMULATING HORMONE; SOMATOTROPIN; and CORTICOTROPIN). This may result from surgical or radiation ablation, non-secretory PITUITARY NEOPLASMS, metastatic tumors, infarction, PITUITARY APOPLEXY, infiltrative or granulomatous processes, and other conditions.Aquaporin 6: Aquaporin 6 is an aquaglyceroporin that is found primarily in KIDNEY COLLECTING DUCTS. AQP6 protein functions as an anion-selective channel.Diabetes Mellitus, Type 1: A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence.Arginine Vasopressin: The predominant form of mammalian antidiuretic hormone. It is a nonapeptide containing an ARGININE at residue 8 and two disulfide-linked cysteines at residues of 1 and 6. Arg-vasopressin is used to treat DIABETES INSIPIDUS or to improve vasomotor tone and BLOOD PRESSURE.Diabetes Mellitus: A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE.Pituitary Gland, Posterior: Neural tissue of the pituitary gland, also known as the neurohypophysis. It consists of the distal AXONS of neurons that produce VASOPRESSIN and OXYTOCIN in the SUPRAOPTIC NUCLEUS and the PARAVENTRICULAR NUCLEUS. These axons travel down through the MEDIAN EMINENCE, the hypothalamic infundibulum of the PITUITARY STALK, to the posterior lobe of the pituitary gland.Hypothalamic Diseases: Neoplastic, inflammatory, infectious, and other diseases of the hypothalamus. Clinical manifestations include appetite disorders; AUTONOMIC NERVOUS SYSTEM DISEASES; SLEEP DISORDERS; behavioral symptoms related to dysfunction of the LIMBIC SYSTEM; and neuroendocrine disorders.Kidney Concentrating Ability: The ability of the kidney to excrete in the urine high concentrations of solutes from the blood plasma.Aquaporins: A class of porins that allow the passage of WATER and other small molecules across CELL MEMBRANES.Renal Agents: Drugs used for their effects on the kidneys' regulation of body fluid composition and volume. The most commonly used are the diuretics. Also included are drugs used for their antidiuretic and uricosuric actions, for their effects on the kidneys' clearance of other drugs, and for diagnosis of renal function.Hypernatremia: Excessive amount of sodium in the blood. (Dorland, 27th ed)Diabetes Mellitus, Type 2: A subclass of DIABETES MELLITUS that is not INSULIN-responsive or dependent (NIDDM). It is characterized initially by INSULIN RESISTANCE and HYPERINSULINEMIA; and eventually by GLUCOSE INTOLERANCE; HYPERGLYCEMIA; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop KETOSIS but often exhibit OBESITY.Thirst: A drive stemming from a physiological need for WATER.Hypothalamic Neoplasms: Benign and malignant tumors of the HYPOTHALAMUS. Pilocytic astrocytomas and hamartomas are relatively frequent histologic types. Neoplasms of the hypothalamus frequently originate from adjacent structures, including the OPTIC CHIASM, optic nerve (see OPTIC NERVE NEOPLASMS), and pituitary gland (see PITUITARY NEOPLASMS). Relatively frequent clinical manifestations include visual loss, developmental delay, macrocephaly, and precocious puberty. (From Devita et al., Cancer: Principles and Practice of Oncology, 5th ed, p2051)Histiocytosis, Langerhans-Cell: A group of disorders resulting from the abnormal proliferation of and tissue infiltration by LANGERHANS CELLS which can be detected by their characteristic Birbeck granules (X bodies), or by monoclonal antibody staining for their surface CD1 ANTIGENS. Langerhans-cell granulomatosis can involve a single organ, or can be a systemic disorder.Diuresis: An increase in the excretion of URINE. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Water Deprivation: The withholding of water in a structured experimental situation.Chlorothiazide: A thiazide diuretic with actions and uses similar to those of HYDROCHLOROTHIAZIDE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p812)Wolfram Syndrome: A hereditary condition characterized by multiple symptoms including those of DIABETES INSIPIDUS; DIABETES MELLITUS; OPTIC ATROPHY; and DEAFNESS. This syndrome is also known as DIDMOAD (first letter of each word) and is usually associated with VASOPRESSIN deficiency. It is caused by mutations in gene WFS1 encoding wolframin, a 100-kDa transmembrane protein.Sella Turcica: A bony prominence situated on the upper surface of the body of the sphenoid bone. It houses the PITUITARY GLAND.Central Nervous System Cysts: Congenital or acquired cysts of the brain, spinal cord, or meninges which may remain stable in size or undergo progressive enlargement.Craniopharyngioma: A benign pituitary-region neoplasm that originates from Rathke's pouch. The two major histologic and clinical subtypes are adamantinous (or classical) craniopharyngioma and papillary craniopharyngioma. The adamantinous form presents in children and adolescents as an expanding cystic lesion in the pituitary region. The cystic cavity is filled with a black viscous substance and histologically the tumor is composed of adamantinomatous epithelium and areas of calcification and necrosis. Papillary craniopharyngiomas occur in adults, and histologically feature a squamous epithelium with papillations. (From Joynt, Clinical Neurology, 1998, Ch14, p50)Diabetes Complications: Conditions or pathological processes associated with the disease of diabetes mellitus. Due to the impaired control of BLOOD GLUCOSE level in diabetic patients, pathological processes develop in numerous tissues and organs including the EYE, the KIDNEY, the BLOOD VESSELS, and the NERVE TISSUE.Fanconi Syndrome: A hereditary or acquired form of generalized dysfunction of the PROXIMAL KIDNEY TUBULE without primary involvement of the KIDNEY GLOMERULUS. It is usually characterized by the tubular wasting of nutrients and salts (GLUCOSE; AMINO ACIDS; PHOSPHATES; and BICARBONATES) resulting in HYPOKALEMIA; ACIDOSIS; HYPERCALCIURIA; and PROTEINURIA.Osmolar Concentration: The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per liter of solution. Osmolality is expressed in terms of osmoles of solute per kilogram of solvent.Water-Electrolyte Balance: The balance of fluid in the BODY FLUID COMPARTMENTS; total BODY WATER; BLOOD VOLUME; EXTRACELLULAR SPACE; INTRACELLULAR SPACE, maintained by processes in the body that regulate the intake and excretion of WATER and ELECTROLYTES, particularly SODIUM and POTASSIUM.Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight [6.938; 6.997]. Salts of lithium are used in treating BIPOLAR DISORDER.Pituitary Neoplasms: Neoplasms which arise from or metastasize to the PITUITARY GLAND. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties (see ADENOMA, BASOPHIL; ADENOMA, ACIDOPHIL; and ADENOMA, CHROMOPHOBE). Pituitary tumors may compress adjacent structures, including the HYPOTHALAMUS, several CRANIAL NERVES, and the OPTIC CHIASM. Chiasmal compression may result in bitemporal HEMIANOPSIA.Kidney Tubules, Collecting: Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of Bellini) which opens on the summit of the papilla.Polydipsia: Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as DIABETES MELLITUS; DIABETES INSIPIDUS; and NEPHROGENIC DIABETES INSIPIDUS. The condition may be psychogenic in origin.Pituitary Gland: A small, unpaired gland situated in the SELLA TURCICA. It is connected to the HYPOTHALAMUS by a short stalk which is called the INFUNDIBULUM.Diabetes Mellitus, Experimental: Diabetes mellitus induced experimentally by administration of various diabetogenic agents or by PANCREATECTOMY.Neuroendoscopy: PROCEDURES that use NEUROENDOSCOPES for disease diagnosis and treatment. Neuroendoscopy, generally an integration of the neuroendoscope with a computer-assisted NEURONAVIGATION system, provides guidance in NEUROSURGICAL PROCEDURES.Inappropriate ADH Syndrome: A condition of HYPONATREMIA and renal salt loss attributed to overexpansion of BODY FLUIDS resulting from sustained release of ANTIDIURETIC HORMONES which stimulates renal resorption of water. It is characterized by normal KIDNEY function, high urine OSMOLALITY, low serum osmolality, and neurological dysfunction. Etiologies include ADH-producing neoplasms, injuries or diseases involving the HYPOTHALAMUS, the PITUITARY GLAND, and the LUNG. This syndrome can also be drug-induced.Urine: Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the URETHRA.Lithium Carbonate: A lithium salt, classified as a mood-stabilizing agent. Lithium ion alters the metabolism of BIOGENIC MONOAMINES in the CENTRAL NERVOUS SYSTEM, and affects multiple neurotransmission systems.Optic Atrophy: Atrophy of the optic disk which may be congenital or acquired. This condition indicates a deficiency in the number of nerve fibers which arise in the RETINA and converge to form the OPTIC DISK; OPTIC NERVE; OPTIC CHIASM; and optic tracts. GLAUCOMA; ISCHEMIA; inflammation, a chronic elevation of intracranial pressure, toxins, optic nerve compression, and inherited conditions (see OPTIC ATROPHIES, HEREDITARY) are relatively common causes of this condition.Pituitary Function Tests: Examinations that evaluate functions of the pituitary gland.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Dehydration: The condition that results from excessive loss of water from a living organism.Hyponatremia: Deficiency of sodium in the blood; salt depletion. (Dorland, 27th ed)Hydronephrosis: Abnormal enlargement or swelling of a KIDNEY due to dilation of the KIDNEY CALICES and the KIDNEY PELVIS. It is often associated with obstruction of the URETER or chronic kidney diseases that prevents normal drainage of urine into the URINARY BLADDER.Kidney: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.Bendroflumethiazide: A thiazide diuretic with actions and uses similar to those of HYDROCHLOROTHIAZIDE. It has been used in the treatment of familial hyperkalemia, hypertension, edema, and urinary tract disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p810)Drinking: The consumption of liquids.Endocrine System Diseases: Pathological processes of the ENDOCRINE GLANDS, and diseases resulting from abnormal level of available HORMONES.Renal Aminoacidurias: A group of inherited kidney disorders characterized by the abnormally elevated levels of AMINO ACIDS in URINE. Genetic mutations of transport proteins result in the defective reabsorption of free amino acids at the PROXIMAL RENAL TUBULES. Renal aminoaciduria are classified by the specific amino acid or acids involved.Aquaporin 3: Aquaporin 3 is an aquaglyceroporin that is expressed in the KIDNEY COLLECTING DUCTS and is constitutively localized at the basolateral MEMBRANE.Diabetes, Gestational: Diabetes mellitus induced by PREGNANCY but resolved at the end of pregnancy. It does not include previously diagnosed diabetics who become pregnant (PREGNANCY IN DIABETICS). Gestational diabetes usually develops in late pregnancy when insulin antagonistic hormones peaks leading to INSULIN RESISTANCE; GLUCOSE INTOLERANCE; and HYPERGLYCEMIA.Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Acidosis, Renal Tubular: A group of genetic disorders of the KIDNEY TUBULES characterized by the accumulation of metabolically produced acids with elevated plasma chloride, hyperchloremic metabolic ACIDOSIS. Defective renal acidification of URINE (proximal tubules) or low renal acid excretion (distal tubules) can lead to complications such as HYPOKALEMIA, hypercalcinuria with NEPHROLITHIASIS and NEPHROCALCINOSIS, and RICKETS.Blood Glucose: Glucose in blood.Adrenal Insufficiency: Conditions in which the production of adrenal CORTICOSTEROIDS falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the ADRENAL GLANDS, the PITUITARY GLAND, or the HYPOTHALAMUS.Urination: Discharge of URINE, liquid waste processed by the KIDNEY, from the body.Halofenate: An antihyperlipoproteinemic agent and uricosuric agent.Sodium Chloride Symporter Inhibitors: Agents that inhibit SODIUM CHLORIDE SYMPORTERS. They act as DIURETICS. Excess use is associated with HYPOKALEMIA.Osmoregulation: The response of cells in sensing a difference in OSMOTIC PRESSURE between the inside and outside of the cell. This response includes signaling from osmotic sensors to activate transcription factors, which in turn regulate the expression of osmocompensatory genes, all functioning to maintain CELL VOLUME and the water concentration inside the cells.Water Intoxication: A condition resulting from the excessive retention of water with sodium depletion.Hemoglobin A, Glycosylated: Minor hemoglobin components of human erythrocytes designated A1a, A1b, and A1c. Hemoglobin A1c is most important since its sugar moiety is glucose covalently bound to the terminal amino acid of the beta chain. Since normal glycohemoglobin concentrations exclude marked blood glucose fluctuations over the preceding three to four weeks, the concentration of glycosylated hemoglobin A is a more reliable index of the blood sugar average over a long period of time.Lithium Compounds: Inorganic compounds that contain lithium as an integral part of the molecule.Hypogonadism: Condition resulting from deficient gonadal functions, such as GAMETOGENESIS and the production of GONADAL STEROID HORMONES. It is characterized by delay in GROWTH, germ cell maturation, and development of secondary sex characteristics. Hypogonadism can be due to a deficiency of GONADOTROPINS (hypogonadotropic hypogonadism) or due to primary gonadal failure (hypergonadotropic hypogonadism).
Diabetes insipidusNeurogenic diabetes insipidusPolyuriaDesmopressinHypophysitis: Hypophysitis refers to an inflammation of the pituitary gland. Hypophysitis is rare and not fully understood.RelcovaptanNeurophysin I: Neurophysin I is a carrier protein with a size of 10 KDa and containing 90 to 97 aminoacids that is a cleavage product (formed by splitting of a compound molecule into a simpler one) of preprooxyphysin. It is a neurohypophysial hormone that is transported in vesicles with oxytocin, the other cleavage product, along axons, from magnocellular neurons of the hypothalamus to the posterior lobe of the pituitary.Vasopressin analogue: Vasopressin analogues are chemicals similar in function but not necessarily similar in structure to vasopressin (ADH), such as desmopressin.ChlorpropamideSheehan's syndromeNetwork for Pancreatic Organ Donors with Diabetes: The Network for Pancreatic Organ donors with Diabetes (nPOD), is a collaborative type 1 diabetes research project funded by JDRF (formerly known as the Juvenile Diabetes Research Foundation). nPOD supports scientific investigators by providing, without cost, rare and difficult to obtain tissues beneficial to their research.Permanent neonatal diabetes mellitus: A newly identified and potentially treatable form of monogenic diabetes is the neonatal diabetes caused by activating mutations of the KCNJ11 gene, which codes for the Kir6.2 subunit of the beta cell KATP channel.Percy Theodore Herring: Percy Theodore Herring (3 November 1872 - 24 October 1967) was a physician and physiologist, notable for first describing Herring bodies in the posterior pituitary gland.AquaporinHypernatremiaOutline of diabetes: The following outline is provided as an overview of and topical guide to diabetes:Songhwa milsuHeat intolerance: Heat intolerance is a symptom reported by people who feel uncomfortable in hot environments. Typically, the person feels uncomfortably hot and sweats excessively.Non-Langerhans cell histiocytosis: Non-Langerhans cell histiocytosis refers to a family of histiocytosis characterized by the absence of Langerhans cells.Wolfram syndromeCentral nervous system cystOrganic anion transporter 1Salting in: Salting in refers to the effect where increasing the ionic strength of a solution increases the solubility of some solute (such as a protein). This effect tends to be observed at lower ionic strengths.Osmoregulation: Osmoregulation is the active regulation of the osmotic pressure of an organism's fluids to maintain the homeostasis of the organism's water content; that is, it keeps the organism's fluids from becoming too diluted or too concentrated. Osmotic pressure is a measure of the tendency of water to move into one solution from another by osmosis.Lithium (medication)Pituitary adenomaPolydipsia in birds: Polydipsia is an excessively large water intake. Its occurrence in captive birds has been recorded, although it is a relatively rare abnormal behaviour.Syndrome of inappropriate antidiuretic hormone secretionOrocobreBerk–Tabatznik syndrome: Berk–Tabatznik syndrome is a condition with an unknown cause that shows symptoms of short stature, congenital optic atrophy and brachytelephalangy. This condition is extremely rare with only two cases being found.Pedigree chart: A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next,pedigree chart Genealogy Glossary - About.com, a part of The New York Times Company.Chronic cellular dehydrationHyponatremiaHydronephrosisKidney: The kidneys are bean-shaped organs that serve several essential regulatory roles in vertebrates. They remove excess organic molecules from the blood, and it is by this action that their best-known function is performed: the removal of waste products of metabolism.BendroflumethiazideBMC Endocrine Disorders: BMC Endocrine Disorders is an open access peer-reviewed scientific journal publishing original research articles in all aspects of the prevention, diagnosis and management of endocrine disorders, as well as related molecular genetics, pathophysiology, and epidemiology.References ==International Association of Plastics DistributorsHyperintensitySilent mutation: Silent mutations are mutations in DNA that do not significantly alter the phenotype of the organism in which they occur. Silent mutations can occur in non-coding regions (outside of genes or within introns), or they may occur within exons.Distal renal tubular acidosis: Distal renal tubular acidosis (dRTA) or Type 1 Renal tubular acidosis (RTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the cortical collecting duct of the distal nephron.Blood glucose monitoring: Blood glucose monitoring is a way of testing the concentration of glucose in the blood (glycemia). Particularly important in the care of diabetes mellitus, a blood glucose test is performed by piercing the skin (typically, on the finger) to draw blood, then applying the blood to a chemically active disposable 'test-strip'.Critical illness-related corticosteroid insufficiency: Critical illness-related corticosteroid insufficiency (CIRCI) is a form of adrenal insufficiency in critically ill patients who have blood corticosteroid levels which are inadequate for the severe stress response they experience. Combined with decreased glucocorticoid receptor sensitivity and tissue response to corticosteroids, this adrenal insufficiency constitutes a negative prognostic factor for intensive care patients.Urination: Urination is the release of urine from the urinary bladder through the urethra to the urinary meatus outside of the body. It is also known medically as micturition, voiding, uresis, or, rarely, emiction, and known colloquially by various names including tinkling, peeing, weeing, and pissing.ThiazideOrganic prepartum and postpartum psychosesPostpartum psychosisClomifene
(1/318) Mutant vasopressin precursors that cause autosomal dominant neurohypophyseal diabetes insipidus retain dimerization and impair the secretion of wild-type proteins.
Autosomal dominant familial neurohypophyseal diabetes insipidus is caused by mutations in the arginine vasopressin (AVP) gene. We demonstrated recently that mutant AVP precursors accumulate within the endoplasmic reticulum of neuronal cells, leading to cellular toxicity. In this study, the possibility that mutant AVP precursors interact with wild-type (WT) proteins to alter their processing and function was explored. WT and mutant precursors were epitope-tagged to allow them to be distinguished in transfected cells. An in vivo cross-linking reaction revealed homo- and heterodimer formation between WT and mutant precursors. Mutant precursors were also shown to impair intracellular trafficking of WT precursors from the endoplasmic reticulum to the Golgi apparatus. In addition to the cytotoxicity caused by mutant AVP precursors, the interaction between the WT and mutant precursors suggests that a dominant-negative mechanism may also contribute to the pathogenesis of familial neurohypophyseal diabetes insipidus. (+info)
(2/318) Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen.
Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension. (+info)
(3/318) Hypertonic saline test for the investigation of posterior pituitary function.
The hypertonic saline test is a useful technique for distinguishing partial diabetes insipidus from psychogenic polydipsia, and for the diagnosis of complex disorders of osmoreceptor and posterior pituitary function. However, there is little information concerning its use in childhood. The experience of using this test in five children (11 months to 18 years) who presented diagnostic problems is reported. In two patients, in whom water deprivation tests were equivocal or impractical, an inappropriately low antidiuretic hormone (ADH) concentration (< 1 pmol/l) was demonstrated in the presence of an adequate osmotic stimulus (plasma osmolality > 295 mosmol/kg). In two children--one presenting with adipsic hypernatraemia and the other with hyponatraemia complicating desmopressin treatment of partial diabetes insipidus--defects of osmoreceptor function were identified. Confirming a diagnosis of idiopathic syndrome of inappropriate ADH secretion (SIADH) was possible in a patient with no other evidence of pituitary dysfunction. The hypertonic saline test was well tolerated, easy to perform, and diagnostic in all cases. (+info)
(4/318) Pituitary involvement by Wegener's granulomatosis: a report of two cases.
We describe two cases of pituitary involvement by Wegener's granulomatosis. At initial presentation, or during subsequent disease "flares," a pattern of pituitary abnormality was suggested. During periods of remission, we found the pituitary returned to a nearly normal appearance. Loss of the normal posterior pituitary T1 hyper-intensity matched a clinical persistence of diabetes insipidus, suggesting there is permanent damage to this structure by the initial disease process. (+info)
(5/318) Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin.
Familial neurohypophyseal diabetes insipidus is an autosomal dominant disorder characterized by post-natal development of arginine vasopressin (AVP) deficiency due to mutations in the AVP gene. All published mutations affect the signal peptide or the neurophysin-II carrier protein and are presumed to interfere with processing of the preprohormone, leading to neuronal damage. We studied an unusual Palestinian family consisting of asymptomatic first cousin parents and three children affected with neurohypophyseal diabetes insipidus, suggesting autosomal recessive inheritance. All three affected children were homozygous and the parents heterozygous for a single novel mutation (C301->T) in exon 1, replacing Pro7 of mature AVP with Leu (Leu-AVP). Leu-AVP was a weak agonist with approximately 30-fold reduced binding to the human V2 receptor. Measured by radioimmunoassay with a synthetic Leu-AVP standard, serum Leu-AVP levels were elevated in all three children and further increased during water deprivation to as high as 30 times normal. The youngest child (2 years old) was only mildly affected but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children. (+info)
(6/318) Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus.
Autosomal dominant neurohypophyseal diabetes insipidus is caused by mutations in the gene encoding the vasopressin precursor protein, prepro-vasopressin-neurophysin II. We analyzed the molecular consequences of a mutation (DeltaG227) recently identified in a Swiss kindred that destroys the translation initiation codon. In COS-7 cells transfected with the mutant cDNA, translation was found to initiate at an alternative ATG, producing a truncated signal sequence that was functional for targeting and translocation but was not cleaved by signal peptidase. The mutant precursor was completely retained within the endoplasmic reticulum. The uncleaved signal did not affect folding of the neurophysin portion of the precursor, as determined by its protease resistance. However, formation of disulfide-linked aggregates indicated that it interfered with the formation of the disulfide bond in vasopressin, most likely by blocking its insertion into the hormone binding site of neurophysin. Preventing disulfide formation in the vasopressin nonapeptide by mutation of cysteine 6 to serine was shown to be sufficient to cause aggregation and retention. These results indicate that the DeltaG227 mutation induces translation of a truncated signal sequence that cannot be cleaved but prevents correct folding and oxidation of vasopressin, thereby causing precursor aggregation and retention in the endoplasmic reticulum. (+info)
(7/318) Hypercalcemia in an euthyroid patient with secondary hypoadrenalism and diabetes insipidus due to hypothalamic tumor.
A 20-year-old Japanese man with a hypothalamic tumor (most likely germ-cell tumor) which caused secondary hypoadrenalism, hypogonadism and diabetes insipidus developed hypercalcemia and acute renal failure. The serum levels of intact PTH (iPTH), PTH-related protein (PTH-rP), 1,25-dihydroxy vitamin D (1,25- (OH)2 D), ACTH, cortisol, gonadotropins and testosterone were decreased, but his serum levels of triiodothyronine (T3) and thyroxine (T4) were within the normal range at admission, with depressed TSH and slightly increased thyroglobulin. The hypercalcemia was refractory to extensive hydration and calcitonin, but was ameliorated by pamidronate. After irradiation of the hypothalamic tumor, panhypopituitarism gradually developed. The patient has been normocalcemic for the last 2 years and is doing well under replacement therapy with glucocorticoid, L-thyroxine, methyltestosterone and 1-desamino D arginine vasopressin (dDAVP). As to the mechanism of euthyroidism at admission, transient destructive thyroiditis associated with hypopituitarism or delayed development of hypothyroidism following the hypoadrenalism was suggested. This is the first reported case of hypercalcemia in secondary hypoadrenalism due to hypothalamic tumor. Hypercalcemia was most likely induced by increased bone resorption, which was probably elicited by the combined effects of deficient glucocorticoid and sufficient thyroid hormones in addition to hypovolemia and reduced renal calcium excretion. Furthermore, severe dehydration due to diabetes insipidus and disturbance of thirst sensation caused by the hypothalamic tumor aggravated the hypercalcemia, leading to acute renal failure. (+info)
(8/318) Mutations in the vasopressin prohormone involved in diabetes insipidus impair endoplasmic reticulum export but not sorting.
Familial neurohypophysial diabetes insipidus is characterized by vasopressin deficiency caused by heterozygous expression of a mutated vasopressin prohormone gene. To elucidate the mechanism of this disease, we stably expressed five vasopressin prohormones with a mutation in the neurophysin moiety (NP14G-->R, NP47E-->G, NP47DeltaE, NP57G-->S, and NP65G-->V) in the neuroendocrine cell lines Neuro-2A and PC12/PC2. Metabolic labeling demonstrated that processing and secretion of all five mutants was impaired, albeit to different extents (NP65G-->V >/= NP14G-->R > NP47DeltaE >/= NP47E-->G > NP57G-->S). Persisting endoglycosidase H sensitivity revealed these defects to be due to retention of mutant prohormone in the endoplasmic reticulum. Mutant prohormones that partially passed the endoplasmic reticulum were normally targeted to the regulated secretory pathway. Surprisingly, this also included mutants with mutations in residues involved in binding of vasopressin to neurophysin, a process implicated in targeting of the prohormone. To mimick the high expression in vasopressin-producing neurons, mutant vasopressin prohormones were transiently expressed in Neuro-2A cells. Immunofluorescence displayed formation of large accumulations of mutant prohormone in the endoplasmic reticulum, accompanied by redistribution of an endoplasmic reticulum marker. Our data suggest that prolonged perturbation of the endoplasmic reticulum eventually leads to degeneration of neurons expressing mutant vasopressin prohormones, explaining the dominant nature of the disease. (+info)