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Two Novel Aquaporin-2 Mutations Responsible for Congenital Nephrogenic Diabetes Insipidus in Chinese Families

Division of Nephrology (S.-H.L., Y.-F.L.), Department of Medicine, Tri-Service General Hospital, National Defense Medical Center; Department of Medicine (D.G.B., M.-F.A., M.L.), Université de Montréal, Hôpital du Sacre-Coeur de Montréal, Montréal, Québec, Canada; and Internal Medicine II (S.S., M.K.), Tokyo Medical and Dental University, Tokyo 113-8519, Japan

Address all correspondence and requests for reprints to: Daniel G. Bichet, M.D., Research Center, Hôpital du Sacré-Coeur de Montréal 5400, Boulevard Gouin West, Montréal (Québec) H4J 1C5, Canada. E-mail (secretary): . D-Binette{at}crhsc.umontreal.ca

Abstract

Mutations in the aquaporin-2 gene (AQP2), encoding the vasopressin-regulated water channel of the renal collecting duct, are responsible for the autosomal recessive or dominant forms of congenital nephrogenic diabetes insipidus. We describe two new families with normal hypotensive and coagulation responses following the administration of desamino-8-D-arginine AVP, a clinical suggestion of normal vasopressin-2 receptors. The patients were compound heterozygotes for point mutations at nucleotide position 170 (CAG to CCG; Q57P) and at position 299 (GGA to GTA; G100V) in exon 1 of the AQP2 gene. Expression of the G57P and G100V AQP2 proteins in Xenopus oocytes showed only 1.3-fold and 1.2-fold increase, respectively, in the water permeability in contrast to 8.0-fold increase in oocytes injected with wild-type cRNA. Immunoblots of oocyte lysate revealed the intensities of the 29-kDa bands were comparable among oocytes injected with wild-type and mutant cRNAs. Immunocytochemistry showed the plasma membrane was not stained in oocytes injected with cRNA of Q57P and of G100V. These results provide evidence that the Q57P and G100V mutations in congenital nephrogenic diabetes insipidus are attributable to the misrouting of AQP2.

NEPHROGENIC DIABETES INSIPIDUS (NDI) is characterized by the inability of the kidney to concentrate urine in response to AVP (1, 2, 3). It can be either acquired or inherited. The common causes of acquired NDI are hypokalemia, hypercalcemia, lithium, and postobstructive NDI. Congenital NDI is a rare disease caused by AVP receptor or post AVP receptor defects (1, 2, 3). Patients with congenital NDI usually present in the first year of life, with clinical features of polyuria, polydipsia, vomiting, anorexia, constipation, fever, and failure to thrive. About 90% of patients with congenital NDI are males with X-linked recessive NDI and have mutations in the AVPR2 gene that codes for the vasopressin V2 receptor, which is located in chromosome region Xq28 (1, 2, 3). In less than 10% of the families studied, congenital NDI has an autosomal recessive or dominant mode of inheritance and mutations have been identified in the aquaporin-2 gene (AQP2) located in chromosome region 12q13, that codes for the vasopressin-sensitive water channel (4, 5, 6, 7, 8). Although the urinary phenotype in congenital NDI is almost always identical, hemodynamic and coagulation responses to desamino-8-D-arginine vasopressin (DDAVP) stimulation test have made it clinically possible to distinguish AVPR2- and AQP2-associated form of congenital NDI. These responses have been shown to be abnormal in patients with AVPR2 mutations, whereas they are normal in patients with AQP2 mutations (6, 9, 10, 11, 12, 13).

More than 155 AVPR2 gene mutations in congenital NDI have been identified up to present (14). However, only 19 AQP2 mutations in patients with congenital NDI have been reported with eight homozygosities and ten compound heterozygosities (see legend of Fig. 1 for identification of each individual mutation). Functional expression studies of these mutated AQP2 genes demonstrated that the major cause underlying autosomal recessive NDI is the misrouting of AQP2 mutant proteins (15, 16, 17, 18, 19), although a disrupted AQP2 water channel has been reported (20).

View larger version (43K): [in this window] [in a new window]   Figure 1. A representation of the AQP2 protein and identification of 21 putative disease causing AQP2 mutations. A monomer is represented with six transmembrane helices. The location of the PKA phosphorylation site (Pa) is indicated. The extracellular, transmembrane, and cytoplasmic domains are defined according to Deen et al. (6 ). Solid symbols indicate the location of the mutations: L22V (31 ), Q57P (this report), G64R (32 ), N68S (16 ), V71M (33 ), R85X (34 ), G100X (12 ), G100V (this report), 369delC (32 ), T125M (20 ), T126M (16 ), A147T (16 ), V168M (34 ), G175R (20 ), C181W (31 ), P185A (33 ), R187C (32 ), A190T (33 ), S216P (6 ), E258K (21 ), and P262L (33 ). GenBank accession numbers—AQP2: AF147092, exon 1; AF147093, exons 2 through 4. NPA motifs and the N-glycosylation site are also indicated.

Patients and Methods

Patients

The pedigree of two families with congenital NDI are shown in Fig. 2. Four patients with congenital NDI belonging to two apparently unrelated Chinese families were investigated. They have a history of frequent bedwetting, fever, polyuria, and polydipsia since childhood. Perinatal history was unremarkable. The diagnosis of congenital NDI was based on clinical symptoms and lack of increase in urine osmolality after desmopressin [Minrin (DDAVP); Ferring, Sweden]. The patient’s characteristics are shown in Table 1. All four patients have been treated with diuretics containing amiloride 5 mg and hydrochlorothiazide 50 mg for polyuria and nocturia. The fluid intake and urine output in these four patients ranged from 4–6 liters with diuretics.

View larger version (28K): [in this window] [in a new window]   Figure 2. A, Pedigree of family 1 with haplotype and mutation analysis of PCR amplified genomic DNA by (a) KpnI digestion: DNA of genotypically normal individuals gives one fragment (471 bp) corresponding to full exon 1 amplified with primers described in the method section; DNA of patients bearing the Q57P mutation yields two fragments (235 and 236 bp); and (b) HpaII digestion: DNA of genotypically normal individuals gives 3 fragments (15, 348, and 108 bp); DNA of patients bearing the Q57P mutation yields 4 fragments (15, 108, 127, and 221 bp); DNA of patients bearing the G100V mutation yields 2 fragments (15 and 456 bp) because mutation is abolishing a HpaII restriction site. Haplotypes consist of markers (AFM259vf9: ID GenBank, Z66878; D12S131 (35 ); AFMb007yg5: ID GenBank, Z67509) that flank the AQP2 gene. AFM259vf9 alleles (1, 2 = 313 and 315 bp, respectively). D12S131 alleles (0, 1, 2, 3, 4 = 152, 154, 156, 158, and 160 bp, respectively). AFMb007yg5 alleles (a, b, c, d, e, f, g, h, i, j, k: 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244 bp, respectively). B, Pedigree of family 2 with haplotype and mutation analysis (see A for description of alleles and PCR amplified products).

Mutation and haplotype analysis

Mutations were identified by DNA sequencing of the exons, part of the introns, about 67 bp of the 5'-untranslated region, and about 155 bp of the 3'-untranslated region of the AQP2 gene in at least one affected person in each family. Once a putative disease-causing mutation was found, DNA sequencing of a region of about 200 bp that included the mutation was done for other family members. In addition to exon 1, the remaining of the AQP2 gene was sequenced with methods previously described (21). The mutations described in this paper were obtained after sequencing exon 1 with the following primers; F1 (forward): 5'-GCGAGAGCGAGTGCCCG-3'; R1 (reverse): 5'-CCCAGGACCTGCCCCTTG-3'.

Genotyping of 3 loci (AFM259vf9, D12S131, AFMb007yg5) that flank the AQP2 gene in chromosome region 12q13 was done to follow the segregation of the nephrogenic diabetes insipidus allele in each family. AFM259vf9, D12S131, and AFMb007yg5 are dinucleotide repeats. A haplotype, which is the specific combination of alleles at closely linked loci was assigned for these three loci and for a putative benign mutation of the AQP2 gene (c.836A > C, 3' untranslated region). For our interpretation of the haplotype data, we assumed no recombination within an approximately 1.5 megabase region spanned by AFM259vf9 and AFMb007yg5. Haplotype data provided support that the pedigree was consistent with stated biologic parentage.

Site-directed mutagenesis and in vitro cRNA

Mutations of human AQP2 were made with the PCR technique using AQP2 cDNA as a template (22). A fragment between the NcoI site at nucleotide 134 and the StuI site at nucleotide 809 in pAQP2/ev1 was replaced by a PCR fragment coding the mutants. Glutamine at position 57 in the amino acid sequence of human AQP2 cDNA was altered to proline with a mutation primer, 5'-GGCACCCTGGTACCGGCTCTGGGCCAC-3'. Glycine at position 100 was altered to valine with a mutation primer, 5'-GGGGCTGTGGCCGTAGCCGCTCTGCT-3'. Mutations were confirmed by DNA sequencing. Capped RNA transcript of wild-type and mutated AQP2 were synthesized in vitro with T₃ RNA polymerase using NotI-digested AQP2 cDNA.

Measurement of osmotic water permeability of oocyte

Oocytes at stage V-VI were obtained from Xenopus laevis. Each oocyte was injected with 40 nl of water (control) or 3 ng wild-type or mutated AQP2 cRNA. Oocytes were incubated for 48 h at 20 C in Barth’s buffer. The osmotic water permeability (Pf) of the oocytes was measured at 20 C from the time course of osmotic cell swelling (16). The oocytes were transferred from 200 milliosmole Barth’s buffer to 70 milliosmole buffer, and then imaged on a charge coupled device camera connected to an area analyzer (Hamamatsu Photonics C3160, Hamamatsu, Japan). Serial images taken at 0.5-sec intervals were stored in a computer. Pf was calculated from the initial 15-sec response of cell swelling, as described.

Immunoblot analysis

Lysates of oocytes were obtained as previously described. After being heated at 70 C for 10 min, samples were separated by SDS-PAGE. Oocyte lysates from 0.2 oocytes or plasma membrane from 20 oocytes were applied in each lane. The samples were transferred to Immobilon-P filter (Millipore Corp., Marlborough, MA) using a semidry system. The filters were incubated for 1 h with an affinity-purified antibody against 15 COOH-terminal amino acids of AQP2. The membranes were further incubated for 1 h with ¹²⁵I-labeled protein A solution, followed by autoradiography.

Immunocytochemistry analysis

Oocytes were fixed in 4% paraformaldehyde for 4 h and cryoprotected overnight in PBS containing 30% sucrose. The samples were embedded in Optimal Cutting Temperature compound (Tissue Tek Products, Miles Laboratories, Inc., Elkhart, IN) and frozen in liquid nitrogen. Cryostat sections (6 µm) were incubated for 30 min in PBS containing 1% BSA. After three washes in PBS, the sections were incubated for 60 min with affinity-purified antibody against AQP2 diluted at 1:500, rinsed with PBS, and further incubated for 30 min with FITC-labeled goat antirabbit IgG (1:200, Sigma, St. Louis, MO). Oocytes were imaged with a fluorescent microscope at x400 magnification (Nikon BIOPHOT, Nihonkougaku, Tokyo, Japan).

Results

Mutational analysis

We determined that these patients with congenital NDI were compound heterozygotes for point mutations in the AQP2 gene. An adenosine to cytosine transversion at nucleotide 170 (A170C, CAG to CCG) and a guanine to thymine transversion at position 299 (G299T, GGA to GTA) were found in exon 1, resulting in a glutamine to proline mutation at codon 57 (Q57P) and a glycine to valine mutation at codon 100 (G100V), respectively. These two novel AQP2 gene mutations were confirmed by restriction analysis. The PCR fragment of exon 1 of AQP2 gene with 471 bp was digested with KpnI and HpaII endonuclease and separated on a 2% agarose gel (Fig. 2). Haplotype analysis using flanking markers in these two families revealed that the alleles bearing individual mutations were identical, a suggestion of a single origin for each mutated allele. We also sequenced the AVPR2 gene in these affected patients and found a normal sequence.

Osmotic water permeability

cRNA encoding wild-type or mutant AQP2 was injected into oocytes to test their water channel function. In oocytes injected with water or cRNA encoding AQP2, average Pf values (in cm/sec x 10^-4) were 25 ± 2 (water, n = 22), 182 ± 7 (wild-type, n = 23), 31 ± 3 (Q57P, n = 20) and 29 ± 2 (G100V, n = 20) (Fig. 3). The relative Pf value for wild-type AQP2 vs. water control was 8.0, whereas those for Q57P and G100V were 1.3 and 1.2, respectively. Coinjection of either of the mutant cRNAs with wild-type cRNA had no effect on Pf of wild-type AQP2 (Data not shown).

View larger version (14K): [in this window] [in a new window]   Figure 3. Pf of wild-type and mutated AQP2. Oocytes were injected with 40 nl water (control) or 3 ng wild-type or mutant AQP2 cRNAs with alteration of glutamine 57 and glycine 100 to proline (Q57P) and valine (G100V), respectively. Pf was calculated from time course of osmotic cell swelling of oocytes. Each bar represents mean ± SEM of 20–25 measurements.

To examine the size and amount of mutant AQP2 proteins expressed in oocytes, oocyte lysates were immunoblotted. A band of 29-kDa AQP2 protein was detected in all lanes except the lane of control oocytes injected with water (Fig. 4). The intensities of the 29-kDa bands were comparable among oocytes injected with wild-type and mutant cRNAs. An additional band of 32 kDa representing a glycosylated form of AQP2 protein was observed in the lanes loaded with oocytes expressing mutant Q57P and G100V. This additional band was absent in the lane of the wild-type.

View larger version (30K): [in this window] [in a new window]   Figure 4. Immunoblot of oocyte lysates probed with an affinity-purified antibody against human AQP2. Oocytes were injected with water (control) or 3 ng cRNA of wild-type or mutated AQP2 (Q57P and G100V). Samples of lysates from 0.2 equivalent oocytes were loaded in each lane. An additional 32-kDa band was identified in the lane of mutated AQP2.

The expression of AQP2 proteins in the oocyte plasma membrane was further determined by immunocytochemistry (Fig. 5). The plasma membrane was not stained in water-injected oocytes (Fig. 5A), in oocytes injected with cRNA of Q57P (Fig. 5C) and of G100V (Fig. 5D), but brightly stained in oocytes injected with cRNA of wild-type (Fig. 5B).

View larger version (41K): [in this window] [in a new window]   Figure 5. Immunocytochemistry of oocytes injected with cRNA encoding wild-type (B), Q57P (C), and G100V (D). Water-injected oocyte was presented as a negative control (A). Oocyte sections were incubated with affinity-purified antibody against AQP2, and immunostained with goat antirabbit IgG conjugated with FITC. Sections were viewed with a fluorescence microscope at magnification x400.

AQP2 is a 29-kDa hydrophobic glycoprotein that functions as a vasopressin-regulated water channel in principal cells of renal kidney collecting ducts (23). Vasopressin binds to specific V2 receptors on the basolateral membrane of principal cells and stimulates adenyl cyclase to produce an increase in cellular cAMP through the GTP-binding protein Gs. The cellular effects of cAMP are to activate protein kinase A and protein phosphorylation, leading to a shift in the localization of AQP2 water channels from an intracellular reservoir of vesicles to the apical membrane and facilitate transcellular water transport (22, 24). Vasopressin withdrawal is associated with endocytic retrieval of functional water channels into an apparently unique, nonacidic endosomal compartment. The apical membrane, which is almost water-tight in the absence of AVP, is rendered water permeable when AVP causes AQP2 proper trafficking.

Two major forms of hereditary NDI have been identified. One is a more common X-linked recessive form caused by mutations in the vasopressin V2 receptor gene, and the other a rare non-X-linked form caused by mutations in the AQP2 water channel gene. Only nineteen AQP2 mutations in patients with congenital NDI have been reported previously (Fig. 1). Patients are either homozygous for a mutation in the AQP2 gene (eight different mutations) or carry two different mutations (ten mutations) resulting in compound heterozygosity. We report here two NDI kindreds with compound heterozygosity for the novel missense mutations, Q57P and G100V, in the AQP2 gene.

To evaluate if these mutated AQP2 genes are functional, Xenopus oocytes have been shown to be ideal for functional expression of many plasma membrane proteins, including water channels. Functional expression studies showed that oocytes injected with either Q57V or G100V mutant cRNA had little increase in water permeability, suggesting that the missense AQP2 protein of Q57P and G100V might be the cause of the NDI in our patients. Immunoblots of oocyte lysate showed that the mutant AQP2 proteins have an additional band of 32-kDa representing a glycosylated form [an endoplasmic reticulum (ER)-retarded form] besides the comparable intensities of the 29-kDa bands with wild-type. The 32-kDa band was shown to be sensitive to endoglycosidase-H treatment and therefore represents a high mannose glycosylated, presumably ER-retarded form of AQP2 (15, 16, 17). The mutant AQP2 proteins are apparently retained in the quality control component of ER and are thus impaired in their routing to the plasma membrane (25). Immunocytochemistry showed that the plasma membrane was not stained in oocytes expressing mutant AQP2 proteins with a more pronounced labeling of the cytoplasm, which confirms the impaired transport of the mutant. These results support that both the Q57P and G100V have significant effect on plasma membrane expression by the misrouting of AQP2 transport. Reminiscent of expression studies done with mutant AVPR2 proteins (26, 27), a number of investigators demonstrated that the major cause underlying autosomal recessive NDI is the misrouting of AQP2 mutants (for review see Ref. 19 , 25). In contrast to the AQP2 mutations in autosomal recessive NDI, which are all impaired in their export from ER, the dominant mutation E258K is retained in the Golgi apparatus (25, 28).

We have used a 12q13 haplotype analysis with markers that flank the AQP2 gene to suggest that all alleles 1,n,G100V,C,2,d share a common ancestor. Likewise, the 1,Q57P,n,A,4,d haplotype is identical by state, suggesting a high likelihood for identity by descent and another common ancestor. We could not obtain blood samples from a sufficient number of persons from Taiwan to assess the frequency of these specific alleles in the general population but we never observed these haplotypes in more than one hundred ancestrally independent AQP2 alleles sequenced in our laboratory.

In summary, the identification of non-X-linked NDI patients offer the opportunity to study the structure-function relationship of naturally occurring nonfunctional or functional AQP2 proteins. A DDAVP infusion test provided a simple valuable tool for clinical diagnosis of a V2-postreceptor defect. We have identified two new AQP2 mutations G100V and Q57P in two families with congenital NDI. These novel AQP2 mutations may be involved in the defects in intracellular trafficking of AQP2 water channels. Of interest, the human diseases, cystic fibrosis, hereditary emphysema, and nephrogenic diabetes insipidus caused by AVPR2 or AQP2 mutations are predominantly the result of the retention of mutant plasma proteins at the endoplasmic reticulum and their consequent failure to function at the plasma membrane (29). The development of novel pharmacotherapeutic strategies to promote cellular protein folding and trafficking and gene therapy may be used in the treatment of selected mutations associated with NDI (27). These new treatments could potentially rescue and allow survival of the transgenic T126M knock-in mice (30), a mouse model of non-X-linked nephrogenic diabetes insipidus characterized like its human counterpart by severe dehydration.

Acknowledgments

Footnotes

D.G.B. is a Career Investigator of le Fonds de la recherche en santé du Québec, and this work received funding from the Kidney Foundation of Canada and the Canadian Institutes of Health Research (MOP-8126).

Abbreviations: AQP2, Aquaporin-2 gene; AQP2, aquaporin-2 protein; DDAVP, desamino-8-D-AVP; ER, endoplasmic reticulum; NDI, nephrogenic diabetes insipidus; Pf, osmotic water permeability.

Received July 23, 2001.

Accepted March 7, 2002.

References

1. Bichet DG, Oksche A, Rosenthal W 1997 Congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 8:1951–1958[Medline]
2. Bichet D 1998 Nephrogenic diabetes insipidus. In: Davison A, Cameron J, Grünfeld J, Kerr D, Ritz E, Winearls C, eds. Oxford textbook of clinical nephrology. 2nd ed. New York: Oxford University Press; 1095–1109
3. Knoers NV, Monnens LL 1999 Nephrogenic diabetes insipidus. Semin Nephrol 19:344–352[Medline]
4. Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S 1993 Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature 361:549–552[CrossRef][Medline]
5. Sasaki S, Fushimi K, Saito H, Saito F, Uchida S, Ishibashi K, Kuwahara M, Ikeuchi T, Inui K, Nakajima K, Watanabe TX, Marumo F 1994 Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct. J Clin Invest 93:1250–1256
6. Deen PMT, Verdijk MAJ, Knoers NVAM, Wieringa B, Monnens LAH, van Os CH, van Oost BA 1994 Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264:92–95[Abstract/Free Full Text]
7. Kuwahara M, Iwai K, Ooeda T, Igarashi T, Ogawa E, Katsushima Y, Shinbo I, Uchida S, Terada Y, Arthus MF, Lonergan M, Fujiwara TM, Bichet DG, Marumo F, Sasaki S 2001 Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus. Am J Hum Genet 69:738–748[CrossRef][Medline]
8. Marr N, Bichet DG, Lonergan M, Arthus M-F, van Os CH, Deen PMT, Misrouting of wild-type aquaporin-2 to late endosomes/lysosomes after heterotetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. Hum Mol Genet, in press
9. Bichet DG, Razi M, Lonergan M, Arthus M-F, Papukna V, Kortas C, Barjon JN 1988 Hemodynamic and coagulation responses to 1-desamino[8-D-arginine]vasopressin (dDAVP) infusion in patients with congenital nephrogenic diabetes insipidus. N Engl J Med 318:881–887[Abstract]
10. Brenner B, Seligsohn U, Hochberg Z 1988 Normal response of factor VIII and von Willebrand factor to 1-deamino-8-D-arginine vasopressin in nephrogenic diabetes insipidus. J Clin Endocrinol Metab 67:191–193[Abstract/Free Full Text]
11. Bichet DG, Razi M, Arthus M-F, Lonergan M, Tittley P, Smiley RK, Rock G, Hirsch DJ 1989 Epinephrine and dDAVP administration in patients with congenital nephrogenic diabetes insipidus. Evidence for a pre-cyclic AMP V2 receptor defective mechanism. Kidney Int 36:859–866[Medline]
12. Hochberg Z, van Lieburg A, Even L, Brenner B, Lanir N, van Oost BA, Knoers NVAM 1997 Autosomal recessive nephrogenic diabetes insipidus caused by an aquaporin-2 mutation. J Clin Endocrinol Metab 82:686–689[Abstract/Free Full Text]
13. Kaufmann JE, Oksche A, Wollheim CB, Gunther G, Rosenthal W, Vischer UM 2000 Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 106:107–116[Medline]
14. Bichet DG, Fujiwara TM 2001 Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, Vallee D, Childs B, Vogelstein B, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 4181–4204
15. Deen PMT, Croes H, van Aubel RAMH, Ginsel LA, van Os CH 1995 Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing. J Clin Invest 95:2291–2296
16. Mulders SB, Knoers NVAM, van Lieburg AF, Monnens LAH, Leumann E, Wühl E, Schober E, Rijss JPL, van Os CH, Deen PMT 1997 New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels. J Am Soc Nephrol 8:242–248[Abstract]
17. Tamarappoo BK, Verkman AS 1998 Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 101:2257–2267[Medline]
18. Tamarappoo BK, Yang B, Verkman AS 1999 Misfolding of mutant aquaporin-2 water channels in nephrogenic diabetes insipidus. J Biol Chem 274:34825–34831[Abstract/Free Full Text]
19. Levin MH, Haggie PM, Vetrivel L, Verkman AS 2001 Diffusion in the endoplasmic reticulum of an aquaporin-2 mutant causing human nephrogenic diabetes insipidus. J Biol Chem 276:21331–21336[Abstract/Free Full Text]
20. Goji K, Kuwahara M, Gu Y, Matsuo M, Marumo F, Sasaki S 1998 Novel mutations in aquaporin-2 gene in female siblings with nephrogenic diabetes insipidus: evidence of disrupted water channel function. J Clin Endocrinol Metab 83:3205–3209[Abstract/Free Full Text]
21. Mulders SM, Bichet DG, Rijss JPL, Kamsteeg E-J, Arthus M-F, Lonergan M, Fujiwara M, Morgan K, Leijendekker R, van der Sluijs P, van Os CH, Deen PMT 1998 An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the golgi complex. J Clin Invest 102:57–66[Medline]
22. Kuwahara M, Fushimi K, Terada Y, Bai L, Marumo F, Sasaki S 1995 cAMP-dependent phosphorylation stimulates water permeability of aquaporin-collecting duct water channel protein expressed in Xenopus oocytes. J Biol Chem 270:10384–10387[Abstract/Free Full Text]
23. Sasaki S, Fushimi K, Ishibashi K, Marumo F 1995 Water channels in the kidney collecting duct. Kidney Int 48:1082–1087[Medline]
24. Katsura T, Gustafson C, Ausiello D, Brown D 1997 Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells. Am J Physiol 272:F817–F822
25. Kamsteeg EJ, Mulders SM, Bichet DG, Deen PM, van Os C 2000 Consequences of aquaporin 2 tetramerization for genetics and routing. Nephrol Dial Transplant 15:26–28[Free Full Text]
26. Ala Y, Morin D, Mouillac B, Sabatier N, Vargas R, Cotte N, Déchaux M, Antignac C, Arthus M-F, Lonergan M, Turner MS, Balestre M-N, Alonso G, Hibert M, Barberis C, Hendy GN, Bichet DG, Jard S 1998 Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol 9:1861–1872[Abstract]
27. Morello JP, Salahpour A, Laperrière A, Bernier V, Arthus M-F, Lonergan M, Petäjä-Repo U, Angers S, Morin D, Bichet DG, Bouvier M 2000 Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105:887–895[Medline]
28. Kamsteeg EJ, Wormhoudt TA, Rijss JP, van Os CH, Deen PM 1999 An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. EMBO J 18:2394–2400[CrossRef][Medline]
29. Aridor M, Hannan LA 2000 Traffic jam: a compendium of human diseases that affect intracellular transport processes. Traffic 1:836–851[CrossRef][Medline]
30. Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS 2001 Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem 276:2775–2779[Abstract/Free Full Text]
31. Canfield MC, Tamarappoo BK, Moses AM, Verkman AS, Holtzman EJ 1997 Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response. Hum Mol Genet 6:1865–1871[Abstract/Free Full Text]
32. van Lieburg AF, Verdijk MAJ, Knoers NVAM, van Essen AJ, Proesmans W, Mallmann R, Monnens LAH, van Oost BA, van Os CH, Deen PMT 1994 Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. Am J Hum Genet 55:648–652[Medline]
33. Bichet D, Arthus M-F, Lonergan M, Balfe W, Skorecki K, Nivet H, Robertson G, Oksche A, Rosenthal W, Fujiwara M, Morgan K, Sasaki S 1995 Autosomal dominant and autosomal recessive nephrogenic diabetes insipidus: novel mutations in the AQP2 gene. J Am Soc Nephrol 6:717 (Abstract)
34. Vargas-Poussou R, Forestier L, Dautzenberg MD, Niaudet P, Déchaud M, Antignac C 1997 Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 8:1855–1862[Abstract]
35. Pedeutour F, Merscher S, Durieux E, Montgomery K, Krauter K, Clevy JP, Barcelo G, Kucherlapati R, Gaudray P, Turc-Carel C 1994 Mapping of the 12q12–q22 region with respect to tumor translocation breakpoints. Genomics 22:512–518[CrossRef][Medline]

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				C. Guyon, Y. Lussier, P. Bissonnette, A. Leduc-Nadeau, M. Lonergan, M.-F. Arthus, R. B. Perez, A. Tiulpakov, J.-Y. Lapointe, and D. G. Bichet Characterization of D150E and G196D aquaporin-2 mutations responsible for nephrogenic diabetes insipidus: importance of a mild phenotype Am J Physiol Renal Physiol, August 1, 2009; 297(2): F489 - F498. [Abstract] [Full Text] [PDF]

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				M. D. Sorani, Z. Zador, E. Hurowitz, D. Yan, K. M. Giacomini, and G. T. Manley Novel variants in human Aquaporin-4 reduce cellular water permeability Hum. Mol. Genet., August 1, 2008; 17(15): 2379 - 2389. [Abstract] [Full Text] [PDF]

				J. H. Robben, N. V. A. M. Knoers, and P. M. T. Deen Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol, August 1, 2006; 291(2): F257 - F270. [Abstract] [Full Text] [PDF]

				F. de Mattia, P. J.M. Savelkoul, D. G. Bichet, E.-J. Kamsteeg, I. B.M. Konings, N. Marr, M.-F. Arthus, M. Lonergan, C. H. van Os, P. van der Sluijs, et al. A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L Hum. Mol. Genet., December 15, 2004; 13(24): 3045 - 3056. [Abstract] [Full Text] [PDF]

				C. Boccalandro, F. de Mattia, D.-C. Guo, L. Xue, P. Orlander, T. M. King, P. Gupta, P. M.T. Deen, V. R Lavis, and D. M. Milewicz Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family: Evidence of Increased Frequency of the Mutation in the Town of Origin J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1223 - 1231. [Abstract] [Full Text] [PDF]

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