Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response
Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin responseMarie C. Canfield1,+, B. K. Tamarappoo2,+, Arnold M. Moses1, A. S. Verkman2 and Eli J. Holtzman3,*
1Endocrine and 3Renal Divisions, Department of Medicine and 3Department of Biochemistry and Molecular Biology , SUNY-Health Science Center, Syracuse, NY 13210, USA and the 2Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, CA, USA
Received May 23, 1997;Revised and Accepted July 9, 1997
Congenital nephrogenic diabetes insipidus (NDI) is a rare disease caused most often by mutations in the vasopressin V2 receptor (AVPR2). We studied a family which included a female patient with NDI with symptoms dating from infancy. The patient responded to large doses of desmopressin (dDAVP) which decreased urine volume from 10 to 4 l/day. Neither the parents nor the three sisters were polyuric. The patient was found to be a compound heterozygote for two novel recessive point mutations in the aquaporin-2 (AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near to the NPA motif conserved in all aquaporins. Osmotic water permeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2 was not increased over water control, while expression of L22V cRNA increased the Pf to ~60% of that for wild-type AQP2. Co-injection of the mutant cRNAs with the wild-type cRNA did not affect the function of the wild-type AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. Water permeability assays showed a high Pf in cells expressing wild-type and L22V AQP2. This study indicates that AQP2 mutations can confer partially responsive NDI.
Congenital nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder in which the renal collecting duct is unresponsive to vasopressin. It was first described 105 years ago by McIlraith (1 ). Patients with NDI excrete large volumes of urine that is consistently hypotonic to plasma, even when the plasma osmolarity and plasma arginine vasopressin (AVP) concentrations are increased substantially. If unrecognized, NDI can provoke repeated episodes of severe hypertonic dehydration, resulting in growth and mental retardation and early death (2 ). NDI is caused by impaired AVP-induced signal transduction in the principal cell of the collecting duct. The water permeability of AVP-responsive cells is normally increased by >20-fold after vasopressin stimulation. AVP binds to V2 receptors on the basolateral surface of principal cells, stimulates adenylyl cyclase and results in the insertion of intracellular vesicles containing water channels in the cell apical plasma membrane (3 -5 ).
The molecular basis of two genetically distinct types of NDI has been defined. The more frequent X-linked form is caused by mutations in the V2-vasopressin receptor (AVPR2). Over 70 different mutations have been described (6 -13 ). The less frequent form is caused by mutations in the collecting duct AVP-regulated water channel, aquaporin-2 (AQP2) (14 ,15 ).
The high water permeability of plasma membranes of several cell types is due to channel-forming proteins that act as hydrophilic pores in the lipid bilayer (16 ). The integral membrane protein CHIP28 (AQP1) is widely expressed and is responsible for high constitutive water permeability in kidney, proximal tubules and in the thin descending limb (17 -20 ). AQP2 is localized to the apical membrane and intracellular vesicles of the collecting duct principal cells (21 ,22 ), and AQPs 3 and 4 are localized to the basolateral plasma membrane of the same cells (23 ).
We report here the molecular basis of NDI in a female patient with autosomal recessive disease characterized by partial response to desmopressin (dDAVP). The AQP2 mutations were identified, characterized functionally in oocytes and expressed in a mammalian cell line. This is the first report describing molecular mechanisms responsible for partially responsive NDI.A
Figure 1 shows two generations of a family with congenital NDI. The affected individual is a 33-year-old female with a history of polyuria and polydipsia from infancy. Relevant clinical data derived from evaluations in 1983 and 1996 are shown in Table 1 . A diagnosis of NDI with partial response to dDAVP was established. As neither parents nor sisters showed any symptoms, an autosomal recessive mode of inheritance involving a post-V2 receptor defect was considered.
Screening of the entire coding region including the exon-intron junctions of the AVPR2 did not reveal any mutations as compared with the published gene sequence (24 ). We found two mutations in the two alleles of the AQP2 gene in the affected patient. PCR sequencing of both strands of the four exons revealed that the patient is a compound heterozygote for two recessive mutations. One point mutation was found in exon 1 (L22V) and another in exon 3 (C181W) (Fig. 1 B). By using long PCR and amplifying most of the AQP2 gene followed by subcloning and sequencing of the amplified fragment, we found that the above mutations are localized to different alleles. In addition, C181W was inherited from the father while L22V was inherited from the mother (Fig. 1 A). One sister of the affected patient carries the C181W mutation and a wild-type allele but is phenotypically normal. Another sister has two wild-type alleles (Fig. 1 A). The fourth sister was not studied. The L22V or C181W genotypes have not been found in 100 normal unrelated alleles studied in the general population (D. Bichet, unpublished observation).
The position of the L22V mutation near the bottom of the first transmembrane segment (Fig. 2 ) may be critical for its function. The Cys181 mutated in the patient is the cysteine which conveys mercurial sensitivity to the molecule (25 ) and is very close to one of the NPA motifs that was found to be conserved in all aquaporins (Fig. 2 , shaded circles).
To determine whether the L22V and the C181W mutations encode functional water channels, the osmotic water permeability (Pf) was measured in oocytes injected with transcribed cRNAs. Xenopus oocytes injected with the mutated cRNAs showed different swelling curves in response to an osmotic gradient (Fig. 3 A). Water permeability was high in oocytes expressing L22V-AQP2, but less than that of wild-type AQP2. Oocytes injected with cRNA encoding C181W-AQP2 had low water permeability similar to that in control water-injected oocytes. Averaged data are shown in Figure 3 B. Co-injection of C181W-AQP2 cRNA did not affect the water permeability conferred by the wild-type cRNA. Co-injection of wild-type and L22V-AQP2 cRNA gave an intermediate water permeability, consistent with an additive effect of independently functioning water channels. Co-injection of the two mutant cRNAs also gave an additive response without a dominant-negative effect.
The mutant and wild-type AQP2 constructs were transfected into CHO cells. For immunolocalization, a polyclonal antibody against the peptide corresponding to the C-terminal amino acids of the human AQP2 was used. Figure 4 A shows immunocytochemical staining of the CHO cells transiently transfected with WT-AQP2. Similar staining was found for stably and transiently transfected cells. This staining pattern is suggestive of plasma membrane and recycling endosome localization. In contrast, CHO cells transfected with the mutant C181W showed no plasma membrane localization but instead showed accumulation of the mutant in an intracellular compartment suggestive of the endoplasmic reticulum (ER) (Fig. 4 C). Transiently transfected cells expressing L22V-AQP2 had a mixed staining pattern, with similarity to both WT-AQP2 (plasma membrane) and to the C181W mutant (ER accumulation) (Fig. 4 B).
The patient studied here has NDI with partial response to the anti-diuretic effect of AVP and dDAVP. She has impaired ability to concentrate urine with dehydration or when dDAVP is administered by injection or by nasal spray. The patient's response to dDAVP was 25-50 times less than that usually seen with central diabetes insipidus (26 ). Since the affected patient is a female, and neither the parents nor her sisters are affected, and because no mutations were found in the AVPR2 gene, a post-receptor autosomal recessive mode of inheritance involving AQP2 was postulated.
Aquaporins are single polypeptide chains that span the membrane six times, as illustrated in Figure 2 (27 ). The C181W mutation is located just before the conserved Asp-Pro-Ala (NPA motif) in the extracellular loop. The first intracellular and the third extracellular loops contain the NPA motif that is found in all members of the membrane integral proteins family. These loops may be critical for the formation of functional water-selective pores (27 ). Low concentrations of mercury compounds inhibit the Pf in most of the water channels (28 ,29 ). The Cys181 mutated in the AQP2 of our patient and the Cys189 in AQP1 are the sites of inhibition of water permeation by mercury compounds (25 ,30 ). Bai et al (25 ) have found that the C181A mutation results in a functional water channel that is mercurial insensitive and that C181W gives a non-functional water channel.
The pedigree of the family with NDI is presented in Figure 1 A. The affected individual previously was evaluated clinically (26 ) and was restudied for this report. Methods for the clinical studies and assays were as described (26 ). The study protocol was approved by the Institutional Review Board of SUNY-Health Science Center at Syracuse, and informed consent was obtained from all study subjects.
Genomic DNA was isolated from blood samples obtained from the five members of the family using the Nucleon II kit (Scotslab, CT). Screening for mutations was carried out by direct sequencing of PCR products amplified from genomic DNA. Four sets of oligonucleotide primers complementary to the 5' and 3' untranslated and intronic sequences flanking each of the four exons of AQP2 were used to amplify the entire coding sequence including exon-intron splice sites (15 ,22 ). For the AVPR2 mutation analysis, one pair of oligonucleotide primers complementary to the 5' and 3' untranslated sequences were used to amplify the entire coding sequence and the two internal introns of AVPR2 (24 ). PCR conditions were as described (12 ). Aliquots of 20 [mu]l of each PCR reaction mixture were subjected to electrophoresis in a 2% agarose gel. The amplified fragments were purified using the QIAquick gel extraction kit (Qiagen, CA) and were subjected to cycle sequencing reaction (Perkin-Elmer, CA) using 33P (New England Nuclear). DNA sequences that differed from those reported for human AQP2 cDNA were confirmed by sequencing of the other strands, and by subcloning of the PCR products (TA cloning kit, Invitrogen, CA) and sequencing of >10 different clones to rule out PCR mutations.
The presence of the mutations in different alleles was shown by additional PCR amplification of an ~5 kb genomic fragment spanning exons I-III, followed by subcloning of the fragment and subsequent sequencing of the mutated regions. In this experiment, we used the Expand Long Template PCR system, which contains Taq and Pwo DNA polymerases (Boeringer Manheim, IN).
WT-AQP2 was cloned from RT-PCR of human kidney mRNA using primers flanking the human 5' and 3' published sequences (15 ,22 ). cDNA sequence was confirmed by double strand sequencing. In vitro site-directed mutagenesis was performed using the Promega altered sites II double-stranded kit. The mutated constructs were checked by sequencing the appropriate regions corresponding to the fragment containing the modified codon.
cDNAs encoding wild-type and mutant AQP2 were subcloned in the pSP64 vector (Promega) which contains an upstream Xenopus globin enhancer sequence. cRNA was transcribed in vitro by SP6 RNA polymerase using 4 [mu]g of plasmid DNA at 37oC for 2 h. dGTP was included in the reaction mixture for capping. At the completion of the reaction, plasmid DNA was digested with RNase-free DNase. cRNA was extracted with phenol-chloroform, precipitated with ethanol, washed with 70% ethanol and resuspended in distilled water for oocyte injection. Stage V and VI oocytes from Xenopus laevis were isolated and defolliculated with collagenase (1 mg/ml) in Barth's buffer. Oocytes were microinjected with 2.5 or 5 ng of cRNA and incubated at 18oC for 24 hs.Osmotic water permeability (Pf in cm/s) was measured from the time course of oocyte swelling at 10oC in response to a 20-fold dilution of the extracellular Barth's buffer with distilled water. Osmotic swelling was observed by videomicroscopy (20 ).
Transfection. CHO cells were stably transfected with pCDNA3 plasmid containing the wild-type or mutant AQP2 insert using Lipofectamine (Gibco) as described previously (36 ). Clonal populations of G418-resistant colonies were isolated and analyzed.Immunolocalization. Cells were fixed in 4% paraformaldehyde, permeabilized with 0.1% Triton X-100 in phosphate-buffered saline (PBS) and incubated with rabbit AQP2 antibody in PBS containing 5 mg/ml bovine serum albumin (BSA) for 1 h at 37oC followed by incubation with rhodamine-conjugated anti-rabbit secondary antibody. Cells were rinsed and coverslips were placed on glass slides. Photographs were obtained using a 60* objective (Nikon, oil immersion). Functional analysis of water permeability. Cells were superfused continuously, and the time course of cell volume was measured in response to changing solution osmolality between 300 and 150 mOsm/kg H2O. Relative cell volume was inferred from phase-contrast microscopy (37 ).
We thank Dr William J. Williams for reading the manuscript, Dr David B. Duggan for his support and Fern Warner for technical assistance. This work was supported by grants from the Endocrine Fellowship Foundation (M.C.C), Dialysis Clinic, Inc.(DCI), Central New York Children's Health Fund/Children's Miracle Network and the American Heart Association, New York State Affiliate, Inc. (E.J.H.), NSRA fellowship (B.K.T) and DK35124 (A.S.V).
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*To whom correspondence should be addressed. Tel: +1 315 464 5279; Fax: +1 315 464 5372; Email: holtzman@vax.cs.hscsyr.edu
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