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Report of 33 Novel AVPR2 Mutations and Analysis of 117 Families with X-Linked Nephrogenic Diabetes Insipidus

MARIE-FRANÇOISE ARTHUS^*, MICHÈLE LONERGAN^*, M. JOYCE CRUMLEY^||, ANNA K. NAUMOVA^,§, DENIS MORIN^¶, LUIZ A. DE MARCO^#, BERNARD S. KAPLAN^**, GARY L. ROBERTSON, SEI SASAKI, KENNETH MORGAN^,,||, DANIEL G. BICHET^* and T. MARY FUJIWARA^,,||

^* Department of Medicine, Université de Montréal and Research Centre, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Department of Human Genetics, McGill University, Montreal, Canada
Department of Medicine, McGill University, Montreal, Canada
^§ Department of Obstetrics and Gynecology, McGill University, Montreal, Canada
^|| Montreal General Hospital Research Institute, Montreal, Canada
^¶ Unité 469, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique-INSERM de Pharmacologie-Endocrinologie, Montpellier, France
^# Department of Pharmacology, University Federal de Minas Gerais, Belo Horizonte, Brazil
^** Division of Nephrology, The Children's Hospital of Philadelphia and Department of Pediatrics, The University of Pennsylvania, Philadelphia, Pennsylvania
Clinical Research Center and Northwestern University Medical School, Chicago, Illinois
Second Department of Internal Medicine, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Dr. Daniel G. Bichet, Centre de Recherche, Hôpital du Sacré-Coeur de Montréal, 5400, Boulevard Gouin Ouest, Montréal (Québec) H4J 1C5 Canada. Phone: 514-338-2486; Fax: 514-338-2694; E-mail: D-Binette{at}crhsc.umontreal.ca

	Abstract

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Abstract. X-linked nephrogenic diabetes insipidus (NDI) is a rare disease caused by mutations in the arginine vasopressin receptor 2 gene (AVPR2). Thirty-three novel AVPR2 mutations were identified in 62 families that were not included in our previous studies. This study describes the diversity of mutations observed in a total of 117 families, the number of affected people at the time of diagnosis, skewed X chromosome inactivation in severely affected females, the inferred parental origin of de novo mutations, and it provides estimates of incidence. Among 117 families, there were 82 different putative disease-causing mutations. Based on haplotype analysis, it can be inferred that when the same AVPR2 mutation is identified in different families that were not known to be related, the mutations most likely arose independently. More than half of the families had only one affected male; two families presented with a severely affected female and no family history of NDI. A de novo mutation arose during oogenesis in the mother in 20% of isolated cases. The estimate of about 8.8 per million male live births of the incidence of X-linked NDI in the province of Quebec, Canada may be representative of the general population except in Nova Scotia and New Brunswick, where the incidence is more than six times higher. Documentation of the diversity of mutations will assist in revealing the full spectrum of clinical variation. Discussion of genetic and population genetic aspects of X-linked NDI may contribute to early diagnosis and treatment.

	Introduction

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X-linked nephrogenic diabetes insipidus (NDI) was identified more than 50 yr ago as a rare disease (1). It is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone arginine vasopressin (AVP) (2). Polyuria and polydipsia are present at birth, and need to be recognized early to avoid repeated episodes of dehydration that can result in mental retardation. The concentration defect is demonstrable within a few days of birth. Other early symptoms include vomiting and anorexia, failure to thrive, fever, and constipation (3).

Mutations in the gene AVPR2, which encodes the AVP receptor 2 (hereafter referred to as the V₂ receptor), cause X-linked NDI (4,5). AVPR2 is located in chromosome region Xq28, and the three exons that comprise the gene consist of 2276 nucleotides of which 1113 code for 371 amino acids (GenBank accession no. L22206) (4,6). The V₂ receptor is a member of the superfamily of G protein-linked receptors, which have seven transmembrane domains (4). The antidiuretic action of AVP occurs by increasing the water permeability in the principal cells of the renal collecting duct: AVP binds to the V₂ receptor, activates adenylyl cyclase, and promotes the incorporation of aquaporin-2 water channels into the luminal membrane, which increases the water permeability of the membrane. In vitro expression studies have shown that AVPR2 mutations can result in V₂ receptors that are impaired in their routing to the cell membrane, have reduced or no binding affinity for AVP, or are defective in signal transduction (reviewed in references (5) and (7).

Here we report 33 unpublished AVPR2 mutations. Based on analysis of 117 X-linked NDI families, we estimate the proportion of de novo mutations, infer the parental (ancestral) origin of the mutations, and estimate the incidence of X-linked NDI. A haplotype that consisted of four loci that flank the AVPR2 gene and benign mutations within the AVPR2 gene was used to follow segregation of the AVPR2 gene region in families. We could infer the parental origin of a de novo mutation in a subset of families and provide evidence that the same mutation in two or more families, which were not known to be related, arose independently; that is, these were recurrent mutations. Finally, we present results of X chromosome inactivation assays in affected females.

	Materials and Methods

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Mutation and Haplotype Analyses
Mutation analysis was done in the laboratory of Dr. Bichet on 62 families not included in our previous studies. The families were referred by 44 physicians and there were two self-referrals. Mutations were identified by DNA sequencing of the exons, introns, about 140 bp of the 5'-untranslated region, and about 220 bp of the 3'-untranslated region of the AVPR2 gene in at least one affected person in each family as described previously (8). 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. Within each family, the disease-causing mutation was not found in unaffected males for whom a DNA sample was available.

Genotyping of four loci (DXS52, DXS15, G6PD, and F8C) that flank the AVPR2 gene in chromosome region Xq28 was done to follow the segregation of the NDI allele in each family (8). DXS52 has a variable number of tandem repeats (9); DXS15 is a dinucleotide repeat (10). A polymorphic EcoRI site 21 kb downstream of the G6PD stop codon and a polymorphic HindIII site in intron 19 of F8C were analyzed by restriction enzyme analysis (11). For G6PD, when the EcoRI site is absent, the PCR fragment is 396 bp based on the sequence in GenBank accession X55448. If the site is present, EcoRI digestion results in PCR fragments of 265 and 131 bp. For F8C, HindIII digestion results in fragment sizes of 497 and 298 bp when the polymorphic HindIII site is absent, and fragment sizes of 497, 217, and 81 bp when the site is present based on the sequence in GenBank accession M88642. A haplotype, which is the specific combination of alleles at closely linked loci, was assigned for these four loci and for putative benign mutations in the AVPR2 gene. This study includes mutation and haplotype data on 117 X-linked NDI families (62 new families and 55 families from previous publications) (8,12,13,14,15,16,17,18,19,20). For our interpretation of the haplotype data, we assumed that there was no mutation of the flanking markers (DXS52 and DXS15) or recombination within the 1.7 Megabase region (The Genetic Location Database, http://cedar.genetics.soton.ac.uk/public_html/ldb.html) (21) spanned by DXS52 and F8C. Haplotype data provided support that the pedigree was consistent with stated biologic parentage.

Parental Origin of de Novo Mutations
We use the term parental origin to designate the ancestor in whose gamete we infer a de novo mutation to have occurred. Although a de novo mutation could occur in early embryonic development of an offspring, we assume that it arose during gametogenesis in the parent. The parental origin of a mutation was assigned to the mother, i.e., it was assumed to have arisen during oogenesis in the mother, if a sample of the mother's DNA was tested and found not to carry the AVPR2 mutation identified in her son. The parental origin of a mutation was assigned to the maternal grandfather, i.e., it was assumed to have arisen during spermatogenesis, if a sample of the grandfather's DNA was tested and found not to carry the AVPR2 mutation identified in his carrier daughter and grandson, and in addition the grandson inherited his grandfather's Xq28 region. Similarly, the parental origin of a mutation was assigned to the maternal grandmother if a sample of the grandmother's DNA was tested and found not to carry the AVPR2 mutation identified in her carrier daughter and grandson, and the grandson inherited his grandmother's Xq28 region. The parental origin was attributed to an ancestor of the mother if she was considered to be a carrier and no information was available on the maternal grandparents; to an ancestor of the maternal grandmother if she was considered to be a carrier; and to an ancestor of the maternal grandfather if he was reported to have NDI by history or examination. In four families, in which there was no DNA sample available for one or both maternal grandparents, the parental origin was inferred to be the grandfather based on segregation of the AVPR2 mutation and the haplotypes in the maternal grandmother or maternal aunts/uncles (Figure 1). In two families with large deletions, the maternal grandfather does not have the deletion, but we have not yet determined whether it arose during gametogenesis in the mother or the maternal grandfather.

View larger version (19K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Pedigree of X-linked nephrogenic diabetes insipidus (NDI) due to a de novo mutation (L94Q) that was inferred to have arisen during spermatogenesis in the maternal grandfather, who was considered by family history to be unaffected. The asterisks indicate the people for whom genotyping and DNA sequence analysis were done; square brackets indicate that haplotypes were inferred. The alleles for DXS52, DXS15, G6PD, and F8C are defined in Table 3. n, normal AVPR2 gene sequence.

Using allele-specific PCR (22), we determined the parental origin of a de novo frameshift mutation, 838-839insT, which was identified in a severely affected female (family O64) (19). The father carried the silent substitution L309(CTG); the mother was homozygous for L309(CTA) and the daughter was heterozygous. We used sequencing primers A998 (5'-GGCTGGCCAGCAACATGATT-3') and G998 (5'-GGCTGGCCAGCAACATGATC-3') in which the first nucleotide in the primers matches the first base in codon 316 and the last nucleotide in the primers matches the third base position in codon 309 for L309(CTA) and L309(CTG), respectively. In addition, the penultimate nucleotide (first base in codon 310) was modified (G T) to increase the specificity of the primers. Sequencing upstream with the G998 primer gave the normal sequence for the father's DNA and revealed the 838-839insT mutation for the daughter's DNA; no sequence was generated from the mother's DNA. Sequencing with the A998 primer gave the normal sequence for DNA from the mother and daughter; no sequence was generated from the father's DNA. Therefore, we concluded that the 838-839insT mutation arose during spermatogenesis in the father.

Incidence of NDI
We attempted to ascertain all of the X-linked NDI males born in the province of Quebec to obtain an estimate of incidence for the general population. One of us (Dr. Bichet) knows all the nephrologists in the province, and there is good communication among the major nephrology units. Because of the relative ease of clinical diagnosis and of the increased awareness due to publicity in the province of Quebec of our ongoing research, we think that there has been close to complete ascertainment since 1986. We think it unlikely that there would be cases that died before diagnosis, especially in the past 10 yr.

In an attempt to identify undiagnosed patients, in 1987 Dr. Bichet reviewed clinical records and examined male patients at Hôpital Louis-H. Lafontaine, one of the largest long-term facilities in the province of Quebec for people with severe mental retardation. Only one patient was clinically diagnosed with NDI, and he was a maternal first cousin once removed of an affected male in one of the families we studied.

We identified an AVPR2 mutation in 23 NDI males residing in the province of Quebec, 21 of whom were born in the province between 1924 and 1999, and four of whom were born during 1988-1997. For our estimate of incidence, we assumed that we had complete ascertainment for the 10-yr period 1988-1997. In addition, we assumed that no affected males were born in the province who moved away before diagnosis, and that there was a 1:1 ratio of males to females. During 1988-1997, there were 454,629 male live births (one-half of 909,257 live births) in the province (Statistics Canada, http://www.statcan.ca).

We also estimated the incidence of X-linked NDI in the two Canadian maritime provinces of Nova Scotia and New Brunswick, where the prevalence was known to be higher (23). We assumed that ascertainment, especially since 1988, was complete because we have done extensive field work in Nova Scotia and New Brunswick, and families are routinely referred to us for mutation analysis. The combined population size of these two provinces is less than one-quarter of the population size of the province of Quebec. We identified an AVPR2 mutation in 35 NDI patients residing in Nova Scotia or New Brunswick, 23 of whom were born in one of these provinces between 1910 and 1994, and six of whom were born during 1988-1997. During this 10-yr period, there were 104,063 male live births (one-half of 208,126 live births) (Statistics Canada). We assumed that the number of males with X-linked NDI was Poisson-distributed and therefore the sample SD was equal to the square root of the mean.

X Inactivation Assays
The degree of X chromosome inactivation skewing in females was determined using the PCR-based assay for differential methylation of HhaI sites in the first exon of the androgen receptor (AR) gene (24). The assays were done on DNA samples from the single affected female in families F18 and O64 and on one of the four females in family O42 (III-8 in Table 1) (16) for whom osmolality measurements were performed during a water deprivation test followed by deamino-8-D-AVP (dDAVP) infusion and for whom DNA was available for analysis. We quantified the degree of skewing by scanning autoradiograms on a laser densitometer (United States Biochemical SciScan 5000; Cleveland, OH) or by using a PhosphorImager (Molecular Dynamics Storm 860; Sunnyvale, CA). The density of each allele was adjusted by subtracting background density measured in the same lane. If the densities of the products of the two alleles, a and b, are [a] and [b], respectively, then the proportion of cells with the a allele active is [b]/([a] + [b]).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
AVPR2 Mutations
Mutation analysis by DNA sequencing of the AVPR2 gene in samples from 62 new NDI families revealed 33 unpublished putative disease-causing mutations that were identified in one family each (Table 1). Sixteen different AVPR2 mutations that were published previously were identified in the remaining 29 families (Table 2). The families are of diverse ethnic and geographic origins.

Two novel missense mutations, R252W and S318T, were considered to be benign because they were identified on the same NDI allele bearing a putative disease-causing mutation (Table 1). R252W was found on the same NDI allele as a frameshift mutation, 452delG, that was considered to be the disease-causing mutation. S318T was found on the same NDI allele as another missense mutation, A294P, that was found in a previously reported family, without the S318T mutation (Table 3). Functional studies showed that the A294P mutant protein was defective (19).

To date we have assembled data on a worldwide collection of 117 NDI families with 82 different putative disease-causing mutations (40 missense, 10 nonsense, 24 deletion, 7 insertion, and 1 splice-site mutation). Fifty-three percent of the families had one affected male, 21% had two affected males, and 25% had three or more affected males at the time of ascertainment. Two families were ascertained with a single affected girl. The large Hopewell kindred and other maritime extended families that have the W71X mutation were counted as one family; 13 affected males were identified at the time of ascertainment of the Hopewell kindred, and now 89 affected males from these families are known (23) (unpublished data).

De Novo AVPR2 Mutations
The parental origin of a de novo mutation was identified or inferred to have occurred on the basis of mutation and haplotype analysis in 32 of the 117 families (Table 4). Figure 1 shows an example of how haplotype information was used to infer the parental origin of the mutation even though a DNA sample from the maternal grandparents was not available. Of the 17 de novo mutations identified in a mother of an affected boy (the proband), 16 mutations occurred during spermatogenesis in the father (the maternal grandfather of the proband), and one occurred during oogenesis in the mother (the maternal grandmother of the proband). The 12 de novo mutations identified in the male patients (i.e., assumed to have occurred during oogenesis in the mother) constitute 12% of the 100 families in which carrier status of the mother was determined, whereas they comprise 20% of the 54 families with isolated cases (i.e., families with only one affected boy and no prior family history of NDI). In one additional family, the 838-839insT mutation, which was identified in a severely affected girl (referred to as 908insT in reference (19), was determined to have arisen during spermatogenesis in her father based on DNA sequencing using allele-specific PCR (see Materials and Methods).

Among the 117 families, 15 different AVPR2 mutations occurred in more than one family (Table 3). In 10 of 51 families, the parental origin of the mutation was attributed to the mother or one of the maternal grandparents. In the remaining families, the same AVPR2 mutation is carried on different haplotypes distinguished by one of the benign mutations in the AVPR2 gene or at one or both of the pairs of flanking loci. (Although the S167L mutations occur on the same haplotype in two families, we assume that the mutations arose independently, because one arose as a de novo mutation during spermatogenesis in the maternal grandfather and the other was transmitted by the maternal grandmother, who is not known to be related to the other family.) Thus, we consider that the mutation arose independently in each of these families and, therefore, they are recurrent mutations. Eight of the 15 recurrent AVPR2 mutations involve CpG dinucleotides (C T or G A transitions), which are potential mutational hot spots (25). There also may be an increased chance of recurrent mutation of the V279del mutation due to slipped mispairing during DNA replication that results in the deletion of one of two direct repeats (26). The V279del mutation has now been identified in seven families from diverse ethnic and geographic regions (Table 2).

Incidence of NDI
We estimated the incidence of X-linked NDI in the general population from patients born in the province of Quebec, Canada, during the 10-yr period 1988-1997 to be 4 in 454,629, or approximately 8.8 per million (SD = 4.4 per million) male live births. Thus, X-linked NDI is generally a rare disorder. By contrast, NDI was known to be a common disorder in Nova Scotia (27). We previously estimated a prevalence of 24/1000 males based on the identification of 30 affected males who resided mainly in two small villages with a total population size of 2500 (23). These males are descendants of members of the Hopewell pedigree studied by Bode and Crawford (27) and carry the nonsense mutation W71X (13,28). To date, we have identified the W71X mutation in 38 affected males who predominantly reside in the maritime provinces of Nova Scotia and New Brunswick. We estimated the incidence in these two maritime provinces to be 6 in 104,063, or approximately 58 per million (SD = 24 per million) male live births for the 10-yr period 1988-1997. Five of the six males born during this period carried the W71X mutation; the remaining male carried a de novo mutation that arose during spermatogenesis in the maternal grandfather.

Affected Females
An X inactivation assay was performed on DNA samples from three affected females who are heterozygous for an AVPR2 mutation. There was extreme skewing (93:7) in favor of the paternal X chromosome being active in the affected female of family O64. This is consistent with our finding based on DNA sequencing that the 838-839insT mutation, which was reported by Ala et al. (19), arose during spermatogenesis in the father. There was strong skewing (84:16) in the severely affected female in family F18, who is heterozygous for the P217T missense mutation. The parental origin of the preferentially active chromosome could not be determined because we do not have DNA samples on the parents. DNA sequencing of the AQP2 gene in both the severely affected females did not reveal any putative disease-causing mutations. Although we have no water deprivation test results for either of these two girls, we consider them to be severely affected. The mother of family O64 reported that her daughter has severe polydipsia and recounts how she has to carry a gallon of water when they travel long distances by car. The affected female in F18 had a history of repeated episodes of dehydration.

The degree of skewing was also strong (89:11) in the female (III-8) in Table 1 of Friedman et al. (16), who was heterozygous for the S315R(g.1412C G) missense mutation and for whom we had DNA. Her urine osmolality after water deprivation was 155 mosmol/kg and rose to 295 mosmol/kg in response to dDAVP administration. For comparison, the urine osmolality of two affected males was 85 and 97 mosmol/kg after water deprivation and did not significantly increase in response to dDAVP administration. The urine osmolality of an unaffected male was 785 mosmol/kg and rose to 850 mosmol/kg in response to dDAVP administration (16).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
We report 33 novel AVPR2 mutations that were identified among 62 newly studied NDI families. This adds to the documentation of the diversity of mutations in this small gene predicted to have 371 amino acids (4), and brings the total number to more than 150 putative disease-causing AVPR2 mutations (http://www.medcon.mcgill.ca/nephros). A missense mutation, S315R(g.1412C G), was identified in a large Brazilian kindred in which NDI appeared to segregate as an X-linked dominant trait (16). Reanalysis of this family indicates that segregation of NDI is consistent with X-linked recessive inheritance and that phenotypic expression in females may be attributed to skewed X chromosome inactivation.

We consider these 33 novel mutations to be disease-causing based on the predicted consequence of the mutation, that the entire gene was sequenced, and that each mutation was found in at least one affected male but not in unaffected males. Proof that a mutation is a cause of disease requires further analysis, especially for missense mutations for which functional analyses would be the best proof (29). Although we consider R252W and S318T to be benign mutations, additional information may show that they contribute to the disease phenotype. We previously, incorrectly, considered the V88M mutation as a benign sequence variant (13). Functional studies now indicate that the V88M mutation, as well as other mutations including A294P, are disease-causing because they produce V₂ receptors that are trapped intracellularly and are unable to reach the plasma membrane (19).

The ascertainment of two severely affected females with no family history of NDI raises awareness that although X-linked NDI patients are overwhelmingly males, this disease should be included in the differential diagnosis of symptomatic females. There was a delay in diagnosis in both of these cases, and intellectual impairment in one of the females can be attributed to repeated episodes of dehydration. We attribute the cause of the severe phenotype in these two females to skewed X chromosome inactivation such that the X chromosome bearing the AVPR2 mutation was preferentially active in the collecting duct cells. Although we observe strong skewing of X chromosome inactivation in DNA samples extracted from peripheral blood, definitive proof would require DNA analysis of collecting duct cells. Our results of X chromosome inactivation assays are similar to those of Nomura et al. (30), who demonstrated almost complete inactivation of the X chromosome inferred to carry the normal AVPR2 allele in a female carrier who displayed severe NDI symptoms.

X chromosome inactivation occurs early in female embryogenesis at about the 32 to 64 cell stage, and the number of progenitor cells for individual tissues is presumed to be small (31,32). Once an X chromosome has been chosen for inactivation, it is irreversible and the same X chromosome is inactivated in all descendants of that cell. The random process of X chromosome inactivation results in a normal distribution of skewing among females. The incidence of extreme skewing (90:10) in peripheral blood of 162 normal neonates was 2% (33). Based on this estimate, only about 1% of females who are heterozygous for an AVPR2 mutation would be expected to have a phenotype as severe as that of NDI males because of excessive skewing with preferential inactivation of the X chromosome bearing the normal AVPR2 allele. The other females who have extreme skewing with the X chromosome bearing the mutant AVPR2 allele preferentially inactivated would be phenotypically normal. This expectation is consistent with observations of relatively few severely affected females, and the fact that carrier sisters and mothers in NDI families usually do not have severe symptoms.

Puck and Willard (34) reviewed three mechanisms that could lead to skewed X inactivation: a chance event; a post-inactivation effect in which a mutation in a gene on one of the X chromosomes affects cell survival in a particular tissue although maternally and paternally derived X chromosomes were randomly inactivated; and a mutation in a gene controlling X inactivation. The third mechanism may be involved in the large Brazilian family reported by Friedman et al. (16), in which there were 12 females affected with NDI. Further investigation of this family is required to find support for or against a gene controlling X chromosome inactivation that is close to the AVPR2 locus, perhaps in the Xq26-27 region proposed by Schmidt et al. (35), Clarke et al. (36,37), and Naumova et al. (38).

The mean life of an X-linked recessive lethal is between two and four generations in a large, randomly mating stationary population in equilibrium, selection being balanced by mutation (39). Each family is likely to have an independent mutation that occurred at random on existing genetic backgrounds of normal X chromosomes (40). NDI is not invariably lethal (for example, there were six affected maternal grandfathers in our study), although greatly reduced viability of affected males may have been the norm in most families in past generations. However, mutation and haplotype analysis indicates that in general each family has an independent mutation. The occurrence of the same mutation on different haplotypes is considered as evidence for recurrent mutation. In addition, the most frequent recurrent mutations occurred at potential mutational hot spots (Table 3). A notable exception is the W71X mutation, which thus far is the oldest documented AVPR2 mutation, and it has segregated to 89 males over eight generations.

Our finding of an excess of parental origin attributed to the maternal grandfather compared to the maternal grandmother (16:1) is consistent with a higher mutation rate in males than females. A higher mutation rate in males than females has been shown for other X-linked genes, especially for point mutations, and is most likely due to the greater opportunity for errors in DNA replication during spermatogenesis (20 and 770 divisions for males at 13 and 30 yr of age, respectively) compared to during oogenesis (24 divisions) (41,42,43).

Identification of the parental origin of the mutation has practical consequences, e.g., for testing subsequent newborn infants of known carriers and for identifying other female members of the family who could be tested to determine whether they are at risk of having affected sons. The possibility of germ-line mosaicism needs to be considered when a de novo mutation is assumed to have occurred; however, a precise recurrence risk estimate is in practice impossible to determine (41). If the mutation occurred late in gametogenesis, then the chance of transmitting a second mutation-bearing gamete is low; however, if the mutation occurred very early in gametogenesis, the chance of transmitting a second mutation-bearing gamete approaches that of an inherited case. Thus, DNA testing should also be offered to siblings of the person in the family who has an apparent de novo mutation (43). In our study, we identified one mother who we consider to have germ-line mosaicism.

Our estimate of the incidence of X-linked NDI due to mutations in the AVPR2 gene of 8.8 per million male live births in Quebec may be representative of the general population. By contrast, due to a chance population genetic event such as founder effect, the incidence can be elevated, as is the case in the Canadian maritime provinces of Nova Scotia and New Brunswick, where we estimated the incidence to be 58 per million male live births.

A mutation in the AVPR2 gene is the cause of NDI in the great majority of congenital NDI families. In the families in which an AVPR2 or AQP2 mutation has been identified, NDI is caused by an AVPR2 mutation in about 90% of the families. There remain a few NDI families for which a mutation has not been identified. NDI in these families may be due to mutations that have not yet been identified, such as in the promoter region or in the large intron of the AQP2 gene. Based on a recent knockout mouse model, a new candidate gene to be investigated is CLCNKA, which encodes a kidney-specific chloride channel (44).

Greater awareness of how families with NDI present may lead to earlier diagnosis of X-linked NDI. Mutation analysis has revealed the diversity of AVPR2 mutations that can cause NDI and a wider spectrum of clinical variation. Functional studies have provided a molecular explanation for a mild clinical phenotype (19). The large number of different mutations with various functional defects hinders the development of a specific therapy (5). However, if a general strategy can be developed to rescue a large number of different mutant V₂ receptors that are trapped in the endoplasmic reticulum, then a new therapeutic approach may be applicable for the treatment of many X-linked NDI patients, as well as for the treatment of other diseases in which the functional defect is due to intracellular retention of improperly folded proteins (45).

	Acknowledgments

 
This work was supported by grants from the Medical Research Council of Canada (MT-8126 to Dr. Bichet), the Kidney Foundation of Canada, Le Fonds de la Recherche en Santé/Hydro-Québec, and the Canadian Genetic Diseases Network (Federal Networks of Centers of Excellence program). Dr. Bichet is a chercheur de carrière of Le Fonds de la Recherche en Santé du Québec. Dr. Fujiwara is supported in part by a donation from Alcan Aluminum Limitée.

We thank Drs. M. Alkan, J. L. André, G. Arbus, J. W. Balfe, C. Belsha, S. Benoit, T. Bettecken, M. Bost, M. Brown, T. F. Campbell, A. Canas, S. Cartier, R. Charbonneau, P. Cochat, H. Colomb, J. F. Crocker, M. De Beukelaer, J. Debrand, F. Di Bona, A. J. Fish, J. Flynn, M. Foulard, G. Friedenberg, M. Freundlich, M. Gagnan-Brunette, S. Gebhart, C. Genin, S. Gilgenkrantz, G. Glaesener, J. Goguen, M. Goldstein, P. Goodyer, M. C. Gregory, L. Guay-Woodford, D. Hébert, F. Hébert, R. Hogg, E. J. Holtzman, R. M. Hurley, E. Ihara, S. Ishikawa, T. Jacques, P. Jaeger, D. R. Johnson, J. J. Jonsson, G. Khodr, F. Kurtz, M. Lebel, C. Loirat, R. S. Mathias, T. Matsumoto, J. G. Mongeau, A. Neu, M. I. New, H. Nivet, A. Oksche, B. Parchoux, A. Pennrath, G. Picon, P. Pinaud, V. Proud, I. Rosenthal, Y. Saint Hillier, J. P. Salles, P. J. Scharffer, J. R. Sherbotie, M. Shoji, M. Simard, S. Simonetti, F. Takemoto, T. Watson, P. Welch, C. White, R. S. Wildin, and E. Zorn for referring patients to us. We also thank Maria Turner for assistance in data collection and Danielle Binette for graphics and secretarial assistance.

	Footnotes

 
Marie-Françoise Arthus and Michèle Lonergan contributed equally to this work.

Journal of the American Society of Nephrology

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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