Molecular Biology of Hereditary Diabetes Insipidus
T. Mary Fujiwara* and
Daniel G. Bichet
* Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada; and Genetics of Renal Diseases, Groupe d’étude des protéines membranaires, and Université de Montréal, Research Center and Nephrology Service, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
Address correspondence to: Dr. Daniel G. Bichet, Research Center, Hôpital du Sacré-Coeur de Montréal, 5400 Boulevard Gouin Ouest, Montréal, Québec, H4J 1C5 Canada. Phone: 514-338-2486; Fax: 514-338-2694; E-mail: daniel.bichet{at}umontreal.ca
The identification, characterization, and mutational analysisof three different genes—the arginine vasopressin gene(AVP), the arginine vasopressin receptor 2 gene (AVPR2), andthe vasopressin-sensitive water channel gene (aquaporin 2 [AQP2])—providethe basis for understanding of three different hereditary formsof "pure" diabetes insipidus: Neurohypophyseal diabetes insipidus,X-linked nephrogenic diabetes insipidus (NDI), and non–X-linkedNDI, respectively. It is clinically useful to distinguish twotypes of hereditary NDI: A "pure" type characterized by lossof water only and a complex type characterized by loss of waterand ions. Patients who have congenital NDI and bear mutationsin the AVPR2 or AQP2 genes have a "pure" NDI phenotype withloss of water but normal conservation of sodium, potassium,chloride, and calcium. Patients who bear inactivating mutationsin genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination,or BSND) that encode the membrane proteins of the thick ascendinglimb of the loop of Henle have a complex polyuro-polydipsicsyndrome with loss of water, sodium, chloride, calcium, magnesium,and potassium. These advances provide diagnostic and clinicaltools for physicians who care for these patients.
Anyone who passes large volumes of urine might be said to beexperiencing diabetes insipidus. Years ago, the initial distinctionmade by physicians in evaluating patients with polyuria waswhether their urine was sweet (diabetes mellitus) or not (diabetesinsipidus) (1). Diabetes insipidus is a disorder characterizedby the excretion of abnormally large volumes (>30 ml/kg bodywt/d for adults) of dilute urine (<250 mmol/kg). This definitionexcludes osmotic diuresis, which occurs when excess solute isbeing excreted, for example, glucose in the polyuria of diabetesmellitus. Four basic defects can be involved: (1) deficientsecretion of the antidiuretic hormone arginine vasopressin (AVP),which is the most common defect and is referred to as neurohypophyseal(also known to as neurogenic, central, or hypothalamic) diabetesinsipidus; (2) renal insensitivity to the antidiuretic effectof AVP, which is known as nephrogenic diabetes insipidus (NDI);(3) excessive water intake that can result in polyuria, whichis referred to as primary polydipsia; and (4) increased metabolismof vasopressin during pregnancy, which is referred to as gestationaldiabetes insipidus. The hereditary forms of diabetes insipidusaccount for <10% of the cases of diabetes insipidus seenin clinical practice. The purpose of this review is to examinerecent developments in the understanding and molecular biologyof the hereditary forms of diabetes insipidus. Here we use thegene symbols approved by the HUGO Gene Nomenclature Committee(http://www.gene.ucl.ac.uk/nomenclature) and provide OMIM entrynumbers (2). Not included in this review are acquired formsof NDI; for further information, see references 3–5.
AVP
The regulation of the release of AVP from the posterior pituitaryis primarily dependent, under normal circumstances, on tonicityinformation relayed by osmoreceptor cells in the anterior hypothalamus(6). AVP and its corresponding carrier, neurophysin II, aresynthesized as a composite precursor by the magnocellular neuronsof the supraoptic and paraventricular nuclei of the hypothalamus(for review, see 7). The precursor is packaged into neurosecretorygranules and transported axonally in the stalk of the posteriorpituitary. En route to the neurohypophysis, the precursor isprocessed into the active hormone. Prepro-vasopressin has 164amino acids and is encoded by the 2.5-kb AVP gene located inchromosome region 20p13 (8,9). The AVP gene (coding for AVPand neurophysin II) and the OXT gene (coding for oxytocin andneurophysin I) are located in the same chromosome region, ata very short distance from each other (12 kb in humans) in head-to-headorientation. Data from transgenic mouse studies indicate thatthe intergenic region between the OXT and the AVP genes containsthe critical enhancer sites for cell-specific expression inthe magnocellular neurons (7). It is phylogenetically interestingto note that cis and trans components of this specific cellularexpression have been conserved between the Fugu isotocin (thehomolog of mammalian oxytocin) and rat oxytocin genes (10).Exon 1 of the AVP gene encodes the signal peptide, AVP, andthe NH2-terminal region of neurophysin II. Exon 2 encodes thecentral region of neurophysin II, and exon 3 encodes the COOH-terminalregion of neurophysin II and the glycopeptide. Pro-vasopressinis generated by the removal of the signal peptide from prepro-vasopressinand from the addition of a carbohydrate chain to the glycopeptide.Additional posttranslation processing occurs within neurosecretoryvesicles during transport of the precursor protein to axon terminalsin the posterior pituitary, yielding AVP, neurophysin II, andthe glycopeptide. The AVP–neurophysin II complex formstetramers that can self-associate to form higher oligomers (11).Neurophysins should be seen as chaperone-like molecules facilitatingintracellular transport in magnocellular cells. In the posteriorpituitary, AVP is stored in vesicles. Exocytotic release isstimulated by minute increases in serum osmolality (hypernatremia,osmotic regulation) and by more pronounced decreases in extracellularfluid (hypovolemia, nonosmotic regulation). Oxytocin and neurophysinI are released from the posterior pituitary by the sucklingresponse in lactating women.
AVPR2 and AQP2
The transfer of water across the principal cells of the collectingducts is now known at such a detailed level that billions ofmolecules of water that traverse the membrane could be representedand are useful teaching tools (http://www.mpibpc.gwdg.de/abteilungen/073/gallery.html;http://www.ks.uiuc.edu/research/aquaporins). The 2003 NobelPrize in chemistry was awarded to Peter Agre and Roderick MacKinnon,who solved two complementary problems presented by the cellmembrane: How does a cell let one type of ion through the lipidmembrane to the exclusion of other ions? How does it permeatewater without ions? This contributed to a momentum and renewedinterest in basic discoveries related to the transport of waterand indirectly to diabetes insipidus. The first step in theaction of AVP on water excretion is its binding to argininevasopressin type 2 receptors (hereafter referred to as V2 receptors)on the basolateral membrane of the collecting duct cells. Thehuman gene that codes for the V2 receptor (AVPR2) is locatedin chromosome region Xq28 and has three exons and two smallintrons (12,13). The sequence of the cDNA predicts a polypeptideof 371 amino acids with seven transmembrane, four extracellular,and four cytoplasmic domains (Figure 1). The V2 receptor isone of 701 members of the rhodopsin family within the superfamilyof guanine-nucleotide (G) protein-coupled receptors (14) (seealso perspective by Perez [15]). The activation of the V2 receptoron renal collecting tubules stimulates adenylyl cyclase viathe stimulatory G protein (Gs) and promotes the cAMP-mediatedincorporation of water pores into the luminal surface of thesecells. This process is the molecular basis of the vasopressin-inducedincrease in the osmotic water permeability of the apical membraneof the collecting tubule (4).
Figure 1. Schematic representation of the vasopressin type 2 (V2) receptor and identification of 183 putative disease-causing arginine vasopressin receptor 2 gene (AVPR2) mutations. Predicted amino acids are given as the one-letter amino acid code. Solid symbols indicate missense or nonsense mutations; a number indicates more than one mutation in the same codon; other types of mutations are not indicated on the figure. The extracellular, transmembrane, and cytoplasmic domains are defined according to Mouillac et al. (88). There are 89 missense, 18 nonsense, 45 frameshift deletion or insertion, seven in-frame deletion or insertion, four splice-site, and 19 large deletion mutations and one complex mutation. See http://www.medicine.mcgill.ca/nephros for a list of mutations.
The gene that codes for the water channel of the apical membraneof the kidney collecting tubule has been designated aquaporin2 (AQP2) and was cloned by homology to the rat aquaporin ofthe collecting duct (16–18). The human AQP2 gene is locatedin chromosome region 12q13 and has four exons and three introns(17–19). It is predicted to code for a polypeptide of271 amino acids that is organized into two repeats orientedat 180 degrees to each other and that has six membrane-spanningdomains, with both terminal ends located intracellularly, andconserved asparagine-proline-alanine boxes (Figure 2). It isnow well recognized that aquaporins are transmembrane channelsthat are found in cell membranes of all life forms and thatefficiently transport water while excluding protons. Moleculardynamic simulations suggest that a global orientation controlmechanism facilitates efficient movement of a single columnof water molecules while preventing proton transport in thechannel (20). Data from mouse models suggest that AQP3 and AQP4may play an important role in urinary concentration at the basolateralmembrane (21). New roles for aquaporins are being discovered,including a possible role of AQP1-facilitated water permeabilityfor cell migration related to angiogenesis (22).
Figure 2. (A) Schematic representation of aquaporin 2 (AQP2) and identification of 35 putative disease-causing AQP2 mutations. The locations of the conserved asparagine-proline-alanine (NPA) boxes and the protein kinase A (PKA) phosphorylation site (Pa) are indicated. The extracellular, transmembrane, and cytoplasmic domains are defined according to Deen et al. (17). Solid symbols indicate the location of the missense or nonsense mutations. There are 25 missense, two nonsense, six frameshift deletion or insertion, and two splice-site mutations. (B) A monomer is represented with six transmembrane helices, A through F. *Where the molecular pseudo-2-fold symmetry is strongest (89).
Inherited Neurohypophyseal Diabetes Insipidus (OMIM 125700) as a Result of Mutations in AVP (OMIM 192340)
The classic animal model for studying diabetes insipidus hasbeen the Brattleboro rat with autosomal recessive neurohypophysealdiabetes insipidus. Brattleboro rats are homozygous for a 1-bpdeletion of a guanine nucleotide (di/di) in the second exonthat results in a shift in the reading frame of the coding sequencefor the carrier neurophysin II (23). The polyuric symptoms arealso observed in heterozygous di/n rats. Homozygous Brattlebororats may still demonstrate some V2 antidiuretic effects, becausethe administration of a selective nonpeptide V2 antagonist (SR121463A,10 mg/kg intraperitoneally) induced a further increase in urineflow rate (200 to 354 ± 42 ml/24 h) and a decline inurinary osmolality (170 to 92 ± 8 mmol/kg) (24). Oxytocin,which is present at enhanced plasma concentrations in Brattlebororats, may be responsible for the observed antidiuretic activity(25,26). Oxytocin is not stimulated by increased plasma osmolalityin humans. The Brattleboro rat model therefore is not strictlycomparable with the rarely observed human cases of autosomalrecessive neurohypophyseal diabetes insipidus (27).
Patients with autosomal dominant neurohypophyseal diabetes insipidusretain some limited capacity to secrete AVP during severe dehydration,and the polyuro-polydipsic symptoms usually appear after thefirst year of life (28), when the infant’s demand forwater is more likely to be understood by adults. More than 50AVP mutations segregating with autosomal dominant or autosomalrecessive neurohypophyseal diabetes insipidus have been described(see http://www.medicine.mcgill.ca/nephros for a list of mutations).The mechanisms by which a mutant allele causes neurohypophysealdiabetes insipidus could involve the induction of magnocellularcell death as a result of the accumulation of AVP precursorswithin the endoplasmic reticulum (29–31). This hypothesiscould account for the delayed onset of the disease. In additionto the cytotoxicity caused by mutant AVP precursors, the interactionbetween the wild-type and the mutant precursors suggests thata dominant negative mechanism may also contribute to the pathogenesisof autosomal dominant diabetes insipidus (32). The absence ofsymptoms in infancy in autosomal dominant neurohypophyseal diabetesinsipidus is in sharp contrast with NDI secondary to mutationsin AVPR2 or in AQP2, in which the polyuro-polydipsic symptomsare present during the first week of life.
Of interest, errors in protein folding represent the underlyingbasis for many inherited diseases (33–35) and are alsopathogenic mechanisms for AVP, AVPR2, and AQP2 mutants. WhyAVP misfolded mutants are cytotoxic to AVP-producing neuronsis an unresolved issue. Protein misfolding, an "unfolded proteinresponse" in cells, and the accumulation of excess misfoldedprotein leading to apoptotic cell death are well documentedfor autosomal dominant retinitis pigmentosa (36).
Three families with autosomal recessive neurohypophyseal diabetesinsipidus in which the patients were homozygous or compoundheterozygotes for AVP mutations have been identified (27,37).Two of these families are characterized phenotypically by severeand early onset in the first 3 mo of life with polyuria, polydipsia,and dehydration. As a consequence, early hereditary diabetesinsipidus can be neurogenic or nephrogenic.
X-Linked NDI (OMIM 304800) as a Result of Mutations in AVPR2
X-linked NDI is generally a rare disease in which the affectedmale patients do not concentrate their urine after administrationof AVP (38). Because this form is a rare, recessive X-linkeddisease, female individuals are unlikely to be affected, butheterozygous female individuals can exhibit variable degreesof polyuria and polydipsia because of skewed X chromosome inactivation.In Quebec, the incidence of this disease among male individualswas estimated to be approximately 8.8 in 1,000,000 male livebirths (39). A founder effect of two particular AVPR2 mutations(40), one in Ulster Scot immigrants (the "Hopewell" mutation,W71X) and one in a large Utah kindred (the "Cannon" pedigree),results in an elevated prevalence of X-linked NDI in their descendantsin certain communities in Nova Scotia, Canada, and in Utah (40).These founder mutations now have spread all over the North Americancontinent. To date, we have identified the W71X mutation in42 affected male individuals who reside predominantly in theMaritime Provinces of Nova Scotia and New Brunswick and theL312X mutation in eight affected male individuals who residein the central United States. We know of 98 living affectedmale individuals of the Hopewell kindred and 18 living affectedmale individuals of the Cannon pedigree. To date, 183 putativedisease-causing AVPR2 mutations have been published in 287 NDIfamilies (Figure 1).
We propose that all families with hereditary diabetes insipidusshould have their molecular defect identified. The molecularidentification underlying X-linked NDI is of immediate clinicalsignificance because early diagnosis and treatment of affectedinfants can avert the physical and mental retardation that resultsfrom repeated episodes of dehydration. Affected premature maleinfants may experience less severe polyuric symptoms and mayneed only increased hydration during their first week withouta need for hydrochlorothiazide treatment. Water should be offeredevery 2 h day and night, and temperature, appetite, and growthshould be monitored. Admission to hospital may be necessaryfor continuous gastric feeding. The voluminous amounts of waterkept in patients’ stomachs will exacerbate physiologicgastrointestinal reflux in infants and toddlers, and many affectedboys frequently vomit. These young patients often improve withthe absorption of an H2 blocker and with metoclopramide (whichcould induce extrapyramidal symptoms) or with domperidone, whichseems to be better tolerated and efficacious. All polyuric states(whether neurogenic, nephrogenic, or psychogenic) can inducelarge dilations of the urinary tract and bladder (41–43),and bladder function impairment has been well documented inpatients who bear AVPR2 or AQP2 mutations (44,45). Chronic renalfailure secondary to bilateral hydronephrosis has been observedas a long-term complication in these patients. Renal and abdominalultrasound should be done annually, and simple recommendations,including frequent urination and "double voiding," could beimportant to prevent these consequences.
Classification of the defects of naturally occurring mutanthuman V2 receptors can be based on a similar scheme to thatused for the LDL receptor (46). Mutations have been groupedaccording to the function and subcellular localization of themutant protein whose cDNA has been transiently transfected ina heterologous expression system. Using this classification,type 1 mutant V2 receptors reach the cell surface but displayimpaired ligand binding and are consequently unable to inducenormal cAMP production. The presence of mutant V2 receptorson the surface of transfected cells can be determined pharmacologically.By carrying out saturation binding experiments using tritiatedAVP, the number of cell surface mutant V2 receptors and theirapparent binding affinity can be compared with that of the wild-typereceptor. In addition, the presence of cell surface receptorscan be assessed directly by using immunodetection strategiesto visualize epitope-tagged receptors in whole-cell immunofluorescenceassays.
Type 2 mutant receptors have defective intracellular transport.This phenotype is confirmed by carrying out, in parallel, immunofluorescenceexperiments on cells that are intact (to demonstrate the absenceof cell surface receptors) or permeabilized (to confirm thepresence of intracellular receptor pools). In addition, proteinexpression is confirmed by Western blot analysis of membranepreparations from transfected cells. It is likely that thesemutant type 2 receptors accumulate in a pre-Golgi compartment,because they are initially glycosylated but fail to undergoglycosyl-trimming maturation.
Type 3 mutant receptors are ineffectively transcribed and leadto unstable mRNA, which are rapidly degraded. This subgroupseems to be rare, because Northern blot analysis of cells expressingmost mutant V2 receptors showed mRNA of normal quantity andmolecular size.
Most of the AVPR2 mutants that we and other investigators havetested are type 2 mutant receptors. They did not reach the cellmembrane and were trapped in the interior of the cell (47–50).Other mutant G protein–coupled receptors (51) and geneproducts that cause genetic disorders are also characterizedby protein misfolding. Mutations that affect the folding ofsecretory proteins; integral plasma membrane proteins; or enzymesdestined to the endoplasmic reticulum, Golgi complex, and lysosomesresult in loss-of-function phenotypes irrespective of theirdirect impact on protein function because these mutant proteinsare prevented from reaching their final destination (52). Foldingin the endoplasmic reticulum is the limiting step: Mutant proteinsthat fail to fold correctly are retained initially in the endoplasmicreticulum and subsequently often degraded (Figure 3). Key proteinsinvolved in the urine countercurrent mechanisms are good examplesof this basic mechanism of misfolding. AQP2 mutations that areresponsible for autosomal recessive NDI are characterized bymisrouting of the misfolded mutant proteins and are trappedin the endoplasmic reticulum (53). Mutants that encode otherrenal membrane proteins that are responsible for Gitelman syndrome(54), Bartter syndrome (55,56), and cystinuria (57) are alsoretained in the endoplasmic reticulum.
The AVPR2 missense mutations are likely to impair folding andto lead to rapid degradation of the misfolded polypeptide andnot to the accumulation of toxic aggregates (as is the casefor AVP mutants), because the other important functions of theprincipal cells of the collecting duct (where AVPR2 is expressed)are entirely normal. These cells express the epithelial sodiumchannel (ENaC). Decreased function of this channel results ina sodium-losing state (58). This has not been observed in patientswith AVPR2 mutations. By contrast, another type of conformationaldisease is characterized by the toxic retention of the misfoldedprotein. The relatively common Z mutation in 1-antitrypsin deficiencynot only causes retention of the mutant protein in the endoplasmicreticulum but also affects the secondary structure by insertionof the reactive center loop of one molecule into a destabilized sheet of a second molecule (59). These polymers clog up theendoplasmic reticulum of hepatocytes and lead to cell deathand juvenile hepatitis, cirrhosis, and hepatocarcinomas in thesepatients (60).
If the misfolded protein/traffic problem that is responsiblefor so many human genetic diseases can be overcome and the mutantprotein transported out of the endoplasmic reticulum to itsfinal destination, then these mutant proteins could be sufficientlyfunctional (34). Therefore, using pharmacologic chaperones orpharmacoperones to promote escape from the endoplasmic reticulumis a possible therapeutic approach (35,52,61). We used selectivenonpeptide V2 and V1 receptor antagonists to rescue the cell-surfaceexpression and function of naturally occurring misfolded humanV2 receptors (47). Because the beneficial effect of nonpeptideV2 antagonists could be secondary to prevention and interferencewith endocytosis, we studied the R137H mutant previously reportedto lead to constitutive endocytosis (62). We found that theantagonist did not prevent the constitutive -arresting-promotedendocytosis (48). These results indicate that as for other AVPR2mutants, the beneficial effects of the treatment result fromthe action of the pharmacologic chaperones. In clinical studies,we administered a nonpeptide vasopressin antagonist SR49059to five adult patients who have NDI and bear the del62–64,R137H, and W164S mutations. SR49059 significantly decreasedurine volume and water intake and increased urine osmolality,whereas sodium, potassium, and creatinine excretions and plasmasodium were constant throughout the study (63). This new therapeuticapproach could be applied to the treatment of several hereditarydiseases resulting from errors in protein folding and kinesis(34,35). Alternatively, bypassing the V2 receptor and stimulatingAQP2 insertion independent of AVP stimulation could be a new,interesting avenue to pursue (64,65).
Because most human gene-therapy experiments using viruses todeliver and integrate DNA into host cells are potentially dangerous(66), other treatments are being actively pursued. Schönebergand colleagues (67) used aminoglycoside antibiotics becauseof their ability to suppress premature termination codons (68).They demonstrated that geneticin, a potent aminoglycoside antibiotic,increased AVP-stimulated cAMP in cultured collecting duct cellsprepared from E242X mutant mice. The urine-concentrating abilityof heterozygous mutant mice was also improved.
Autosomal Recessive (OMIM 222000) and Dominant (OMIM 125800) NDI as a Result of Mutations in AQP2 (OMIM 107777)
On the basis of desmopressin infusion studies and phenotypiccharacteristics of both male and female individuals who areaffected with NDI, a non–X-linked form of NDI with a postreceptor(post cAMP) defect was suggested (69–71). A patient whopresented shortly after birth with typical features of NDI butexhibited normal coagulation and normal fibrinolytic and vasodilatoryresponses to desmopressin was shown to be a compound heterozygotefor two missense mutations (R187C and S217P) in the AQP2 gene(17). To date, 35 putative disease-causing AQP2 mutations havebeen identified in 40 NDI families (Figure 2). The oocytes ofthe African clawed frog (Xenopus laevis) have provided a mostuseful experimental system for studying the function of manychannel proteins. This convenient expression system was keyto the discovery of AQP1 by Agre (72) because frog oocytes havevery low permeability and survive even in freshwater ponds.Control oocytes are injected with water alone; test oocytesare injected with various quantities of synthetic transcriptsfrom AQP1 or AQP2 DNA (cRNA). When subjected to a 20-mOsm osmoticshock, control oocytes have exceedingly low water permeabilitybut test oocytes become highly permeable to water. These osmoticwater permeability assays demonstrated an absence or very lowwater transport for all of the cRNA with AQP2 mutations. Immunofluorescenceand immunoblot studies demonstrated that these recessive mutantswere retained in the endoplasmic reticulum.
AQP2 mutations in autosomal recessive NDI, which are locatedthroughout the gene, result in misfolded proteins that are retainedin the endoplasmic reticulum. In contrast, the dominant mutationsreported to date are located in the region that codes for thecarboxyl terminus of AQP2 (73–75). Dominant AQP2 mutantsform heterotetramers with wt-AQP2 and are misrouted. Investigationof P262L, the only recessive mutation in the carboxyl terminus,provided new insights into the loss of function and oligomerizationof AQP2 proteins. Functional analysis in oocytes of P262L cRNAindicated that, unlike other AQP2 mutants in recessive NDI,it is a functional water channel and that trafficking to theplasma membrane was not impaired (76). Furthermore, unlike otherAQP2 recessive mutants, P262L cRNA forms heterotetramers withwt-AQP2 and is routed to the apical membrane and thus in cellularexperimental systems has most of the features of AQP2 mutantsin dominant NDI. Carriers of the P262L mutation seem to be asymptomatic,but more precise measurements are needed to determine whetherthere is a partial NDI phenotype.
In contrast to a "pure" NDI phenotype, with loss of water butnormal conservation of sodium, potassium, chloride, and calcium,in Bartter syndrome, patients’ renal wasting starts prenatallyand polyhydramnios often leads to prematurity. Bartter syndrome(OMIM 601678, 241200, 607364, and 602522) refers to a groupof autosomal recessive disorders caused by inactivating mutationsin genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination,or BSND) that encode membrane proteins of the thick ascendinglimb of the loop of Henle (for review, see 77,78). AlthoughBartter syndrome and Bartter’s mutations are commonlyused as a diagnosis, it is likely, as explained by Jeck et al.(79), that the two patients with a mild phenotype originallydescribed by Dr. Bartter had Gitelman syndrome, a thiazide-likesalt-losing tubulopathy with a defect in the distal convolutedtubule (79). As a consequence, salt-losing tubulopathy of thefurosemide type is a more physiologically appropriate definition.
Thirty percent of the filtered sodium chloride is reabsorbedin the thick ascending limb of the loop of Henle through theapically expressed sodium-potassium-chloride co-transporterNKCC2 (encoded by the SLC12A1 gene), which uses the sodium gradientacross the membrane to transport chloride and potassium intothe cell. The potassium ions must be recycled through the apicalmembrane by the potassium channel ROMK (encoded by the KCNJ1gene). In the large experience of Seyberth and colleagues (80),who studied 85 patients with a hypokalemic salt-losing tubulopathy,all 20 patients with KCNJ1 mutations (except one) and all 12patients with SLC12A1 mutations were born as preterm infantsafter severe polyhydramnios. Of note, polyhydramnios is neverseen during the pregnancy that leads to infants bearing AVPR2or AQP2 mutations. The most common causes of increased amnioticfluid include maternal diabetes mellitus, fetal malformationsand chromosomal aberrations, twin-to-twin transfusion syndrome,rhesus incompatibility, and congenital infections (81). Postnatally,polyuria was the leading symptom in 19 of the 32 patients. Renalultrasound revealed nephrocalcinosis in 31 of these patients.These patients with complex polyuro-polydipsic disorders areoften poorly recognized and may be confused with "pure" NDI.As a consequence, congenital polyuria does not suggest automaticallyAVPR2 or AQP2 mutations, and polyhydramnios, salt wasting, hypokalemia,and nephrocalcinosis are important clinical and laboratory characteristicsthat should be assessed. In patients with Bartter syndrome (salt-losingtubulopathy/furosemide type), the dDAVP test (Figure 4) willindicate only a partial type of NDI. The algorithm proposedby Peters et al. (80) is useful because most mutations in SLC12A1and KCNJ1 are found in the carboxyl terminus or in the lastexon and, as a consequence, are amenable to rapid DNA sequencing.
Figure 4. Measurements on two sisters with Bartter syndrome compared with a patient with nephrogenic diabetes insipidus (NDI). The two sisters with polyuria, polydipsia, hypokalemia, hypocalcemia, and nephrocalcinosis are homozygous for the A177T mutation in the KCNJ1 gene (55; M.-F. Arthus, M. Lonergan, and D.G.B., unpublished data). Both sisters were born as preterm infants after severe polyhydramnios. The dDAVP infusion tests (91) were done at 9 yr (patient 1, left) and 11 yr (patient 2, middle) of age. Indomethacin treatment was discontinued 1 wk before testing; water was not restricted during the test. Plasma vasopressin was very low (<0.5 pg/ml) during the test, but plasma renin activity was elevated (20 ng/ml per h in patient 1, 10 ng/ml per h in patient 2). By contrast, patients with AVPR2 (4-yr-old patient with NDI and the AVPR2 A132D mutation [40], right) or AQP2 mutations generally have low urine osmolality unresponsive to dDAVP, normal plasma potassium, high vasopressin levels, and normal plasma renin activity.
The study of diabetes insipidus has been a fascinating journeyfor >100 yr since Magnus and Schaffer (82), as early as 1901,demonstrated that posterior pituitary extracts had oxytocic,pressor, and antidiuretic activities. This was followed by Farini(83) and von den Velden (84), who successfully used posteriorpituitary extracts to treat diabetes insipidus in 1913. du Vigneaud(85) (http://nobelprize.org/chemistry/laureates/1955/vigneaud-bio.html)received the 1955 Nobel Prize in chemistry for the first synthesisof a polypeptide hormone AVP. Sachs and Takabatake (86) proposedthe remarkable concept that AVP and neurophysin might be synthesizedon ribosomes via a common precursor protein. This was provedby Land et al. (87) in 1982. After the discovery that loss-of-functionmutations in the rhodopsin gene cause retinitis pigmentosa (OMIM180380), numerous examples of other human diseases caused byloss-of-function mutations in G protein–coupled receptorswere identified, including X-linked NDI. The small sizes ofthe genomic and coding regions of the genes involved (AVP, AVPR2,and AQP2) allows for relatively easy mutation analysis, therebyallowing for carrier, prenatal, and perinatal testing. We concludethat hereditary diabetes insipidus is a good model system thatcould bring further insights into various basic biologic processesand approaches to treatment of disease.
Acknowledgments
This research was supported by grants from the Canadian Institutesof Health Research (MOP-8126), the Kidney Foundation of Canada,and the Network of Centres of Excellence Program–the CanadianGenetic Diseases Network (to Kenneth Morgan). D.G.B. holds aCanada Research Chair in Genetics of Renal Diseases.
We thank our co-workers, Marie-Françoise Arthus, DanielleBinette, Michèle Lonergan, and Kenneth Morgan, and manycolleagues who contributed families and ideas to our work.
Footnotes
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Top
Abstract
Introduction
1-antitrypsin deficiency not only causes retention of the mutant protein in the endoplasmic reticulum but also affects the secondary structure by insertion of the reactive center loop of one molecule into a destabilized 
sheet of a second molecule (59). These polymers clog up the endoplasmic reticulum of hepatocytes and lead to cell death and juvenile hepatitis, cirrhosis, and hepatocarcinomas in these patients (60). 
q13.
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: 260
–262, 1994[Medline]
