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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 7 3351-3355
Copyright © 2002 by The Endocrine Society

Other Original Articles

Autosomal Dominant Neurohypophyseal Diabetes Insipidus due to Substitution of Histidine for Tyrosine2 in the Vasopressin Moiety of the Hormone Precursor

Søren Rittig, Charlotte Siggaard, Metin Ozata, Ilhan Yetkin, Niels Gregersen, Erling B. Pedersen and Gary L. Robertson

Department of Pediatrics (S.R., C.S.) and Research Unit for Molecular Medicine (N.G.), Skejby University Hospital, Aarhus DK-8200, Denmark; Department of Endocrinology (M.O., I.Y.), Gulhane School of Medicine, 06019 Ankara, Turkey; Department of Medicine (E.B.P.), Holstebro Hospital, DK-7500 Holstebro, Denmark; and Department of Medicine (G.L.R.), Northwestern University Medical School, Chicago, Illinois 60611-3008

Address all correspondence and requests for reprints to: Dr. Søren Rittig, M.D., Department of Pediatrics, Skejby University Hospital, DK-8200 Aarhus N, Denmark. E-mail: . rittig{at}iekf.au.dk

Abstract

The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) has been linked to 40 different mutations of the gene encoding the vasopressin-neurophysin II (AVP-NPII) precursor. All of these mutations have been located in either the signal peptide or neurophysin II moiety. We now report a three-generation Turkish kindred in which severe adFNDI cosegregates with a novel missense mutation in the part of the AVP-NPII gene encoding the AVP moiety. This mutation (T->C at position 285 in the genomic sequence) was found in only one allele and predicts a substitution of histidine for tyrosine at position 2 in AVP. Like other adFNDI mutations, this substitution is expected to impair folding and processing of the precursor, in this case by interfering with normal binding of the AVP and NPII moieties. It is associated clinically with inability to concentrate urine during fluid deprivation, a greater than 80% deficiency of AVP secretion, and absence of the posterior pituitary bright spot on magnetic resonance imaging. These findings are consistent with the hypothesis that mutations in the AVP-NPII gene cause adFNDI by directing the production of a folding incompetent precursor that prevents the expression of the normal allele via a cytotoxic effect on the magnocellular neurons.

FAMILIAL NEUROHYPOPHYSEAL DIABETES insipidus (FNDI) is a rare, hereditary disease characterized by severe thirst, polydipsia, and polyuria (1). It is caused by deficient neurosecretion of the antidiuretic hormone, arginine vasopressin (AVP). In most cases, the diabetes insipidus (DI) is not present at birth but develops several months to years later. In the few patients in which it has been studied, AVP secretion appears to be normal at birth but diminishes progressively during early childhood (2). By far the most common form of FNDI is transmitted in a completely penetrant, autosomal dominant mode (adFNDI). Autopsy studies in a few of these patients have shown gliosis and a decreased number of magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus (3, 4), suggesting that the disease is due to degeneration of the cells that normally produce large amounts of AVP.

AdFNDI is now known to be caused by diverse mutations in one allele of the gene that encodes the AVP precursor protein, AVP-neurophysin II (AVP-NPII) (1, 5, 6, 7, 8, 9, 10). Of the 40 different mutations identified to date, five are located in the part encoding the signal peptide, and the rest affect various loci in the neurophysin II (NPII) moiety. None have been reported in parts of the gene that encode the AVP moiety or the glycosylated peptide known as copeptin. Despite considerable variety in location and type, all but possibly one of these mutations are predicted to alter one or more amino acids known or reasonably presumed to be important for proper folding and/or self-association of pre-pro-AVP-NPII in the endoplasmic reticulum (11). This pattern as well as the clinical features of the disease has led to the hypothesis that adFNDI results from the production of a mutant AVP precursor that accumulates and kills the neuron because it cannot be processed and/or folded into the conformation required for routing into the regulated pathway in which final processing and secretion occur (11). This hypothesis receives support from in vitro expression studies of several mutations that have been linked to adFNDI (12, 13, 14, 15, 16, 17, 18, 19, 20). In this paper we report the first mutation identified in the region of the gene encoding the AVP moiety itself and discuss the implications for this theory of pathogenesis.

Subjects and Methods

Subjects

Studies were performed on seven living members from two generations of a Turkish kindred in which DI was segregating in an autosomal dominant mode (Fig. 1Go). The local ethical committee approved the study, and appropriate informed consent was obtained from all human subjects.



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  		Figure 1. Pedigree of a Turkish kindred with adFNDI. Members with historical or laboratory evidence of DI are indicated by closed symbols. The arrow indicates the proband. The + or - symbols indicate, respectively, the presence or absence of the T->C mutation at position 285 by either sequencing or restriction enzyme digestion.

 
Clinical procedures

Twenty-four-hour urine collections, 8-h overnight fluid deprivation tests, magnetic resonance imaging (MRI) of the brain, and assessment of the therapeutic response to DDAVP were made in an outpatient setting in Turkey. Samples of whole blood, serum, and urine were shipped for analysis to the University of Aarhus Medical School (Aarhus, Denmark).

Laboratory procedures

Plasma and urine samples were measured for osmolality by freezing point depression (advanced cryometric osmometer, 3C2, Advanced Instruments, Norwood, MA). Urinary AVP was measured by RIA (21) after lyophilization and reconstitution with distilled water to a total solute concentration of 300 mosm/kg (2). Assay cross-reactivity against Tyr2His-AVP was determined using chemically synthesized peptide (KJ Ross-Petersen A/S, Hørsholm, Denmark) identical to authentic AVP except for the Tyr2-to-His substitution. The cross-reactivity against Tyr2His-AVP was more than 82% (data not shown), and measured levels of AVP in the urine were therefore not adjusted. Results were expressed as picogram per milligram of creatinine in the reconstituted samples. Genomic DNA was extracted from the buffy coat of peripheral leukocytes as described previously (2). All exons of the AVP-NPII gene were amplified separately by PCR using 31-bp primers flanking each exon. Bidirectional sequence analysis was performed with automated dye-terminator sequencing (Applied Biosystems Inc., Foster City, CA) using T7DNA polymerase (Sequenase). The amplification and sequencing method including primer sequences and cycle conditions are described in detail elsewhere (11). Because the identified mutation did not involve a recognition site of a known restriction enzyme, an oligonucleotide-based detection assay was performed using mismatched primers that converted the mutant sequence to an artificial recognition site for the enzyme BanI (Table 2Go).


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  		Table 2. Nucleotide sequence of mismatched primer set used to generate a PCR product with an artificial restriction site that involves the T->C mutation at position 285

 
Results

Clinical studies

As shown in Table 1Go, four of the seven family members tested (II-3, III-1, III-2, and III-3) had FNDI as evidenced by: 1) a history of polyuria and polydipsia beginning between age 6 months and 3 yr; 2) a high 24-h urine volume, a low random urine osmolality, and low urinary AVP under basal conditions of ad libitum fluid intake; and 3) failure to concentrate urine or normally increase urinary excretion of AVP during fluid deprivation. These individuals also had absence of the normal posterior pituitary bright spot on MRI (22) and had complete correction of their thirst, polydipsia and polyuria with evidence of water intoxication when treated with intranasal 10–20 µg DDAVP two to three times a day. The other three family members (II-3a, III-4, and III-5) denied histories of polyuria and polydipsia and had normal urine osmolalities and urinary AVP before and during fluid deprivation. By family history, two deceased members from the first and second generation (I-2 and II-1) also had DI.


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  		Table 1. Clinical data on seven living family members from a Turkish kindred with adFNDI

 
Genetic studies

In the affected subjects (II-3, III-1, III-2, and III-3) two nucleotides, T and C, were detected at position 285 in exon 1 of the AVP-NPII gene (Fig. 2AGo). The three unaffected individuals (II-3a, III-4, and III-5) had only the normal T at this position. The results were the same when the exon was sequenced in the sense and antisense direction. Sequencing the rest of the coding region of the AVP-NPII gene revealed no other deviations from the wild-type gene (23) as corrected by subsequent analysis (11, 24). Furthermore, we have not detected this T->C transversion in 40 Danish normal subjects or in 112 affected and unaffected members of other FNDI kindreds (11). The restriction enzyme assay showed a digestion pattern that was consistent with a substitution in one allele and that cosegregated completely with the phenotype (Fig. 2BGo). The mutant allele in affected members of this family predicts the substitution of histidine for the tyrosine normally found at position 2 of the AVP moiety in the preprohormone (Fig. 3Go).



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  		Figure 2. A, Sequencing chromatogram from a fragment of exon 1 of the AVP-NPII gene in a clinically affected subject (FIII-2) and a normal subject (FIII-4). A heterozygous mutation T->C (arrows) is seen in both the sense (s) and antisense (as) chromatograms of the patient. B, Restriction enzyme cleavage (BanI) using mismatched primers in seven members of a Turkish adFNDI kindred. By this method, the T->C mutation at position 285 creates a new restriction site for this enzyme, which is seen on the agarose gel as an extra band (102 bp). As shown, the mutation is verified in all four affected (closed symbols) and in none of the three unaffected subjects (open symbols).

 


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  		Figure 3. Schematic representation of the NPII-binding pocket containing the three amino-terminal residues of the wild-type (left) or mutant (right) AVP moiety. The dotted lines indicate hydrogen bonding. Note that the substitution of histidine for tyrosine at position 2 does not reduce hydrogen bonding or sterically hinder association between the ligand and neurophysin. Rather, it increases the hydrophilicity of the side chain, which requires a more polar environment for binding. Modified from (27 ) with permission.

 
Discussion

This study describes the first association of adFNDI with a mutation in the part of the AVP-NPII gene that codes for the hormone moiety itself. The mutation (285T->C) predicts the substitution of histidine for tyrosine in position 2 of AVP. Like the 40 other mutations that have been identified in this gene in adFNDI, the AVP2 mutation in this Turkish family is heterozygous and the only one found in the coding region and segregates perfectly with clinical signs of the disease. It also results in a clinical phenotype similar to the other mutations in that the DI begins in the first few years of life, is caused by a severe though incomplete deficiency of AVP, and is completely corrected by treatment with small doses of an AVP analog, DDAVP. Like most other patients with adFNDI, the affected members of the kindred also lacked the normal posterior pituitary bright spot on MRI (22). This finding is consistent with but not necessarily indicative of degeneration of the magnocellular neurons that normally produce vasopressin.

The mechanism by which the AVP2 mutation produces adFNDI also appears to be similar to that postulated for the other mutations (11) because it alters an amino acid known to be important for folding and processing of the precursor. Like other proteins destined for secretion (25), newly synthesized pre-pro-AVP-NPII is translocated into the endoplasmic reticulum in which the signal peptide is removed, enabling the prohormone to fold, form the appropriate intrachain disulfide bonds, and dimerize. This conformation permits it to move to the Golgi to be packaged into neurosecretory granules in which it is cleaved into its individual moieties (AVP, NPII, and copeptin) and transported down the axon to be stored in nerve terminals until release. Biochemical and crystallographic studies (26, 27, 28, 29) indicate that the folding and dimerization of neurophysin and, presumably, intact pro-AVP-NPII require that the three N-terminal amino acids of the AVP moiety bind in a pocket formed by several residues in the amino terminal domain of neurophysin (Fig. 3Go). This binding is markedly impaired by substitution of histidine for the tyrosine normally present at position 2, probably because the histidine is more hydrophilic and requires a more polar environment for binding (30). Loss of the hydroxyl group of tyrosine appears to be unimportant in this effect because binding is relatively unaffected by replacement of tyrosine with phenylalanine, which also has no hydroxyl group. In any case, the impaired binding that would result from the mutation observed in this family would also be expected to impair folding and/or dimerization of the mutant precursor and thereby interfere with normal intracellular trafficking and processing of the prohormone through the regulated secretory pathway (31). Consistent with this hypothesis, expression studies in murine neuroblastoma Neuro2A cells have shown that a slightly different substitution at position 2 in the AVP moiety (tyrosine to glycine) results in the formation of a mutant precursor that is not processed properly (32).

Because patients with adFNDI are heterozygous for mutations of the AVP-NPII gene, some mechanism in addition to impaired processing of the mutant precursor must be operative to account for the fact that their capacity to produce AVP is reduced by more than 50% (2). In the Turkish kindred with the AVP2 mutation, urinary excretion of AVP by affected members was less than 15% of that in their unaffected kin or a large control group of healthy Danish and American adults (Table 1Go). The levels observed in this kindred are comparable with those found in affected members of other adFNDI kindreds (2). To account for the dominant negative effect on expression of the wild-type gene, we have also postulated that the misfolded, unprocessed mutant precursor accumulates and gradually kills the magnocellular neurosecretory neurons in which it is produced (11). This misfolding/neurotoxicity hypothesis is consistent with other clinical features of the disease including the delayed onset and progressive worsening of the AVP deficiency, autopsy evidence of neurohypophyseal degeneration, and absence of the posterior pituitary bright spot on MRI (22). Moreover, expression studies in vitro have also shown that select adFNDI mutations direct the production of a mutant preprohormone that is not processed correctly, is retained in the endoplasmic reticulum, and is toxic for the cells (12, 13, 14, 15, 16, 17, 18, 19, 20). An alternative explanation for the dominant negative effect is that the mutant precursor inhibits full expression of the normal allele not by killing magnocellular neurons but by combining with wild-type precursor to form unprocessable heteroligomers (1). In this scenario, magnocellular neurons might degenerate but only as a nonessential and possibly inconstant feature of the disease occurring after the onset of the AVP deficiency. Further study of neurohypophyseal morphology especially before and during the onset of the AVP deficiency may be helpful in deciding between these two mechanisms.

The recent report (33) of a family with an autosomal recessive form of FNDI provides an important negative control that supports the hypothesis that impaired binding and/or folding of the prohormone is responsible for the dominant negative effect of adFNDI mutations. In the family with the autosomal recessive form of FNDI, a missense mutation was also identified in the part of the AVP-NPII gene that encodes the AVP moiety (301C->T). However, it predicts the substitution of leucine for proline at position 7 of AVP, a residue nearer the C terminus that has not been implicated in the binding and folding of neurophysin. In the heterozygous state, this substitution also does not result in a clinically significant deficiency of native AVP, indicating that it does not cause degeneration of the neurohypophysis or exert a dominant-negative effect by any other means. Instead, it appears to act simply by directing the production of a biologically less active analog of AVP and, as a consequence, results in DI only if present in both alleles of the gene. This important finding further supports the idea that the only AVP-NPII gene mutations that cause adFNDI are those that impair folding and/or dimerization of the prohormone. The corollary is that other types of mutations may reduce production of AVP by the mutant allele but they will be recessive because they will not kill the cell or otherwise interfere appreciably with full expression of the normal allele. It will be of interest to determine whether this prediction is borne out by future studies of natural and artificial mutations of the AVP-NPII gene.

Acknowledgments

We thank Dorte Rønde and Jane Hagelskjær Knudsen for skilled laboratory assistance. Dr. M. Ali Gundogan (Department of Endocrinology, Gulhane School of Medicine, Ankara, Turkey) is thanked for his help with the clinical studies.

Footnotes

This work was supported by grants from The Danish Medical Research Council, Novo Nordic Foundation, and the University of Aarhus, Denmark.

Abbreviations: adFNDI, Autosomal dominant familial neurohypophyseal diabetes insipidus; AVP, arginine vasopressin; AVP-NPII, AVP-neurophysin II; DI, diabetes insipidus; FNDI, familial neurohypophyseal diabetes insipidus; MRI, magnetic resonance imaging; NPII, neurophysin II.

Received October 18, 2001.

Accepted April 4, 2002.

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