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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 11 3643-3646
Copyright © 1997 by The Endocrine Society

Original Studies

Autosomal Dominant Neurohypophyseal Diabetes Insipidus Associated with a Missense Mutation Encoding Gly23->Val in Neurophysin II1

Priscila C. Gagliardi, Sergio Bernasconi and David R. Repaske

Division of Endocrinology, Children’s Hospital Medical Center (P.C.G., D.R.R.), Cincinnati, Ohio 45229; and Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, Universita Degli Studi di Modena (S.B.), 41100 Modena, Italy

Address all correspondence and requests for reprints to: David Repaske, Ph.D., M.D., NWM-1 TCHRF, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039. E-mail: repaskdr{at}ucunix.san.uc.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is an inherited disease caused by progressive degeneration of the magnocellular neurons of the hypothalamus leading to decreased ability to produce the hormone arginine vasopressin (AVP). Affected individuals are not symptomatic at birth, but usually develop diabetes insipidus at 1–6 yr of age. The genetic locus of the disease is the AVP-neurophysin II (NPII) gene, and mutations that cause ADNDI have been found in both the signal peptide of the prepro-AVP-NPII precursor and within NPII itself. An affected girl who presented at 9 months of age and her similarly affected younger brother and father were all found to have a novel missense mutation (G1758->T) encoding the amino acid substitution Gly23->Val within NPII. The mutation was confirmed by restriction endonuclease analysis. A T1-weighted magnetic resonance imaging of the father’s pituitary gland demonstrates an attenuated posterior pituitary bright spot. This mutation may be valuable for developing models of dominantly inherited neurodegeneration, as the early age of onset of symptoms suggests that this mutation may be particularly deleterious to the magnocellular neuron.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AUTOSOMAL dominant neurohypophyseal diabetes insipidus (ADNDI) is an inherited deficiency of the peptide hormone arginine vasopressin (AVP). Affected individuals are normal at birth, but become symptomatic with polyuria and polydipsia typically at 1–6 yr of age due to progressive AVP deficiency (1, 2, 3). Most inherited hormone deficiencies are transmitted as an autosomal recessive trait, as the presence of one normal allele can generate enough hormone to maintain normal function. It has been postulated that in ADNDI the dominant inheritance results from progressive neurological degeneration of the hypothalamic magnocellular neurons that produce circulating AVP (3, 4). The genetic locus of ADNDI is the 2.5-kilobase AVP-neurophysin II (NPII) gene located on chromosome 20p13 (5, 6). This gene produces a preproprecursor peptide that comprises a signal peptide and the nine-amino acid AVP peptide (encoded in exon I), the AVP-binding protein NPII (partially encoded in each of exons I, II, and III), and copeptin, a glycopeptide of unproved function (encoded in exon III) (7). The precursor polypeptide is produced in magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus, where processing is initiated with removal of the signal peptide and subsequent glycosylation and folding of the propeptide. Successful folding places the AVP portion of the precursor into the NPII binding pocket, which promotes dimerization and facilitates packaging into neurosecretory granules (8, 9). The three product polypeptides are cleaved from one another within neurosecretory granules during axonal transport to the posterior pituitary (10). These neurosecretory granules have been postulated to generate the high intensity bright spot in T1-weighted magnetic resonance images (MRI) of the posterior pituitary in normal individuals (11, 12, 13, 14).

Affected members of ADNDI families have been found to be heterozygous for mutations in the AVP-NPII gene. Four different ADNDI mutations have been described that encode changes in the signal peptide that theoretically and/or in vitro decrease the ability of signal peptidase to remove the signal peptide from the precursor polypeptide (2, 15, 16, 17, 18). One missense mutation within the vasopressin-coding sequence (19) and 12 missense mutations, 1 deletion, and 5 nonsense mutations within the coding sequence of the 93 amino acids of NPII, have also been described to cause ADNDI (17, 20, 21, 22, 23, 24, 25). ADNDI mutations have been postulated to cause alterations in processing and folding of the precursor and/or abnormality of binding of AVP to NPII. Determination of the mechanism by which these dominant mutations lead to degeneration of hypothalamic neurons may provide insight into mechanisms of other neurodegenerative diseases. Here we report a missense mutation that falls within the coding sequence for NPII that causes ADNDI with early onset and, therefore, may represent a mutation with particularly detrimental effects on the hypothalamic magnocellular neurons.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

An Italian family with inherited diabetes insipidus was identified. The index case is a 4-yr-old girl who presented at 1 yr and 1 month of age with a 4-month history of polyuria and polydipsia, including the necessity to wake at least three times per night to drink water. In a water deprivation test, her peak plasma osmolality rose to 288 mosmol/kg, but her urinary osmolality rose only to 302 mosmol/kg. One month later, her urine osmolality rose from 157 to 609 mosmol/kg in response to desmopressin challenge. Her father also was diagnosed with central diabetes insipidus, with onset at 9 months of age, and a younger brother recently became symptomatic at 10 months of age. Her mother is clinically unaffected. This study is approved by the institutional review board, and informed consent was obtained from the subjects or legal representative.

Nucleotide sequences of exons of AVP-NPII gene

Genomic DNA was isolated from peripheral blood leukocytes (26). Each of the three exons of the AVP-NPII gene was amplified by PCR in 10% dimethylsulfoxide, and the nucleotide sequence of both strands of the PCR products was determined directly by thermocycle sequencing as previously described (23).

Restriction endonuclease analysis to confirm mutations

Exon II of the AVP-NPII gene was amplified by PCR as described for nucleotide sequencing. The PCR product was agarose gel purified and digested with restriction endonuclease ApaI, according to the manufacturer’s recommendations. Digestion products were visualized after electrophoresis in a 3% NuSieve (FMC Bioproducts, Rockland, ME) gel and staining with ethidium bromide as previously described (4).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The AVP-NPII gene from the affected father and that from a normal unrelated subject were evaluated. Each of the three exons of the AVP-NPII gene was amplified by PCR, and the nucleotide sequences of both coding and noncoding DNA strands were determined. The father’s genomic DNA revealed the normal nucleotide sequence plus the presence of a single transversion mutation of a T for a G at nucleotide 1758 (7) in exon II (Fig. 1Go). This mutation encodes the substitution of valine for glycine at amino acid 23 of NPII. To confirm the presence of this single point mutation in the affected family members, restriction endonuclease digestion of PCR-amplified exon II was performed in all four family members (Fig. 2Go). There is a single ApaI endonuclease restriction site in the normal 304-bp exon II PCR product at nucleotides 1757–1762. The mutation alters this restriction site and should eliminate cleavage of the PCR product by ApaI. As predicted, agarose gel electrophoresis of ApaI-digested exon II PCR product revealed only the normal 114- and 190-bp digestion products in the unaffected mother. The affected girl and her affected father and brother all have these same fragments from their normal AVP-NPII allele as well as the presence of an undigested 304-bp PCR product from the mutant allele. This confirms both the presence of the mutation and heterozygosity of the mutation, consistent with autosomal dominant inheritance.



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  		Figure 1. Heterozygous AVP-NPII gene mutation detected by DNA sequencing. Autoradiograms of DNA sequencing gels using an upstream sequencing primer and PCR-amplified exon II from a normal subject (left) and the affected father (right). The sequences of nucleotides 1751–1765 and the encoded NPII amino acids 21–25 are indicated.

 


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  		Figure 2. Confirmation of mutation by restriction endonuclease digestion. Genomic DNA from the affected father (closed square), the unaffected mother (open circle), and the affected daughter (closed circle), and son (closed square) was used as a template for PCR amplification of exon II of the AVP-NPII gene. Exon II was amplified to yield a 304-bp product that normally has one ApaI restriction site. Half of the PCR product was digested with restriction endonuclease ApaI (+ lanes), and the other half was left undigested (- lanes). Digestion of normal exon II with ApaI yields only 190- and 114-bp fragments, as seen in the unaffected mother. The presence of the mutation predicts ablation of the ApaI site on one chromosome. The restriction digests from the affected family members yield 190-, 114-, and intact 304-bp fragments, confirming heterozygosity for the loss of the ApaI site.

 
A T1-weighted MRI scan of the father’s brain reveals a posterior pituitary bright spot that is both small and less intense than the marrow fat of the adjoining dorsum sellae on both sagittal and coronal images (Fig. 3Go).



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  		Figure 3. MRI of hypothalamus and pituitary of affected father. Left, Sagittal image with a small bright spot in the posterior pituitary. The signal intensity is greater than that in the anterior pituitary, but less intense than that in the marrow of the dorsum sellae. Right, Coronal image, with arrow indicating the posterior pituitary bright spot. These uncontrasted T1-weighted images were acquired with a 1.5T magnet and parameters TR = 310, TE = 15, four signal averages, and 3-mm slice thickness.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
ADNDI is not clinically manifest at birth, but typically first produces symptoms of vasopressin deficiency at 1–6 yr of age. The absence of symptoms in early life suggests that one or both AVP-NPII genes initially allow the production of sufficient AVP to generate an adequate antidiuretic response. This is in contrast to nephrogenic diabetes insipidus, which is associated with severe symptoms and complications of diabetes insipidus from birth (27, 28). Progressive development of clinical and biochemical vasopressin deficiency (1, 2) and autopsy findings of magnocellular neuron degeneration in symptomatic individuals (4, 29, 30, 31) suggest that the pathophysiology of ADNDI is a progressive postnatal degeneration of the magnocellular neurons that produce AVP.

The four signal peptide mutations that cause ADNDI have been shown in vitro or in theory to decrease the ability of signal peptidase to initiate proper processing of the prepro-AVP-NPII by removal of the signal peptide (15, 32, 33). An accumulation of abnormally processed precursor may be hypothesized to lead to the degenerative changes in hypothalamic nuclei that occur in ADNDI. A second class of mutations that cause ADNDI occur within the AVP or amino-terminal domain of the NPII-coding sequence. Interestingly, these cause disease that is clinically indistinguishable from that associated with signal peptide mutations and, therefore, might also involve a misprocessing or misfolding of the precursor. These mutations all involve amino acids involved in binding of AVP to NPII. The first three amino acids of AVP enter the binding site of NPII, with Cys1 of AVP forming a strong salt bridge with Glu47 of NPII and with hydrogen bonding to Leu50 and Ser52 (34). Tyr2 tightly binds to both apolar and hydrogen bond interactions involving Cys10, Cys21, Phe22, Gly23, Pro24, Cys44, Glu47, Asn48, and Cys54 (34). AVP has additional interactions with Leu50, Pro51, Ser52, and Cys54. Thus, the previously described mutations that alter Tyr2 of AVP and Gly14, Gly17, Arg20, Pro24, Glu47, and Leu50 of NPII as well as our newly described Gly23 substitution could all reasonably be expected to directly alter the binding of AVP to NPII or to disrupt the architecture of the NPII binding site. Proper binding of AVP to NPII is required for the subsequent establishment of the critical unstable disulfide Cys10-Cys54 that joins the amino and carboxyl domains of NPII and holds the molecule in its proper conformation (35, 36). Therefore, this cluster of mutations suggests one mechanism for development of ADNDI in which disruption of proper binding of AVP by NPII inhibits complete processing of the precursor (9, 36, 37, 38).

MRI studies of the posterior pituitary show a high intensity bright spot on T1-weighted images in prospective studies of normal individuals (11, 13). Most retrospective reviews of MRI scans from individuals without DI, being evaluated for neurological disease, also reveal the presence of a bright spot in all subjects (13, 39, 40, 41), although other studies have shown only 63–98% (14, 42, 43) incidence of the bright spot. The exact nature of the posterior bright spot remains a subject of investigation (44), but it appears to result from the presence of neurosecretory granules. Individuals with acquired forms of neurohypophyseal DI have been uniformly found to lack the posterior bright spot (14, 39, 41, 44, 45, 46, 47, 48, 49). However, patients with ADNDI have been reported to have a posterior bright spot absent (18, 24) or present (40) or to have mixed findings within one family (50). Bright spots tend to be absent in older patients with longer duration of symptomatic ADNDI. Our patient also has persistence of a small posterior bright spot consistent with the finding that some AVP (and/or OT)-containing neurosecretory granules may persist in the posterior pituitary long after the onset of significant symptoms.

ADNDI usually presents at 1–6 yr of age. This mutation encoding a Gly23->Val substitution within the binding pocket of NPII is associated with an unusually early age of onset of symptoms in this family. As additional families with this mutation are identified, it will be of interest to determine whether this mutation is particularly deleterious to the survival of AVP-producing magnocellular neurons and may be particularly valuable for further study of ADNDI as a model of a dominant neurodegenerative disease.


   Footnotes
 
1 This work was supported by funds from the Children’s Hospital and the Children’s Hospital Research Foundation (Cincinnati, OH). Back

Received November 11, 1996.

Revised June 4, 1997.

Accepted June 6, 1997.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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N. Beuret, J. Rutishauser, M. D. Bider, and M. Spiess
Mechanism of Endoplasmic Reticulum Retention of Mutant Vasopressin Precursor Caused by a Signal Peptide Truncation Associated with Diabetes Insipidus
J. Biol. Chem., July 2, 1999; 274(27): 18965 - 18972.
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F. D. Grant, A. Ahmadi, C. M. Hosley, and J. A. Majzoub
Two Novel Mutations of the Vasopressin Gene Associated with Familial Diabetes Insipidus and Identification of an Asymptomatic Carrier Infant
J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 3958 - 3964.
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