Download Full Text

Annu. Rev. Med. 1995. 46:331–43
Copyright © 1995 by Annual Reviews Inc. All rights reserved
MOLECULAR BIOLOGY OF
DIABETES INSIPIDUS
T. Mary Fujiwara, M.Sc.* and Kenneth Morgan, Ph.D.**
*Departments of Human Genetics, Medicine, and Pediatrics and **Departments of
Epidemiology and Biostatistics, Human Genetics, and Medicine, McGill University,
Montreal, Quebec, H3G 1A4, Canada
Daniel G. Bichet, M.D.
Center of Research and Nephrological Service, Department of Medicine, Sacré-Coeur
Hospital of Montreal, Montreal, Quebec, H4J 1C5, Canada
KEY WORDS: antidiuretic hormone, arginine vasopressin, aquaporin, V2 receptor, mutation
ABSTRACT
The identification, characterization, and mutational analysis of three different
genes, namely the prepro-arginine-vasopressin-neurophysin II gene (preproAVP-NPII), the arginine-vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin-2, AQP2), provide the basis
for our understanding of three different hereditary forms of diabetes insipidus:
autosomal dominant neurogenic diabetes insipidus, X-linked nephrogenic diabetes insipidus, and autosomal recessive nephrogenic diabetes insipidus, respectively. These advances provide diagnostic tools for physicians caring for
these patients.
INTRODUCTION
Anyone passing large volumes of urine might be said to be suffering from
diabetes insipidus. Years ago, the initial distinction made by physicians in
evaluating patients with polyuria was whether their urine was sweet (diabetes
FUJIWARA,INSIPIDUS
DIABETES
MORGAN & BICHET
0066-4219/95/0401-0331$05.00
331
332
FUJIWARA, MORGAN & BICHET
mellitus) or not (diabetes insipidus) (1). Diabetes insipidus is a disorder characterized by the excretion of abnormally large volumes (30 ml/kg of body
weight per day for adult subjects) of dilute urine (<250 mmol/kg). Three basic
defects can be involved: (a) deficient secretion of the antidiuretic hormone
arginine vasopressin (AVP), which is the most common defect and is referred
to as neurogenic (or central, or hypothalamic) diabetes insipidus; (b) renal
insensitivity to the antidiuretic effect of AVP, which is known as nephrogenic
diabetes insipidus; and (c) excessive water intake that can result in polyuria,
which is referred to as primary polydipsia. The hereditary forms of diabetes
insipidus account for less than 10% of the cases of diabetes insipidus seen in
clinical practice. The purpose of this review is to examine recent developments
in the understanding and molecular biology of the hereditary forms of diabetes
insipidus.
GENES INVOLVED IN DIABETES INSIPIDUS
The regulation of the release of AVP from the posterior pituitary is primarily
dependent, under normal circumstances, on tonicity information relayed by
osmoreceptor cells in the anterior hypothalamus (for review see Ref. 2). AVP
and its corresponding carrier, neurophysin II (NPII), are synthesized as a
composite precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus (for review see Ref. 3). The precursor is
packaged into neurosecretory granules and transported axonally in the stalk of
the posterior pituitary. En route to the neurohypophysis, the precursor is processed into the active hormone. Prepro-vasopressin has 164 amino acids and is
encoded by the 2.5-kb prepro-AVP-NPII gene located in chromosome region
20p13 (4, 4a). Exon 1 of this gene encodes the signal peptide AVP and the
NH2-terminal region of NPII. Exon 2 encodes the central region of NPII, and
exon 3 encodes the COOH-terminal region of NPII and the glycopeptide.
Pro-vasopressin is generated by the removal of the signal peptide from preprovasopressin and from the addition of a carbohydrate chain to the glycopeptide.
Additional posttranslation processing occurs within neurosecretory vesicles
during transport of the precursor protein to axon terminals in the posterior
pituitary, yielding AVP, NPII, and glycopeptide. The AVP-NPII complex
forms tetramers that can self-associate to form higher oligomers (5).
The first step in the action of AVP on water excretion is its binding to
arginine-vasopressin type 2 receptors (V2 receptors) on the basolateral membrane of the collecting duct cells. The human V2 receptor gene, AVPR2, is
located in chromosome region Xq28 and has three exons and two small introns
(6, 7). The sequence of the cDNA predicts a polypeptide of 371 amino acids
with a structure typical of guanine-nucleotide (G) protein-coupled receptors
with seven transmembrane, four extracellular, and four cytoplasmic domains
DIABETES INSIPIDUS
333
Figure 1 Schematic representation of the V2 receptor and identification of 63 AVPR2 mutations,
which include 31 missense, 10 nonsense, 16 frameshift, 2 inframe deletion, 1 splice-site, and 3 large
deletion mutations. The three large deletions are incompletely characterized (8a) and are not included
in the figure. Predicted amino acids are given in the one-letter code. Solid symbols indicate the
predicted location of the mutations; an asterisk indicates two different mutations in the same codon.
The names of the mutations were assigned according to the conventional nomenclature (9). The
extracellular (EI to EIV), cytoplasmic (CI to CV), and transmembrane (TMI to TMVII) domains are
labelled according to Sharif & Hanley (10). EI: 98del28, 98ins28, 113delCT. TMI: L44F, L53R,
A61V, L62P. TMI and CI: 253del35, 255del9. CI: 274insG, W71X. TMII: H80R, L83P, D85N,
V88M, P95L. EII: R106C, 402delCT, C112R, R113W. TMIII: Q119X, Y124X, S126F, Y128S,
A132D. CII: R137H, R143P, 528del7, 528delG. TMIV: W164S, S167L. EIII: R181C, G185C,
R202C, T204N, 684delTA, Y205C, V206D. TMV: Q225X, 753insC. CIII: E231X, 763delA, E242X,
804insG, 804delG, 834delA, 855delG. TMVI: V277A, ∆V278, Y280C, W284X, A285P, P286R,
L292P, W293X. EIV: 977delG, 980A → G. TMVII: L312X, W323R. CIV: R337X. For a complete
description of these mutations see Refs. 8a and 10a–10i.
(8; see also Figure 1). The activation of the V2 receptor on renal collecting
tubules stimulates adenylyl cyclase via the stimulatory G protein (Gs) and
promotes the cyclic adenosine monophosphate (cAMP)–mediated incorporation of water pores into the luminal surface of these cells. This process is the
molecular basis of the vasopressin-induced increase in the osmotic water
permeability of the apical membrane of the collecting tubule.
The gene that codes for the water channel of the apical membrane of the
kidney-collecting tubule has been designated aquaporin-2 (AQP2) and was
cloned by homology to the rat aquaporin of collecting duct (11, 12, 13). The
334
FUJIWARA, MORGAN & BICHET
Figure 2 Schematic representation of the aquaporin-2 protein and identification of four AQP2
mutations (12, 12a).
human AQP2 gene is located in chromosome region 12q13 and has four exons
and three introns (12, 13, 14). It is predicted to code for a polypeptide of 271
amino acids that is organized into two repeats oriented at 180° to each other
and that has six membrane-spanning domains, with both terminal ends located
intracellularly, and conserved Asn-Pro-Ala boxes (Figure 2). These features
are characteristic of the major intrinsic protein family (13). There is 48%
amino acid sequence identity between AQP2 and the human channel–forming
integral protein of 28 kDa (CHIP28 or aquaporin-1), a water channel in erythrocytes and in the kidney proximal and descending tubules (15).
aThe names were assigned following the suggested nomenclature for mutations (9). The nucleotides and amino acids are numbered according to the prepro-AVP-NPII gene sequence published by
Sausville et al (4) and to GenBank accession number M11166. The codons corresponding to the
moieties are 1–19, signal peptide; 20–28 , AVP; 29–31, cleavage site; 32–124, NPII; and 126–164,
glycopeptide. The amino acids of AQP2 are numbered according to Refs. 12 and 12a. The
nucleotides, which are numbered according to GenBank accession number Z29491 (excluding the
partial introns), correspond to the nucleotide number plus 70 in Figure 2 of Ref. 12a.
a
Type of mutation
Nucleotide change
Predicted amino
acid change
Restrictionenzyme analysis
Gly → Val at codon 48
Deletion of Glu at
codon 77
Gly → Ser at codon 88
G → T at nucleotide
1740
Deletion of 3 nucleotides in region 1824–
1831
G → A at nucleotide
1859
Missense
Inframe deletion
Missense
G48V
∆E77
G88S
Frameshift 3′ to codon 123; codon
131 → stop
Arg → Cys at codon 187
Ser → Pro at codon 216
Deletion of C at nucleotide 439
C → T at nucleotide
629
T → C at nucleotide
716
Frameshift
Missense
Missense
439delC
R187C
S216P
Gly → Arg at codon 64
G → A at nucleotide
260
Missense
G64R
AQP2 mutations causing autosomal recessive nephrogenic diabetes insipidus
Ala → Thr at codon 19
G → A at nucleotide
279
Missense
A19T
ApaI site created
MspI site abolished
MnlI site abolished
BglI site abolished
BstUI site abolished
prpprepro-AVP-NPII mutations causing autosomal dominant neurogenic diabetes insipidus
Name
Distortion of the α-helical
structure
CG → TG
CG → CA
CG → CA; alteration of
the cleavage of the leader
peptide
Disruption of a β turn in
AVP-NPII precursor
3 sets of staggered 3 bp tandem repeats; unable to
form a salt bridge between
AVP and NPII
Failure of dimerization of
NPII, alteration of axonal
transport or postranslational processing
Comments and putative
functional consequence
12, 12a
12a
12a
18
23
19
20–22
Reference
Table 1 Mutations segregating with autosomal dominant neurogenic diabetes insipidus and autosomal recessive nephrogenic diabetes insipidus
336
FUJIWARA, MORGAN & BICHET
AUTOSOMAL DOMINANT NEUROGENIC DIABETES
INSIPIDUS AND MUTATIONS IN THE PREPRO-AVP-NPII
GENE
The classical animal model for studying diabetes insipidus has been the Brattleboro rat with autosomal recessive diabetes insipidus, di/di (16). This form of
hereditary diabetes insipidus is not found in humans. di/di rats are homozygous for a 1-bp deletion in the second exon that results in a frameshift mutation in the coding sequence of the carrier NPII. The mutant allele encodes a
normal AVP but an abnormal NPII moiety that impairs transport and processing of the AVP-NPII precursor and results in retention of the abnormal
polypeptide in the endoplasmic reticulum of the magnocellular cells (17).
Four prepro-AVP-NPII mutations segregating with autosomal dominant
neurogenic diabetes insipidus have been described (18–23; Table 1). The
mechanism(s) by which a mutant allele causes neurogenic diabetes insipidus
could be a gain of function of the mutant protein, a loss of function due to
insufficient normal product, or an interaction of the mutant and normal product
by degradation, functional inactivation of an oligomer, or interference with
processing. If defective protein slowly accumulates and results in the death of
magnocellular neurons, this could explain the absence of symptoms in the first
years of life of a heterozygote, when expression of the normal allele is sufficient to mount an appropriate antidiuretic response (20, 25). The absence of
symptoms in infancy is in sharp contrast to X-linked and probably also to
autosomal recessive nephrogenic diabetes insipidus, in which the polyuropolydipsic symptoms are present during the first week of life.
X-LINKED NEPHROGENIC DIABETES INSIPIDUS AND
MUTATIONS IN THE AVPR2 GENE
X-linked nephrogenic diabetes insipidus [MIM 304800 (26)] is generally a
rare disease in which the affected male patients do not concentrate their urine
after administration of AVP (27). Because this form is a rare, recessive Xlinked disease, females are unlikely to be affected, but heterozygous females
exhibit variable degrees of polyuria and polydipsia because of X inactivation.
In Quebec, the incidence of this disease among males was estimated to be
approximately 4 in 1,000,000 (28). A founder effect for a particular AVPR2
mutation in Ulster Scot immigrants resulted in an elevated prevalence of
X-linked NDI in their descendants and was estimated to afflict approximately
24 in 1000 males in certain communities in Nova Scotia. The W71X mutation
was identified as the cause of NDI in the extended kindred studied by Bode &
Crawford (29; the so-called Hopewell kindred) and in families in the Canadian
Maritime provinces (10a, 31). Among X-linked NDI patients in North Amer-
DIABETES INSIPIDUS
337
Figure 3 Parental origin of a de novo mutation. The mother of the affected male (solid symbol) is
a carrier of the S167L mutation. None of her three sisters carries this mutation, although all the
daughters received the same haplotype from their father. These data are consistent with a new
mutation arising during spermatogenesis in the maternal grandfather of the patient. The distance
spanned by the markers is sufficiently large that recombination between the markers has been
observed (8a). In this pedigree the affected male inherited a recombinant chromosome; recombination occurred between AVPR2 and G6PD.
ica, the W71X mutation is more common than any other AVPR2 mutation. The
W71X mutations of these patients are likely identical by descent, although a
common ancestor has not been identified in all cases.
The natural history of untreated disease includes hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy.
Mental retardation is a consequence of repeated episodes of dehydration and
was present in 73 of 82 patients (89%) in the Crawford & Bode study (32).
Early recognition and treatment of X-linked NDI with an abundant intake of
water allow a normal life span with normal physical and mental development
(33; DG Bichet, personal observations).
Sixty-three (8a, 10a–10i) putative disease-causing mutations in AVPR2
have now been reported in 90 presumably unrelated families with X-linked
NDI from diverse ethnic groups (see Figure 1). In X-linked NDI, loss of
mutant alleles from the population occurs because of the higher mortality of
affected males compared with normal males, whereas gain of mutant alleles
occurs by mutation. If affected males with a rare X-linked recessive disease do
not reproduce and if mutation rates are equal in mothers and fathers, then, at
genetic equilibrium, one third of new cases of affected males will be due to
new mutations (34). The gametic origins of new mutations could be identified
or inferred in 18 families and included 5 maternal, 9 grandpaternal, and 2
grandmaternal gametes, 1 great-grandmaternal gamete, and 1 gamete that was
either of grandpaternal or grandmaternal origin (8a, 10c, 10d, 35). Figure 3
illustrates the identification of a new mutation.
338
FUJIWARA, MORGAN & BICHET
Figure 4 Proposed mechanisms of mutagenesis. Boxes enclose repeat units considered to be
involved in the generation of a deletion. The codons are numbered according to Ref. 6. Dashes
indicate nucleotide deletions. The mechanism generating the 253del35 mutation (8a) is consistent
with the slipped-mispairing model (36–39). This mechanism involves the misalignment, during
DNA replication, of short direct repeats of 2 to 11 bp. If the direct repeat in box R2 forms base pairs
with the complementary box R1 repeat (R1′ ), a single-stranded loop containing the 1 repeat and the
intervening sequence between box R1 and box R2 is generated. Excision of the loop and rejoining
of the sequence would generate the 35-bp deletion. (a) Duplex DNA containing direct repeat
sequence. (b) Duplex becomes single stranded at replication fork. (c) Backward slip of the template
strand and formation of a single-stranded loop. (d) Daughter duplexes, one of which contains only
one of the two repeats and lacks the intervening sequence.
Eleven different AVPR2 mutations were observed in more than one independent NDI family, suggesting that there are hot spots for mutations. Additional evidence for recurrent mutation is the observation that the mutation
occurs on different haplotypes defined by markers in or very close to the
AVPR2 gene (8a, 10c). Seven of the 11 mutations (V88M, R113W, R137H,
S167L, R181C, R202C, and R337X) were single nucleotide substitutions at a
CpG dinucleotide. Methylated CpG dinucleotides are recognized hot spots for
mutation (36). Thirteen of 18 small deletion or insertion mutations (1 to 35 bp)
DIABETES INSIPIDUS
339
involved direct or complementary repeats (2 to 9 bp) or strings of 4 to 6
guanines (see Figure 2 or Ref. 8a and Figure 4). This finding suggests that
these deletions, like many others that have been described in other genes,
resulted from DNA strand slippage and mispairing during replication (36–39).
The cause of loss of function of mutant V2 receptors has been studied in in
vitro expression systems. Truncated polypeptides, which are expected to be
nonfunctional, or absent protein is expected in the case of nonsense mutations
(W71X, Q119X, Y124X, Q225X, E231X, E242X, W284X, W293X, L312X,
and R337X). A missense mutation could result in misfolding of the protein
and trapping in the endoplasmic reticulum or in alteration of the binding
pocket or the contact surface that activates the stimulatory G protein. The
R137H mutant protein expressed in cultured kidney cells from African green
monkey (COS cells) from transfected mutant cDNA exhibited a normal binding affinity for AVP but failed to stimulate the Gs/adenylyl cyclase system
(40). The R113W mutant cDNA was also transfected into COS cells, and the
mutant protein exhibited a combination of functional defects: lowered affinity
for vasopressin, diminished ability to stimulate adenylyl cyclase, and diminished ability to reach the cell surface (41). No adenylyl cyclase activity was
detected in COS cells transfected with cDNA of a nonsense mutation
(Q119X), a frameshift mutation (763delA or 855delG), or missense mutations
(10i). In addition, functional analysis of AVPR2 mutations indicated that the
810del12 mutation was not the cause of NDI in a patient who had this mutation as well as the R181C mutation (10i, 35). The R181C mutant receptor had
less than half of the normal adenylyl cyclase activity, and although it was
expressed at the same level as the normal V2 receptor, the EC50 for adenylyl
cyclase stimulation was increased, presumably owing to its altered structure.
AUTOSOMAL RECESSIVE NEPHROGENIC DIABETES
INSIPIDUS AND MUTATIONS IN THE AQP2 GENE
On the basis of (a) phenotypic characteristics of both males and females
affected with NDI and (b) dDAVP infusion studies, a non-X-linked form of
NDI with a postreceptor defect was suggested (42–45). In contrast to male
patients affected with X-linked NDI (46, 47), two male and two female NDI
patients experienced a normal rise, e.g. two- to threefold, in the plasma concentrations of factor VIII and von Willebrand factor after dDAVP infusion, but
urinary osmolality remained low (42). X-linked NDI was excluded for two
sisters with vasopressin-resistant hypotonicity because they inherited different
alleles of an Xq28 marker from their mother; autosomal recessive inheritance
was suggested on the basis of gender, parental consanguinity, and normal
urine concentration in the parents (44). Two male patients were described who
had normal stimulation of plasma cAMP after dDAVP administration but in
340
FUJIWARA, MORGAN & BICHET
whom no AVPR2 mutation was identified (45). A patient who presented
shortly after birth with typical features of NDI but who exhibited normal
coagulation and normal fibrinolytic and vasodilatory responses to dDAVP was
recently shown to be a compound heterozygote for two missense mutations
(R187C and S217P) in the AQP2 gene (12, 43; Figure 2 and Table 1). Three
NDI patients from consanguineous matings were found to be homozygous for
missense mutations (R187C or G64R) or a frameshift mutation (369delC) in
the AQP2 gene. Functional expression studies showed that Xenopus oocytes
injected with mutant cRNA had abnormal coefficients of water permeability,
while Xenpous oocytes injected with both mutant and normal cRNAs had
coefficients of water permeability similar to those of normal constructs alone
(12, 12a). These findings provide conclusive evidence that NDI can be caused
by homozygosity for mutations in the AQP2 gene. The increased frequency of
consanguinity between normal parents of affected children of both genders
with AQP2 mutations is consistent with autosomal recessive inheritance of a
rare genetic disease.
CARRIER DETECTION AND POSTNATAL DIAGNOSIS
The identification of mutations in three genes that cause diabetes insipidus
allows the early diagnosis and management of at-risk members of families
with identified mutations. We encourage physicians who follow families with
X-linked NDI to recommend mutation analysis before the birth of a male
infant because early diagnosis and treatment of male infants can avert the
physical and mental retardation associated with episodes of dehydration. Diagnosis of X-linked NDI within 48 h of birth was accomplished by mutation
testing of a sample of cord blood (8a). Early diagnosis of autosomal recessive
NDI is also essential for early treatment of affected infants in order to avoid
repeated episodes of dehydration. Mutation detection in families with inherited
neurogenic diabetes insipidus provides a powerful clinical tool for early diagnosis and management of subsequent cases, especially in early childhood,
when diagnosis is difficult and the clinical risks are the greatest (25).
SUMMARY
It is hoped that an understanding of the pathophysiology of defects in the
antidiuretic hormone, the V2 receptor, and the water channel due to mutations
in the prepro-AVP-NPII, AVPR2, and AQP2 genes, respectively, will provide
insight into the more numerous cases of sporadic diabetes insipidus. In turn,
the study of diabetes insipidus caused by mutations in these and additional
genes will increase our knowledge of normal vasopressin-regulated water
transport across the kidney epithelium.
DIABETES INSIPIDUS
341
ACKNOWLEDGMENTS
This work was supported by grants from the Medical Research Council of
Canada (MT-8126), FRSQ/Hydro-Québec, the Canadian Kidney Foundation,
the Heart and Stroke Foundation of Quebec, and the Canadian Genetic Diseases Network (Networks of Centers of Excellence). DGB is a career investigator of Le Fonds de la Recherche en Santé du Québec.
Any Annual Review chapter, as well as any article cited in an Annual Review chapter,
may be purchased from the Annual Reviews Preprints and Reprints service.
1-800-347-8007; 415-259-5017; email: [email protected]
Literature Cited
1. Maffly RH. 1977. Diabetes insipidus. In
Disturbances in Body Fluid Osmolality, ed.
TE Andreoli, JJ Grantham, FC Rector, pp.
285–307. Washington, D.C.: Am. Physiol.
Soc.
2. Bichet DG. 1994. Posterior pituitary. In
The Pituitary, ed. S Melmed, pp. 277–
306. Oxford, UK: Blackwell Scientific. In
press
3. Richter D. 1988. Molecular events in the
expression of vasopressin and oxytocin and
their cognate receptors. Am. J. Physiol.
255:F207–F219
4. Sausville E, Carney D, Bettey J. 1985. The
human vasopressin gene is linked to the
oxytocin gene and is selectively expressed
in a cultured lung cancer cell line. J. Biol.
Chem. 260(18):10236–41
4a. Gopal Rao VVN, Loffler C, Battey J,
Hansmann I. 1992. The human gene for
oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in
situ hybridization. Cell Genet. 61:271–73
5. Chen L, Rose JP, Breslow E, et al. 1991.
Crystal structure of a bovine neurophysin
II dipeptide complex at 2.8 Å determined
from the single-wave length anomalous
scattering signal of an incorporated iodine
atom. Proc. Natl. Acad. Sci. USA 88:4240–
44
6. Birnbaumer M, Seibold A, Gilbert S, et al.
1992. Molecular cloning of the receptor for
human antidiuretic hormone. Nature 357:
333–35
7. Seibold A, Brabet P, Rosenthal W, Birnbaumer M. 1992. Structure and chromosomal localization of the human antidiuretic
hormone receptor gene. Am. J. Hum.
Genet. 51:1078–83
8. Watson S, Arkinstall S, eds. 1994. The GProtein Linked Receptor Facts Book, London: Academic, Hartcourt Brace & Co. 427
pp.
8a. Bichet DG, Birnbaumer M, Lonergan M,
et al. 1994. Nature and recurrence of
AVPR2 mutations in X-linked nephrogenic
diabetes insipidus. Am. J. Hum. Genet. 55:
278–86
9. Beaudet AL, Tsui LC. 1993. Special feature: a suggested nomenclature for designating mutations. Hum. Mutat. 2:245–48
10. Sharif M, Hanley MR. 1992. Stepping up
the pressure. Nature 357:279–80
10a. Bichet DG, Arthus MF, Lonergan M, et al.
1993. X-linked nephrogenic diabetes insipidus mutations in North America and the
Hopewell hypothesis. J. Clin. Invest. 92:
1262–68
10b. Tsukaguchi H, Matsubara H, Aritaki S, et
al. 1993. Two novel mutations in the vasopressin V2 receptor gene in unrelated Japanese kindreds with nephrogenic diabetes
insipidus. Biochem. Biophys. Res. Commun. 197:1000–10
10c. Knoers NVAM, van den Ouweland
AMW, Verdijk M, et al. 1994. Inheritance
of mutations in the V2 receptor gene in
thirteen families with nephrogenic diabetes
insipidus. Kidney Int. 46:170–76
10d. Wildin RS, Antush MJ, Bennett RL, et
al. 1994. Heterogeneous AVPR2 gene
mutations in congenital nephrogenic diabetes insipidus. Am. J. Hum. Genet. 55:266–
77
10e. Wenkert D, Merendino JJ Jr, Shenker A,
et al. 1994. Novel mutations in the V2 vasopressin receptor gene of patients with
X-linked nephrogenic diabetes insipidus.
Hum. Mol. Genet. 3:1429–30
10f. Yuasa H, Ito M, Oiso Y, et al. 1994. Novel
mutations in the V2 vasopressin receptor
gene in two pedigrees with congenital
nephrogenic diabetes insipidus. J. Clin. Endocrinol. Metab. 79:361–65
10g. Holtzman EJ, Kolakowski LF Jr, Geifman-Holtzman O, et al. 1994. Mutations in
342
FUJIWARA, MORGAN & BICHET
the vasopressin V2 receptor gene in two
families with nephrogenic diabetes insipidus. J. Am. Soc. Nephrol. 5:169–76
10h. Friedman E, Bale AE, Carson E, et al.
1994. Nephrogenic diabetes insipidus: an
X chromosome–linked dominant inheritance pattern with a vasopressin type 2
receptor gene that is structurally normal.
Proc. Natl. Acad. Sci. USA 91:8457–61
10i. Pang Y, Metzenberg A, Ravnan B, et al.
1993. Molecular and functional analysis of
the V2 vasopressin receptor in patients with
nephrogenic diabetes indipidus. Am. J.
Hum. Genet. 53(3):938 (Abstr.)
11. Fushimi K, Uchida S, Hara Y, et al. 1993.
Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature 361:549–52
12. Deen PMT, Verdijk MAJ, Knoers NVAM,
et al. 1994. Requirement of human renal
water channel aquaporin-2 for vasopressindependent concentration of urine. Science
264:92–95
12a. van Lieburg AF, Verdijk MAJ, Knoers
NVAM, et al. 1994. Patients with autosomal nephrogenic diabetes insipidus: homozygous for mutations in the aquaporin 2
water-channel gene. Am. J. Hum. Genet.
55:648–52
13. Sasaki S, Fushimi K, Saito H, et al. 1994.
Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct. J. Clin. Invest. 93:1250–56
14. Deen PMT, Weghuis DO, Sinke RJ, et al.
1994. Assignment of the human gene for
the water channel of renal collecting duct
aquaporin 2 (AQP2) to chromosome 12
region q12 → q13. Cytogenet. Cell. Genet.
66:260–62
15. Agre P, Preston GM, Smith BL, et al. 1993.
Aquaporin CHIP: the archetypal molecular
water channel. Am. J. Physiol. 265:F463–
76
16. Valtin H. 1982. The discovery of the Brattelboro rat, recommended nomenclature,
and the question of proper controls. Ann. N.
Y. Acad. Sci. 394:1–9
17. Richter D. 1993. Reflections on central diabetes insipidus: retrospective and perspective. In Vasopressin, ed. P Gross, D Richter,
GL Robertson, pp. 3–14. Berlin: John Libbey Eurotex
18. Ito M, Mori Y, Oiso Y, Saito H. 1991. A
single base substitution in the coding region
for neurophysin II associated with familial
central diabetes insipidus. J. Clin. Invest.
87:725–28
19. Bahnsen U, Oosting P, Swaab DF, et al.
1992. A missense mutation in the vasopressin-neurophysin precursor gene cosegregates with human autosomal dominant neurohypophyseal diabetes insipidus.
EMBO J. 11(1):19–23
20. Ito M, Oiso Y, Murase T, et al. 1993. Pos-
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
sible involvement of inefficient cleavage of
preprovasopressin by signal peptidase as a
cause for familial central diabetes insipidus. J. Clin. Invest. 91:2565–71
Krishnamani MRS, Phillips JA III, Copeland KC. 1993. Detection of a novel arginine vasopressin defect by dideoxy fingerprinting. J. Clin. Endocrinol. Metab. 77:
596–98
McLeod JF, Kovàcs L, Gaskill MB, et al.
1993. Familial neurohypophyseal diabetes
insipidus associated with a signal peptide
mutation. J. Clin. Endocrinol. Metab. 77:
599A–99G
Yuasa H, Ito M, Nagasaki H, et al. 1993.
Glu-47, which forms a salt bridge between
neurophysin-II and arginine vasopressin, is
deleted in patients with familial central diabetes insipidus. J. Clin. Endocrinol. Metab.
77:600–4
Deleted in proof
Miller WL. 1993. Molecular genetics of
familial central diabetes insipidus. J. Clin.
Endocrinol. Metab. 77:592–95
McKusick VA, ed. 1990. Diabetes insipidus renal type I. In Mendelian Inheritance
In Man, pp. 1585–90. Baltimore: Johns
Hopkins Univ. Press. 9th ed.
Bichet DG. 1992. Nephrogenic diabetes
insipidus. In Oxford Textbook of Clinical
Nephrology, ed. JS Cameron, AM Davison, JP Grunfeld, et al, pp. 789–800. New
York: Oxford Univ. Press
Bichet DG, Hendy GN, Lonergan M, et al.
1992. X-linked nephrogenic diabetes insipidus: from the ship Hopewell to RFLP
studies. Am. J. Hum. Genet. 51:1089–102
Bode HH, Crawford JD. 1969. Nephrogenic diabetes insipidus in North America.
The Hopewell hypothesis. New Engl. J.
Med. 280:750–54
Deleted in proof
Holtzman EJ, Kolakowski LF, O’Brien D,
et al. 1993. A null mutation in the vasopressin V2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus in
the Hopewell kindred. Hum. Mol. Genet.
2:1201–4
Crawford JD, Bode HH. 1975. Disorders of
the posterior pituitary in children. In Endocrine and Genetic Diseases of Childhood
and Adolescence, ed. LI Gardner, pp. 126–
58. Philadelphia: Saunders
Niaudet P, Dechaux M, Trivin C, et al.
1984. Nephrogenic diabetes insipidus:
clinical and pathophysiological aspects. In
Advances in Nephrology, ed. JP Grünfeld,
MH Maxwell, pp. 247–60. Chicago: Yearb.
Med.
Vogel F, Motulsky AG. 1986. Human Genetics: Problems and Approaches, pp.
347–49. Berlin: Springer. 2nd ed.
Pan Y, Metzenberg A, Das S, et al. 1992.
Mutations in the V2 vasopressin receptor
DIABETES INSIPIDUS
36.
37.
38.
39.
40.
41.
gene are associated with X-linked nephrogenic diabetes insipidus. Nat. Genet. 2:
103–6
Cooper DN, Krawczak M. 1993. Human
Gene Mutation. Oxford, UK: BIOS Sci.
Publ.
Krawczak M, Cooper DN. 1991. Gene deletions causing human genetic disease:
mechanisms of mutagenesis and the role of
the local DNA sequence environment.
Hum. Genet. 86:425–41
Sinden RR, Wells RD. 1992. DNA structure, mutations, and human genetic disease.
Curr. Opin. Biotechnol. 3:612–22
Eng CM, Resnick-Silverman LA, Niehaus
DJ, et al. 1993. Nature and frequency of
mutations in the α-galactosidase A gene
that cause Fabry disease. Am. J. Hum.
Genet. 53:1186–97
Rosenthal W, Antaramian A, Gilbert A,
Birnbaumer M. 1993. Nephrogenic diabetes insipidus: a V2 vasopressin receptor
unable to stimulate adenylyl cyclase. J.
Biol. Chem. 268:13030–33
Birnbaumer M, Gilbert S, Rosenthal W.
1994. An extracellular congenital nephrogenic diabetes indipidus mutation of the
vasopressin receptor reduces cell surface
expression, affinity for ligand, and coupling to the Gs/adenylyl cyclase system.
343
Mol. Endocrinol. 8:886–94
42. Brenner B, Seligsohn U, Hochberg Z.
1988. Normal response of factor VIII and
von Willebrand factor to 1-deamino-8D-arginine vasopressin in nephrogenic diabetes
insipidus. J. Clin. Endocrinol. Metab. 67:
191–93
43. Knoers N, Monnens AH. 1991. A variant of
nephrogenic diabetes insipidus: V2 receptor abnormality restricted to the kidney.
Eur. J. Pediatr. 150:370–73
44. Langley JM, Balfe JW, Selander T, et al.
1991. Autosomal recessive inheritance of
vasopressin-resistant diabetes insipidus.
Am. J. Med. Genet. 38:90–94
45. Lonergan M, Birnbaumer M, Arthus MF,
Bichet DG. 1993. Non-X-linked nephrogenic diabetes insipidus: phenotype and
genotype features. J. Am. Soc. Nephrol.
4:264 (Abstr.)
46. Bichet DG, Razi M, Lonergan M, et al.
1988. Hemodynamic and coagulation responses to 1-desamino[8-D-arginine] vasopressin in patients with congenital nephrogenic diabetes insipidus. New Engl. J.
Med. 318:881–87
47. Bichet DG, Razi M, Arthus MF, et al. 1989.
Epinephrine and dDAVP administration in
patients with congenital nephrogenic diabetes insipidus. Kidney Int. 36:859–66