Molecular characterization of nephrogenic diabetes insipidus

??

Molecular Characterization of Nephrogenic Diabetes Insipidus Nine V.A.M. Knoers

Nephrogenic diabetes insipidus (NDI) is characterized by insensitivity of the distal renal nephron to the antidiuretic effect of the neurohypophyseal hormone arginine vasopressin. In the last 2 years, two different genetic defects causing the NDI phenotype have been identified. The genes involved encode proteins that reside at both ends of the cellular vasopressin signaling cascade, namely the vasopressin V, receptor and the aquaporin-2 water channel. Analysis of naturally occurring mutations in the V, receptor and the aquaporin-2 water channel will facilitate the study of structure-function correlates of both proteins, which will lead to substantial progress in elucidating the cellular mechanisms involved in the antidiuretic effect of vasopressin. (Trends Endocrinol Metab 1994;5:422-428) Diabetes insipidus (DI), a condition characterized by failure of the kidney to concentrate urine can occur in two forms. In one, there is a lack of production of the neurohypophyseal hormone arginine vasopressin (AVP). This form, referred to as central DI, is responsive to treatment with exogenous AVP. In the second form endogenous AVP is present, but the principal target organ, the renal collecting duct, fails to respond to ASP. This form is resistent to treatment with AVP and has been termed nephrogenic diabetes insipidus (NDI). ND1 was appreciated as a separate clinical entity almost 50 years ago (Waring et al. 1945), and in the following five decades more than 200 cases have been published. The renal abnormality in ND1 is present from birth, and manifestations of the disorder may emerge within the first weeks of life (Knoers and Monnens 1992). Polyuria and excessive thirst are the most typical symptoms, but they may not be recognized in early infancy. Instead, the initial clinical picture is dominated by signs of

Nine V.A.M. Knoers is at the Department of Human Genetics, Nijmegen UniversityHospital, 6500 HB Nijmegen, The Netherlands.

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dehydration, such as irritability, poor feeding, poor weight gain, and fever. Unless recognized and treated early, recurrent episodes of dehydration may lead to failure to thrive, repeated bouts of cerebral dehydration with resultant mental retardation, or death. It has been known for long that ND1 is an inherited disorder and is transmitted as an X-linked recessive trait in most cases (McKusick 1990). However, some cases are not compatible with X-linked inheritance, suggesting that ND1 may in fact be heterogeneous. Recent studies have provided us with an understanding of the genetic abnormality underlying X-linked recessive ND1 (Rosenthal et al. 1992, Pan et al. 1992, v.d. Ouweland et al. 1992b). In addition, evidence for the assumption of heterogeneity in ND1 was found very recently by the identification of a second genetic cause of the disease (Deen et al. 1994). In this review, I first discuss the present knowledge of the vasopressin signaling cascade in the renal medulla and then summarize the most important data that have led to the discovery of the genes underlying both genetic forms of NDI. In addition, I give an overview of all the disease mutations that have been identified up to now. 01994, Elsevier Science Inc., 1043-2760/94/$7.00

Pathway of AW Action in the Renal Collecting Duct

The action of AVP on the collecting duct has been one of the most intensively studied processes in the kidney (Figure 1) (Ishikawa 1993). The initial step involves the binding of AVP to specific receptors located at the outer surface of the basolateral membrane of responsive principal inner medullary collecting duct cells. It is generally accepted that these vasopressin receptors are coupled to the enzyme adenylate cyclase. These receptors are classified as V, receptors to distinguish them from the so-called V, receptors that, via phospholipase C and intracellular calcium mobilization, mediate the pressor response to AVP and other actions such as glycogenolysis and platelet aggregation (Michell et a1.1974). Recent genetic studies have clarified the structure of the V, receptor: Birnbaumer et al. (1992) have sequenced the human V, receptor gene and cDNA by expression cloning. The V, receptor gene is relatively small and consists of three exons separated by two short intervening sequences (Seibold et al. 1992). The mRNA for the human V, receptor gene has been found exclusively in the kidney, specifically in the cortical and medullary collecting ducts. The cDNA encodes a receptor protein of 371 amino acids containing one unique consensus site for glycosylation, two consensus phosphorylation sites for protein kinase C, and one consensus phosphorylation site for casein kinase II. The protein has a predicted molecular weight of approximately 41,000 and shares the general structure of a G-proteincoupled receptor consisting of seven putative transmembrane domains of 20-25 hydrophobic residues, connected by extracellular and intracellular loops. The cellular events secondary to vasopressin-binding are only partly known. V, receptor occupancy results, via the intermediacy of a G,protein, in activation of adenylate cyclase and an increase in CAMPfrom ATP. CAMPactivates a protein kinase that, in turn, initiates a complex sequence of events, ultimately resulting in increased permeability of the apical membrane of the collecting duct. The final event is the insertion of intracellular vesicles, containing functional water channels, into the normally watertight apical membrane to give an increase in water permeability (Harris et al. 1991). In this

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way osmotic water movement from the lumen to the hypertonic medullary inter-

APICAL

stitium is achieved, which leads to the formation of a concentrated urine. As long as vasopressin is present, the water channels are continuously recycled to and from the apical membrane. In response to vasopressin removal, water channels are retrieved from the apical membrane by an endocytotic process and subsequently water reabsorption decreases. In 1993, Fushimi et al. reported the cloning and expression of the cDNA for an apical membrane water channel of the rat renal collecting duct cell (WCH-CD). The WCHCD gene (recently renamed aquaporin-2 gene) encodes a 271-amino-acid protein with a molecular weight of 28,928. This protein is a member of a diverse family of transport proteins, of which the major intrinsic protein (MIP) of the lens fiber cell is the prototype (Baker and Saier 1990). Aquaporin-2 (AQPZ) has 42.7% sequence identity with CHIP-28, the channel-like integral protein of 28 kD, also referred to as aquaporin-1 (AQPl) or aquaporin-CHIP. The latter is a water channel in red blood cells and the renal proximal tubule and was the first molecular water channel identified (Preston and Agre 1991, Agre et al. 1993). Hydropathy analysis of the predicted amino acid sequence indicated that aquaporin-2 is a remarkable hydrophobic protein with six putative membrane-spanning ahelical domains similar to those in aquaporin-CHIP. Aquaporin-2 is expressed exclusively in the kidney, predominantly in the medulla, and less in the cortex. Immunohistochemically, aquaporin-2 is localized in the apical region of the renal collecting duct cells. Moreover, thirsting of rats enhanced expression of the aquaporin-2 transcript. These findings all suggest that aquaporin-2 is the vasopressinregulated water channel. The intermediate steps between the generation of CAMP and the final step of AVP action at the apical membrane are not well understood. It is believed that cytoskeletal structures, the calciumcalmodulin complex, and possibly protein kinase C, prostaglandins, and natriuretic factors play important roles (Ishikawa et al. 1993).

??

X-Linked NDI: Mutations in the Vasopressin V, Receptor Gene

The defect in ND1 could be located at any

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__

CAMP

-)

vesicles with

waterchannels

PROTEIN KINASE

BASAL

Figure 1. Hypothetical model of the cellular events involved in the hydroosmotic action of vasopressin in responsive epithelial collecting duct ceils. VP, vasopressin; R, V, receptor; G, G, protein: C, catalytic subunit of the adenylate cyclase complex: PKC, protein kinase C; PG, prostaglandins; and ANP, atria1 natriuretic factors. Adapted from Verkman (1989). of the aforementioned steps from vasopressin binding to the final effect of the hormone on the luminal membrane. As for X-linked NDI, there was ample evidence that the defect should be in the vasopressin V, receptor. This evidence was based on receptor studies in patients, which used the V, specific agonist 1 -desamino-8-D-arginine vasopressin (DDAVP). In addition to mediating antidiuresis, DDAVP causes release of factor VIII coagulant activity (fVIII:C), von Willebrand factor antigen (vWF:Ag) and tissue-type plasminogen activator (t-PA) from endothelial storage sites (Cash et al. 1974) and induces a short vasodilatory response (Brommer et al. 1982). These coagulation, fibrinolytic, and vasodilatory responses to DDAVP are assumed to be mediated by extrarenal V, receptors. The extrarenal responses to DDAW appeared to be absent in patients with X-linked ND1 (Kobrinsky et al. 1985, Bichet et al. 1988, Knoers et al. I990), suggesting that there may be a general V, receptor defect in these patients. Further evidence implicating a defective V, receptor in X-linked ND1 has come from genetic linkage studies and functional expression studies. By linkage analysis, the ND1 gene was mapped to the subtelomeric region of the X chromosome long arm, at band Xq28 (Knoers et al. 1989). In experiments with somatic cell hybrid derivatives carrying different fragments of the human X

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chromosome, the expression of functional V, receptors was examined by measuring V, binding activity and induction of CAMP production in response to vasopressin. It was shown that somatic cell hybrids that carried at least the human Xq28 region express functional V, receptors (v.d. Ouweland et al. 1992a). The results of these expression studies were consistent with the hypothesis that the V, receptor gene co-localizes with the ND1 gene and strongly supported the view that both loci are one and the same. The availability of the human V, receptor cDNA sequence in 1992 (Birnbaumer et al. 1992) enabled testing of the hypothesis that certain alleles of the V, receptor gene are the underlying cause of X-linked NDI. The V, receptor gene was mapped close to the color blindness genes in region Xq28 (Lolait et al. 1992, v.d. Ouweland et al. 1992b), a location entirely compatible with the genetic map location of the ND1 gene. Subsequently, numerous groups have demonstrated the association of mutations in the V, receptor gene and X-linked NDI. To date, 46 distinct V, receptor mutations occurring in ND1 patients have been reported (Table 1 and Figure 2). Remarkably, the mutations are not clustered in one domain of the V, receptor but are found throughout the receptor. Twenty-four mutations result in substitution of single amino acids (missense mutations), of which 10 are in

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Table 1. Summary of mutations in the vasopressin V, receptor gene in X-linked NDI Amino acid change

7Lpeof

NUCbOtide

Name

mutation

change

T7S 113delCT L44F L62P 253de135 255de19

A to T at 90 Deletion of CT at 113-l 14 CtoTat201 TtoCat256 Deletion of 35 bp (253-287) Deletion of 9 bp (255-263)

274insG

Missense Frameshift Missense Missense Frameshift In-frame deletion Frameshift

w71x

Nonsense

D85N V88M

Locafio/l

Reference

EI EI TM1 TM1 TM1 TM1 and CI CI

Bichet et al. (1994) Bichet et al. (1994) Knoers et al. (1994) Knoers et al. (1994) Bichet et al. (1994) Bichet et al. (1994)

GtoAat284

Thr to Ser at 7 Frameshift 3’to codon 16; Leu to Phe at 44 Leu to Pro at 62 Frameshift 3’to codon 62 Deletion of Leu62-Ala63Arg64 Frameshift 3’to codon 70 Trp to stop at 71

CI

Missense Missense

GtoAat324 GtoAat333

Asp to Asn at 85 Val to Met at 88

TM11 TM11

R106C 402delCT Cl 12R R113W

Missense Frameshift Missense Missense

CtoTat387 Deletion of CT at 402-403 TtoCat405 CtoTat408

Arg to Cys at 106 Frameshift 3’to codon 111; CystoArgat 112 ArgtoTrpat 113

EII EII EII EII

Q119X Y124X S126F Y128S

Nonsense Nonsense Missense Missense

CtoTat426 TtoGat443 CtoTat448 AtoCat454

Gln to stop at 119 Tjr to stop at 124 Ser to Phe at 126 Tyr to Ser at 128

TM111 TM111 TM111 TM111

A132D

Missense

CtoAat466

Ala to Asp at 132

TM111

R137H R143P

Missense Missense

CtoAat481 GtoCat499

Arg to His at 137 Arg to Pro at 143

CII CII

A147V 528de17 W164S S167L

Missense Frameshift Missense Missense

CtoTat511 Deletion of 7 bp (528-534) GtoCat562 CtoTat571

AIatoVaIat 147 Frameshift 3’to codon 153 Trp to Ser at 164 Ser to Leu at 167

CII CII TMIV TMIV

R181C

Missense

CtoTat612

Arg to Cys at 181

EIII

G185C

Missense

GtoTat624

Gly to Cys at 185

EIII

R202c

Missense

CtoTat675

Ax-gto Cys at 202

EIII

T204N 684delTA Y205C

Missense Frameshift Missense

CtoAat682 Deletion of TA at 684685 AtoGat685

Thr to Asn at 204 Frameshift 3’to codon 205; Tyr to Cys at 205

EIII EIII EIII

V206D Q225X 753insC 763deIA 804insG

Missense Nonsense Frameshift Frameshift Frameshift

TtoAat688 CtoTat744 Insertion of C at 754 Deletion of A at 763 Insertion of G in region 804-809

Val to Asp at 206 Gin to stop at 225 Frameshift 3’to codon 228; Frameshift 3’to codon 23 1; Frameshift 3’to codon 247;

EIII TMV TMV CIII CIII

Holtzman et al. ( 1993b) Bichet et al. (1994) Knoers et al. (1994) Knoers et al. (1994) Bichet et al. (1994) Bichet et al. (1994) Bichet et al. (1994) Bichet et al. (1994) Holtzman et al. (1993a) Knoers et al. (1994) Bichet et al. (1994) Pan et al. (1992) Bichet et al. (1994) Bichet et al. (1994) Pan et al. (1992) Bichet et al. (1994) Rosenthal et al. (1992) Bichet et al. (1993) Bichet et al. (1993) Tsakaguchi et al. (1993) Bichet et al. (1994) Knoers et al. (1994) Bichet et al. (1994) Knoers et al. (1994) Bichet et al. (1994) Pan et al. (1992) Knoers et al. (1994) Bichet et al. (1994) Quweland v.d. et al. (1992b) Ouweland v.d. et al. (1992b) Bichet et al. (1993) Knoers et al. (1994) Bichet et al. (1994) Ouweland v.d. et al. (1992) Knoers et al. (1994) Knoers et al. (1994) Merendino et al. (1993) Pan et al. (1992) Bichet et al. (1994)

Insertion of G in 274-277

Bichet et al. (1994)

(Continued)

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Table 1 (co~~fMed). Summary of mutations in the vasopressin V, receptor gene in X-linked NDI Name

muttion

lLpe of

Nucleotide change“

Amino acid chunge

Location

R&+tMc6+

804delG

Frameshift

Deletion of G in region 804-809 Deletion of 12 bp between 810-821 Deletion of 3 bp in region 903-908 G to A at 922 G to C at 924 C to G at 928 G to A at 949 Deletion of G at 977 (978)

Frameshift 3’to codon 247;

CIII

Deletion of Arg247-Ax-g248 Arg249-Gly250 Deletion of Val 278 (279)

CIII

Rosenthal et al. (1992) Bichet et al. (1994) Pan et al. (1992)

Trp to stop at 284 Ala to Pro 285 Pro to At-g286 Trp to stop at 293 Frameshift 3’to codon 303

TMVI TMVI TMVI TMVI EIV

Leu to stop at 312

TMVII CIV

810de112

In-frame deletion 278(279) delV In-frame deletion W284X Nonsense A285P Missense P286R Missense w293x Nonsense 977 (978) Frameshift delG L312X Nonsense R337X Nonsense

TtoAat 1006 C to T at 1080

Arg to Stop at 337

TMVI

Tsukaguchi et al. (1993) Bichet et al. (1994) Bichet et al. (1994) Pan et al. (1992) Bichet et al. (1994) Knoers et al. (1994) Bichet et al. (1993) Knoers et al. (1994) Bichet et al. (1994)

0 The nucleotides are numbered according to the sequence numbering of Gen Bank entry Z11687; this corresponds to the nucleotide plus 71 base pairs presented in Figure 1 of Bimbaumer et al. (1992).

the extracellular portion of the receptor, 11 in transmembrane segments, and three in the second intracellular loop of the receptor. To prove that these missense mutations can indeed result in loss of receptor function, Rosenthal et al. ( 1993) introduced one of these naturally occurring mutations, R137H, into wildtype cDNA. Examination of the functional properties of this mutant receptor indicated that it has normal binding properties but is unable to stimulate the G,-adenylate cyclase system, reflecting a reduced ability of the mutant receptor to couple G,. Recently, similar results of functional analysis of three other missense mutations were reported by Pan et al. (1993). Of the remaining 22 mutations, eight are substitutions of an amino acid to a termination codon (nonsense mutations), causing premature termination of translation; eight are deletions of nucleotides that result in a frameshift and premature termination of translation; and three are base-pair insertions with the same consequences. It is very likely that mRNAs with these mutations encode inactive protein products. Finally, three mutations are in-frame deletions. By functional analysis of the 12 bp in-frame deletion in the third cytoplasmatic loop, it was shown that the deletion mutant yields a normal adenylate cyclase activity (Pan et al. 1993) and, therefore, does not seem to cause the ND1 phenotype. Considering the fact that this deletion occurs in a short region

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of striking sequence divergence between human (Birnbaumer et al. 1992) and rat (Lolait et al. 1992) vasopressin Vz receptors, the finding that this deletion has no effect on the function of the receptor is not surprising. As for the other two in-frame deletions, expression studies are now underway to examine whether these affect receptor function. As yet, only one sequence variant not causing the ND1 phenotype has been identified (Bichet et al. 1994). This variant was determined to be a polymorphism, because it was found not only on ND1 chromosomes, but also on non-ND1 chromosomes. The finding of so many diverse mutations in the V, receptor gene in patients with X-linked ND1 demonstrates that this disease is heterogeneous at the molecular level, as expected for a typical X-linked disorder with reduced reproductive fitness in affected males. As yet, no significant variation in phenotypic expression has been found in the patients studied, despite the different mutations discovered.

??

Autosomal NDI: Mutations in the Aquaporin-2 Water Channel Gene

Although the X-linked type of ND1 is by far the most frequent form of the disease encountered, there is ample evidence for the existence of another genetic form of the disease. Thus, several authors have described the complete clinical picture to occur in females. In this respect, the 01994. Elsevier Science Inc., 1043-2760i94/$7.00

most intriguing case was reported by Langley et al. ( 199 1), who described two sisters with NDI, born to healthy consanguineous Pakistani parents. DNA analysis with one of the DNA markers known to be very closely linked to the ND1 locus on the X chromosome showed that each girl inherited different Xq28 regions, ruling out a diagnosis of classical Xlinked NDI. On the basis of parental consanguinity along with the observation that both parents concentrated urine well and the results of DNA analysis, it was suggested that ND1 in these girls must be the result of inheritance of an autosomal recessive mutation. Another indication for a variant type of ND1 came from the study of a Dutch male ND1 patient (Knoers and Monnens 1991), who could be differentiated from the patients with X-linked ND1 on the basis of a DDAVP infusion test. In contrast to the blunted coagulation, fibrinolysis, and vasodilatory responses seen in most patients, this Dutch patient showed completely normal extrarenal responses to DDAVP, indicating that the unresponsiveness to vasopressin in this patient is restricted to the kidney. Interestingly, linkage between the ND1 gene and Xq28 markers was excluded in the family of this patient, and sequencing of the V, receptor gene did not result in the identification of a potentially harmful mutation. Therefore, a mutation in another protein in the renal vasopressin signaling cascade was considered. Deen 425

Extracellular

Intracellular

tion in exon 3 resulted in a substitution of Cys for Arg (R187C) in one of the two most strongly conserved regions of the MIP family (Reizer et al. 1993). The point mutation in exon 4 caused a substitution of Pro for Ser (S2 16P) in the sixth transmembrane domain of the water channel protein. In the other members of the MIP family either serine or short-chain aliphatic ammo acids are found at this position. The introduction of a proline residue might distort the a-helical structure in this part of the region. Van membrane-spanning Lieburg et al. (1994) subsequently identified homozygous mutations in the aquapork-2 gene in three additional ND1

patients, all born from consanguineous parents (Figure 3). One patient carried a single C deletion at position 369 (369delC) in exon 2, which shifted the reading frame and resulted in the generation of a sequence of eight missense amino acids followed by premature termination of translation. In the second patient, a G to A transition at position 190 in exon 1 was found that caused a substitution of Arg for Gly at codon 64 (G64R). The third patient was homozygous for the R187C mutation. To investigate whether the mutations found in aquaporin-2 resulted in nonfunctional water channels, Xenopus oocytes were injected with both cRNA encoding the wild-type aquaporin2 as well as the mutant cRNAs (Deen et al. 1994, van Lieburg et al. 1994). The water permeability (P& of oocytes injected with the mutant cRNAs did not differ from that of water-injected controls, whereas the Pf of oocytes injected with the wild-type cRNA was more than

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Figure 2. Model of the vasopressin V, receptor and location of the various mutations implicated in causing X-linked NDI. The predicted domain structure with seven membranespanning regions, four extracellular domains, and four intracelluar domains was taken from Sharif and Hanley (1992). Solid symbols, nonsense mutations; solid symbols with mutated amino acid in italics, missense mutation: bars, frame-shift mutations; and open squares, in-frame deletions. * Deletion of Val at 278 or 279.

et al. (1994) tested the hypothesis that in this patient with an intact V, receptor ND1 is caused by a mutation in the water channel gene. They isolated the human structural and genomic DNAs from aquaporin-2 by screening kidney cDNA and cosmid libraries with the rat aquaporin-2 cDNA as a probe. The human aquaporin-2 gene was assigned to chromosome 12. Sequencing of the aquaporin-2 gene in the Dutch variant ND1 patient revealed a C to T transition at position 559 in exon 3 and a T to C conversion at position 646 in exon 4. Thus, the patient appeared to be a compound heterozygote for two mutations in the aquaporin-2 gene. The mutaaquaporin-2

426

Extracellular

Intracellular lo-fold higher. Co-injection of mutant cRNAs with the wild-type cRNA resulted in a P, similar to that of wild-type aquaporin-2 alone. This indicates that simultaneous expression of nonfunctional aquaporin-2 has no functional consequences for the wild-type aquaporin-2, which is consistent with the autosomal recessive inheritance of the disease observed in all four families described. The finding of mutations in the aquaporin-2 gene in patients with ND1 is the definite evidence that aquaporin-2 is the vasopressin-regulated water channel in the kidney essential for concentration of urine in response to vasopressin.

Figure 3. Proposed topology of the aquaporin-2 protein. The Positions of the single nucleotide deletion and amino acid substitutions found in the patients with autosomal ND1 are indicated by arrows. The amino acid residues that are conserved within the MIP family are indicated by solid symbols.

valuable for dissecting the relationship between structure and function of both proteins. Whether a third catagory of ND1 patients, who do not have mutations in either the V, receptor gene or in the aquaporin-2 gene, exists remains to be seen. The identification of such patients should help to identify other proteins essential in the cellular pathway of vasopressin-induced antidiuresis.

Acknowledgements

0 Conclusions

??

Two different genetic defects causing the ND1 phenotype have been identified so far. The genes involved encode proteins that are located at both ends of the cellular vasopressin-signaling cascade. Analysis of naturally occuring mutations in the vasopressin V, receptor and the aquaporin-2 water channel should be

This review is written on behalf of our ND1 research group: A. van Lieburg, M. Verdijk, B.A. van Oost, N. Knoers, P. Deen, C. van OS, and L.A.H. Monnens. Research in our laboratories has been financially supported by the Dutch Ridney Foundationgrants C89.864, C92.1262, and C93.1299.

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