Review

Molecular Biology of Hereditary

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’e´tude des prote´ines membranaires, and Universite´de Montre´al, Research Center and Nephrology Service, Hoˆpital du Sacre´-Coeur de Montre´al, Montre´al, Que´bec, Canada

The identification, characterization, and mutational analysis of three different —the arginine (AVP), the arginine 2 gene (AVPR2), and the vasopressin-sensitive water channel gene ( 2 [AQP2])— provide the basis for understanding of three different hereditary forms of “pure” diabetes insipidus: Neurohypophyseal diabetes insipidus, X-linked nephrogenic diabetes insipidus (NDI), and non–X-linked NDI, respectively. It is clinically useful to distinguish two types of hereditary NDI: A “pure” type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a “pure” NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium. Patients who bear inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. These advances provide diagnostic and clinical tools for physicians who care for these patients. J Am Soc Nephrol 16: 2836–2846, 2005. doi: 10.1681/ASN.2005040371

nyone who passes large volumes of urine might be review are acquired forms of NDI; for further information, see said to be experiencing diabetes insipidus. Years ago, references 3–5. A the initial distinction made by physicians in evaluat- ing patients with polyuria was whether their urine was sweet Genes Involved in “Pure” Diabetes Insipidus (diabetes mellitus) or not (diabetes insipidus) (1). Diabetes in- AVP sipidus is a disorder characterized by the excretion of abnor- The regulation of the release of AVP from the posterior Ͼ mally large volumes ( 30 ml/kg body wt/d for adults) of pituitary is primarily dependent, under normal circumstances, Ͻ dilute urine ( 250 mmol/kg). This definition excludes osmotic on tonicity information relayed by osmoreceptor cells in the diuresis, which occurs when excess solute is being excreted, for anterior (6). AVP and its corresponding carrier, example, glucose in the polyuria of diabetes mellitus. Four neurophysin II, are synthesized as a composite precursor by the basic defects can be involved: (1) deficient secretion of the magnocellular neurons of the supraoptic and paraventricular antidiuretic arginine vasopressin (AVP), which is the nuclei of the hypothalamus (for review, see 7). The precursor is most common defect and is referred to as neurohypophyseal packaged into neurosecretory granules and transported ax- (also known to as neurogenic, central, or hypothalamic) diabe- onally in the stalk of the posterior pituitary. En route to the tes insipidus; (2) renal insensitivity to the antidiuretic effect of neurohypophysis, the precursor is processed into the active AVP, which is known as nephrogenic diabetes insipidus (NDI); hormone. Prepro-vasopressin has 164 amino acids and is en- (3) excessive water intake that can result in polyuria, which is coded by the 2.5-kb AVP gene located in region referred to as primary polydipsia; and (4) increased metabolism 20p13 (8,9). The AVP gene (coding for AVP and neurophysin II) of vasopressin during pregnancy, which is referred to as ges- and the OXT gene (coding for and neurophysin I) are tational diabetes insipidus. The hereditary forms of diabetes located in the same chromosome region, at a very short dis- Ͻ insipidus account for 10% of the cases of diabetes insipidus tance from each other (12 kb in humans) in head-to-head ori- seen in clinical practice. The purpose of this review is to exam- entation. Data from transgenic mouse studies indicate that the ine recent developments in the understanding and molecular intergenic region between the OXT and the AVP genes contains biology of the hereditary forms of diabetes insipidus. Here we the critical enhancer sites for cell-specific expression in the use the gene symbols approved by the HUGO Gene Nomencla- magnocellular neurons (7). It is phylogenetically interesting to ture Committee (http://www.gene.ucl.ac.uk/nomenclature) note that cis and trans components of this specific cellular and provide OMIM entry numbers (2). Not included in this expression have been conserved between the Fugu isotocin (the homolog of mammalian oxytocin) and rat oxytocin genes (10).

Published online ahead of print. Publication date available at www.jasn.org. Exon 1 of the AVP gene encodes the signal peptide, AVP, and the NH2-terminal region of neurophysin II. Exon 2 encodes the Address correspondence to: Dr. Daniel G. Bichet, Research Center, Hoˆpital du Sacre´-Coeur de Montre´al, 5400 Boulevard Gouin Ouest, Montre´al, Que´bec, H4J 1C5 central region of neurophysin II, and exon 3 encodes the Canada. Phone: 514-338-2486; Fax: 514-338-2694; E-mail: [email protected] COOH-terminal region of neurophysin II and the glycopeptide.

Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1610-2836 J Am Soc Nephrol 16: 2836–2846, 2005 Diabetes Insipidus 2837

Pro-vasopressin is generated by the removal of the signal pep- brane-spanning domains, with both terminal ends located in- tide from prepro-vasopressin and from the addition of a car- tracellularly, and conserved asparagine-proline-alanine boxes bohydrate chain to the glycopeptide. Additional posttransla- (Figure 2). It is now well recognized that are trans- tion processing occurs within neurosecretory vesicles during membrane channels that are found in cell membranes of all life transport of the precursor to axon terminals in the forms and that efficiently transport water while excluding pro- posterior pituitary, yielding AVP, neurophysin II, and the gly- tons. Molecular dynamic simulations suggest that a global ori- copeptide. The AVP–neurophysin II complex forms tetramers entation control mechanism facilitates efficient movement of a that can self-associate to form higher oligomers (11). Neuro- single column of water molecules while preventing proton physins should be seen as chaperone-like molecules facilitating transport in the channel (20). Data from mouse models suggest intracellular transport in magnocellular cells. In the posterior that AQP3 and AQP4 may play an important role in urinary pituitary, AVP is stored in vesicles. Exocytotic release is stim- concentration at the basolateral membrane (21). New roles for ulated by minute increases in serum osmolality (hypernatre- aquaporins are being discovered, including a possible role of mia, osmotic regulation) and by more pronounced decreases in AQP1-facilitated water permeability for cell migration related extracellular fluid (hypovolemia, nonosmotic regulation). Oxy- to angiogenesis (22). tocin and neurophysin I are released from the posterior pitu- itary by the suckling response in lactating women. Inherited Neurohypophyseal Diabetes AVPR2 and AQP2 Insipidus (OMIM 125700) as a Result of The transfer of water across the principal cells of the collect- Mutations in AVP (OMIM 192340) ing ducts is now known at such a detailed level that billions of The classic animal model for studying diabetes insipidus has molecules of water that traverse the membrane could be rep- been the Brattleboro rat with autosomal recessive neurohy- resented and are useful teaching tools (http://www.mpibpc. pophyseal diabetes insipidus. Brattleboro rats are homozygous gwdg.de/abteilungen/073/gallery.html; http://www.ks.uiuc. for a 1-bp deletion of a guanine nucleotide (di/di) in the second edu/research/aquaporins). The 2003 Nobel Prize in chemistry exon that results in a shift in the reading frame of the coding was awarded to Peter Agre and Roderick MacKinnon, who sequence for the carrier neurophysin II (23). The polyuric solved two complementary problems presented by the cell symptoms are also observed in heterozygous di/n rats. Ho- membrane: How does a cell let one type of ion through the lipid mozygous Brattleboro rats may still demonstrate some V membrane to the exclusion of other ions? How does it permeate 2 antidiuretic effects, because the administration of a selective water without ions? This contributed to a momentum and nonpeptide V antagonist (SR121463A, 10 mg/kg intraperito- renewed interest in basic discoveries related to the transport of 2 neally) induced a further increase in urine flow rate (200 to water and indirectly to diabetes insipidus. The first step in the 354 Ϯ 42 ml/24 h) and a decline in urinary osmolality (170 to action of AVP on water excretion is its binding to arginine 92 Ϯ 8 mmol/kg) (24). Oxytocin, which is present at enhanced vasopressin type 2 receptors (hereafter referred to as V2 recep- plasma concentrations in Brattleboro rats, may be responsible tors) on the basolateral membrane of the collecting duct cells. for the observed antidiuretic activity (25,26). Oxytocin is not The human gene that codes for the V2 receptor (AVPR2)is located in chromosome region Xq28 and has three exons and stimulated by increased plasma osmolality in humans. The two small introns (12,13). The sequence of the cDNA predicts a Brattleboro rat model therefore is not strictly comparable with polypeptide of 371 amino acids with seven transmembrane, the rarely observed human cases of autosomal recessive neu- four extracellular, and four cytoplasmic domains (Figure 1). rohypophyseal diabetes insipidus (27). Patients with autosomal dominant neurohypophyseal diabe- The V2 receptor is one of 701 members of the family within the superfamily of guanine-nucleotide (G) protein- tes insipidus retain some limited capacity to secrete AVP dur- coupled receptors (14) (see also perspective by Perez [15]). The ing severe dehydration, and the polyuro-polydipsic symptoms usually appear after the first year of life (28), when the infant’s activation of the V2 receptor on renal collecting tubules stimu- lates via the stimulatory (Gs) and demand for water is more likely to be understood by adults. promotes the cAMP-mediated incorporation of water pores More than 50 AVP mutations segregating with autosomal dom- into the luminal surface of these cells. This process is the inant or autosomal recessive neurohypophyseal diabetes insip- molecular basis of the vasopressin-induced increase in the os- idus have been described (see http://www.medicine.mcgill. motic water permeability of the apical membrane of the collect- ca/nephros for a list of mutations). The mechanisms by which ing tubule (4). a mutant allele causes neurohypophyseal diabetes insipidus The gene that codes for the water channel of the apical could involve the induction of magnocellular cell death as a membrane of the kidney collecting tubule has been designated result of the accumulation of AVP precursors within the endo- (AQP2) and was cloned by homology to the rat plasmic reticulum (29–31). This hypothesis could account for aquaporin of the collecting duct (16–18). The human AQP2 the delayed onset of the disease. In addition to the cytotoxicity gene is located in chromosome region 12q13 and has four exons caused by mutant AVP precursors, the interaction between the and three introns (17–19). It is predicted to code for a polypep- wild-type and the mutant precursors suggests that a dominant tide of 271 amino acids that is organized into two repeats negative mechanism may also contribute to the pathogenesis of oriented at 180 degrees to each other and that has six mem- autosomal dominant diabetes insipidus (32). The absence of 2838 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 2836–2846, 2005

Figure 1. Schematic representation of the vasopressin type 2 (V2) receptor and identification of 183 putative disease-causing arginine 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. symptoms in infancy in autosomal dominant neurohypophy- compound heterozygotes for AVP mutations have been identi- seal diabetes insipidus is in sharp contrast with NDI secondary fied (27,37). Two of these families are characterized phenotyp- to mutations in AVPR2 or in AQP2, in which the polyuro- ically by severe and early onset in the first 3 mo of life with polydipsic symptoms are present during the first week of life. polyuria, polydipsia, and dehydration. As a consequence, early Of interest, errors in protein folding represent the underlying hereditary diabetes insipidus can be neurogenic or nephro- basis for many inherited diseases (33–35) and are also patho- genic. genic mechanisms for AVP, AVPR2, and AQP2 mutants. Why AVP misfolded mutants are cytotoxic to AVP-producing neu- rons is an unresolved issue. Protein misfolding, an “unfolded X-Linked NDI (OMIM 304800) as a Result of protein response” in cells, and the accumulation of excess mis- Mutations in AVPR2 folded protein leading to apoptotic cell death are well docu- X-linked NDI is generally a rare disease in which the affected mented for autosomal dominant retinitis pigmentosa (36). male patients do not concentrate their urine after administra- Three families with autosomal recessive neurohypophyseal tion of AVP (38). Because this form is a rare, recessive X-linked diabetes insipidus in which the patients were homozygous or disease, female individuals are unlikely to be affected, but J Am Soc Nephrol 16: 2836–2846, 2005 Diabetes Insipidus 2839

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 (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). heterozygous female individuals can exhibit variable degrees of We propose that all families with hereditary diabetes insip- polyuria and polydipsia because of skewed X chromosome idus should have their molecular defect identified. The molec- inactivation. In Quebec, the incidence of this disease among ular identification underlying X-linked NDI is of immediate male individuals was estimated to be approximately 8.8 in clinical significance because early diagnosis and treatment of 1,000,000 male live births (39). A founder effect of two partic- affected infants can avert the physical and mental retardation ular AVPR2 mutations (40), one in Ulster Scot immigrants (the that results from repeated episodes of dehydration. Affected “Hopewell” mutation, W71X) and one in a large Utah kindred premature male infants may experience less severe polyuric (the “Cannon” pedigree), results in an elevated prevalence of symptoms and may need only increased hydration during their X-linked NDI in their descendants in certain communities in first week without a need for hydrochlorothiazide treatment. Nova Scotia, Canada, and in Utah (40). These founder muta- Water should be offered every 2 h day and night, and temper- tions now have spread all over the North American continent. ature, appetite, and growth should be monitored. Admission to To date, we have identified the W71X mutation in 42 affected hospital may be necessary for continuous gastric feeding. The male individuals who reside predominantly in the Maritime voluminous amounts of water kept in patients’ stomachs will Provinces of Nova Scotia and New Brunswick and the L312X exacerbate physiologic gastrointestinal reflux in infants and mutation in eight affected male individuals who reside in the toddlers, and many affected boys frequently vomit. These central United States. We know of 98 living affected male young patients often improve with the absorption of an H2 individuals of the Hopewell kindred and 18 living affected blocker and with metoclopramide (which could induce extra- male individuals of the Cannon pedigree. To date, 183 putative pyramidal symptoms) or with domperidone, which seems to be disease-causing AVPR2 mutations have been published in 287 better tolerated and efficacious. All polyuric states (whether NDI families (Figure 1). neurogenic, nephrogenic, or psychogenic) can induce large di- 2840 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 2836–2846, 2005 lations of the urinary tract and bladder (41–43), and bladder autosomal recessive NDI are characterized by misrouting of the function impairment has been well documented in patients misfolded mutant proteins and are trapped in the endoplasmic who bear AVPR2 or AQP2 mutations (44,45). Chronic renal reticulum (53). Mutants that encode other renal membrane failure secondary to bilateral hydronephrosis has been ob- proteins that are responsible for Gitelman syndrome (54), Bar- served as a long-term complication in these patients. Renal and tter syndrome (55,56), and cystinuria (57) are also retained in abdominal ultrasound should be done annually, and simple the endoplasmic reticulum. recommendations, including frequent urination and “double The AVPR2 missense mutations are likely to impair folding voiding,” could be important to prevent these consequences. and to lead to rapid degradation of the misfolded polypeptide Classification of the defects of naturally occurring mutant and not to the accumulation of toxic aggregates (as is the case human V2 receptors can be based on a similar scheme to that for AVP mutants), because the other important functions of the used for the LDL receptor (46). Mutations have been grouped principal cells of the collecting duct (where AVPR2 is ex- according to the function and subcellular localization of the pressed) are entirely normal. These cells express the epithelial mutant protein whose cDNA has been transiently transfected (ENaC). Decreased function of this channel in a heterologous expression system. Using this classification, results in a sodium-losing state (58). This has not been observed type 1 mutant V2 receptors reach the cell surface but display in patients with AVPR2 mutations. By contrast, another type of impaired ligand binding and are consequently unable to induce conformational disease is characterized by the toxic retention of normal cAMP production. The presence of mutant V2 receptors the misfolded protein. The relatively common Z mutation in on the surface of transfected cells can be determined pharma- ␣1-antitrypsin deficiency not only causes retention of the mu- cologically. By carrying out saturation binding experiments tant protein in the endoplasmic reticulum but also affects the using tritiated AVP, the number of cell surface mutant V2 secondary structure by insertion of the reactive center loop of receptors and their apparent binding affinity can be compared one molecule into a destabilized ␤ sheet of a second molecule with that of the wild-type receptor. In addition, the presence of (59). These polymers clog up the endoplasmic reticulum of cell surface receptors can be assessed directly by using immu- hepatocytes and lead to cell death and juvenile hepatitis, cir- nodetection strategies to visualize epitope-tagged receptors in rhosis, and hepatocarcinomas in these patients (60). whole-cell immunofluorescence assays. If the misfolded protein/traffic problem that is responsible Type 2 mutant receptors have defective intracellular trans- for so many human genetic diseases can be overcome and the port. This phenotype is confirmed by carrying out, in parallel, mutant protein transported out of the endoplasmic reticulum to immunofluorescence experiments on cells that are intact (to its final destination, then these mutant proteins could be suffi- demonstrate the absence of cell surface receptors) or permeabil- ciently functional (34). Therefore, using pharmacologic chaper- ized (to confirm the presence of intracellular receptor pools). In ones or pharmacoperones to promote escape from the endo- addition, protein expression is confirmed by Western blot anal- plasmic reticulum is a possible therapeutic approach (35,52,61). ysis of membrane preparations from transfected cells. It is We used selective nonpeptide V2 and V1 receptor antagonists to likely that these mutant type 2 receptors accumulate in a pre- rescue the cell-surface expression and function of naturally

Golgi compartment, because they are initially glycosylated but occurring misfolded human V2 receptors (47). Because the ben- fail to undergo glycosyl-trimming maturation. eficial effect of nonpeptide V2 antagonists could be secondary Type 3 mutant receptors are ineffectively transcribed and to prevention and interference with endocytosis, we studied the lead to unstable mRNA, which are rapidly degraded. This R137H mutant previously reported to lead to constitutive en- subgroup seems to be rare, because Northern blot analysis of docytosis (62). We found that the antagonist did not prevent the ␤ cells expressing most mutant V2 receptors showed mRNA of constitutive -arresting-promoted endocytosis (48). These re- normal quantity and molecular size. sults indicate that as for other AVPR2 mutants, the beneficial Most of the AVPR2 mutants that we and other investigators effects of the treatment result from the action of the pharma- have tested are type 2 mutant receptors. They did not reach the cologic chaperones. In clinical studies, we administered a non- cell membrane and were trapped in the interior of the cell peptide vasopressin antagonist SR49059 to five adult patients (47–50). Other mutant G protein–coupled receptors (51) and who have NDI and bear the del62–64, R137H, and W164S gene products that cause genetic disorders are also character- mutations. SR49059 significantly decreased urine volume and ized by protein misfolding. Mutations that affect the folding of water intake and increased urine osmolality, whereas sodium, secretory proteins; integral plasma membrane proteins; or en- potassium, and creatinine excretions and plasma sodium were zymes destined to the endoplasmic reticulum, Golgi complex, constant throughout the study (63). This new therapeutic ap- and lysosomes result in loss-of-function phenotypes irrespec- proach could be applied to the treatment of several hereditary tive of their direct impact on protein function because these diseases resulting from errors in protein folding and kinesis mutant proteins are prevented from reaching their final desti- (34,35). Alternatively, bypassing the V2 receptor and stimulat- nation (52). Folding in the endoplasmic reticulum is the limiting ing AQP2 insertion independent of AVP stimulation could be a step: Mutant proteins that fail to fold correctly are retained new, interesting avenue to pursue (64,65). initially in the endoplasmic reticulum and subsequently often Because most human gene-therapy experiments using vi- degraded (Figure 3). Key proteins involved in the urine coun- ruses to deliver and integrate DNA into host cells are poten- tercurrent mechanisms are good examples of this basic mech- tially dangerous (66), other treatments are being actively pur- anism of misfolding. AQP2 mutations that are responsible for sued. Scho¨neberg and colleagues (67) used aminoglycoside J Am Soc Nephrol 16: 2836–2846, 2005 Diabetes Insipidus 2841

Figure 3. Synthesis and processing of secretory and other proteins, including arginine vasopressin (AVP), the V2 receptor, and AQP2. Ribosomes that synthesize the proteins attach to the cytosolic face of the endoplasmic reticulum via a signal recognition peptide (SRP) and the SRP receptor (SR). The growing peptide passes through the membrane via a translocon. Chaperones may ensure correct folding for exit through coat protein II (COPII)-coated vesicles to the Golgi apparatus. Misfolded proteins may be retained initially in the endoplasmic reticulum but eventually are translocated back across the membrane and degraded by the ubiquitin-proteasome degradation system. Modified with permission from Kaufman et al.: The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol 3: 411–421, 2002. © 2002 Macmillan Magazines Ltd. (http://www. nature.com).

antibiotics because of their ability to suppress premature ter- disease-causing AQP2 mutations have been identified in 40 mination codons (68). They demonstrated that geneticin, a po- NDI families (Figure 2). The oocytes of the African clawed frog tent aminoglycoside antibiotic, increased AVP-stimulated (Xenopus laevis) have provided a most useful experimental sys- cAMP in cultured collecting duct cells prepared from E242X tem for studying the function of many channel proteins. This mutant mice. The urine-concentrating ability of heterozygous convenient expression system was key to the discovery of mutant mice was also improved. AQP1 by Agre (72) because frog oocytes have very low perme- ability and survive even in freshwater ponds. Control oocytes Autosomal Recessive (OMIM 222000) and are injected with water alone; test oocytes are injected with Dominant (OMIM 125800) NDI as a Result various quantities of synthetic transcripts from AQP1 or AQP2 of Mutations in AQP2 (OMIM 107777) DNA (cRNA). When subjected to a 20-mOsm osmotic , On the basis of infusion studies and pheno- control oocytes have exceedingly low water permeability but typic characteristics of both male and female individuals who test oocytes become highly permeable to water. These osmotic are affected with NDI, a non–X-linked form of NDI with a water permeability assays demonstrated an absence or very postreceptor (post cAMP) defect was suggested (69–71). A low water transport for all of the cRNA with AQP2 mutations. patient who presented shortly after birth with typical features Immunofluorescence and immunoblot studies demonstrated of NDI but exhibited normal coagulation and normal fibrino- that these recessive mutants were retained in the endoplasmic lytic and vasodilatory responses to desmopressin was shown to reticulum. be a compound heterozygote for two missense mutations AQP2 mutations in autosomal recessive NDI, which are (R187C and S217P) in the AQP2 gene (17). To date, 35 putative located throughout the gene, result in misfolded proteins 2842 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 2836–2846, 2005

Figure 4. Measurements on two sisters with 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 (Ͻ0.5 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. that are retained in the endoplasmic reticulum. In contrast, AQP2 proteins. Functional analysis in oocytes of P262L the dominant mutations reported to date are located in the cRNA indicated that, unlike other AQP2 mutants in recessive region that codes for the carboxyl terminus of AQP2 (73–75). NDI, it is a functional water channel and that trafficking to Dominant AQP2 mutants form heterotetramers with wt- the plasma membrane was not impaired (76). Furthermore, AQP2 and are misrouted. Investigation of P262L, the only unlike other AQP2 recessive mutants, P262L cRNA forms recessive mutation in the carboxyl terminus, provided new heterotetramers with wt-AQP2 and is routed to the apical insights into the loss of function and oligomerization of membrane and thus in cellular experimental systems has J Am Soc Nephrol 16: 2836–2846, 2005 Diabetes Insipidus 2843 most of the features of AQP2 mutants in dominant NDI. Conclusion Carriers of the P262L mutation seem to be asymptomatic, but The study of diabetes insipidus has been a fascinating jour- more precise measurements are needed to determine ney for Ͼ100 yr since Magnus and Schaffer (82), as early as whether there is a partial NDI phenotype. 1901, demonstrated that posterior pituitary extracts had oxyto- cic, pressor, and antidiuretic activities. This was followed by Farini (83) and von den Velden (84), who successfully used Complex Polyuro-Polydipsic Syndrome posterior pituitary extracts to treat diabetes insipidus in 1913. In contrast to a “pure” NDI phenotype, with loss of water but du Vigneaud (85) (http://nobelprize.org/chemistry/laureates/ normal conservation of sodium, potassium, chloride, and cal- 1955/vigneaud-bio.html) received the 1955 Nobel Prize in cium, in Bartter syndrome, patients’ renal wasting starts pre- chemistry for the first synthesis of a polypeptide hormone AVP. natally and polyhydramnios often leads to prematurity. Bartter Sachs and Takabatake (86) proposed the remarkable concept syndrome (OMIM 601678, 241200, 607364, and 602522) refers to that AVP and neurophysin might be synthesized on ribosomes a group of autosomal recessive disorders caused by inactivat- via a common precursor protein. This was proved by Land et al. ing mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA (87) in 1982. After the discovery that loss-of-function mutations and CLCNKB in combination, or BSND) that encode membrane in the rhodopsin gene cause retinitis pigmentosa (OMIM proteins of the thick ascending limb of the loop of Henle (for 180380), numerous examples of other human diseases caused review, see 77,78). Although Bartter syndrome and Bartter’s by loss-of-function mutations in G protein–coupled receptors mutations are commonly used as a diagnosis, it is likely, as were identified, including X-linked NDI. The small sizes of the explained by Jeck et al. (79), that the two patients with a mild genomic and coding regions of the genes involved (AVP, phenotype originally described by Dr. Bartter had Gitelman AVPR2, and AQP2) allows for relatively easy mutation analy- syndrome, a thiazide-like salt-losing tubulopathy with a defect sis, thereby allowing for carrier, prenatal, and perinatal testing. in the distal convoluted tubule (79). As a consequence, salt- We conclude that hereditary diabetes insipidus is a good model losing tubulopathy of the furosemide type is a more physiolog- system that could bring further insights into various basic ically appropriate definition. biologic processes and approaches to treatment of disease. Thirty percent of the filtered sodium chloride is reabsorbed in the thick ascending limb of the loop of Henle through the Acknowledgments apically expressed sodium-potassium-chloride co-transporter This research was supported by grants from the Canadian Institutes NKCC2 (encoded by the SLC12A1 gene), which uses the so- of Health Research (MOP-8126), the Kidney Foundation of Canada, and dium gradient across the membrane to transport chloride and the Network of Centres of Excellence Program–the Canadian Genetic potassium into the cell. The potassium ions must be recycled Diseases Network (to Kenneth Morgan). D.G.B. holds a Canada Re- through the apical membrane by the ROMK search Chair in Genetics of Renal Diseases. (encoded by the KCNJ1 gene). In the large experience of Sey- We thank our co-workers, Marie-Franc¸oise Arthus, Danielle Binette, berth and colleagues (80), who studied 85 patients with a Miche`le Lonergan, and Kenneth Morgan, and many colleagues who hypokalemic salt-losing tubulopathy, all 20 patients with contributed families and ideas to our work. KCNJ1 mutations (except one) and all 12 patients with SLC12A1 mutations were born as preterm infants after severe polyhy- dramnios. Of note, polyhydramnios is never seen during the References pregnancy that leads to infants bearing AVPR2 or AQP2 mu- 1. Maffly RH: Diabetes insipidus. In: Disturbances in Body tations. 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