Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: AVP
SNOMEDCT: 45369008;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:3,082,556-3,084,724 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | Diabetes insipidus, neurohypophyseal | 125700 | Autosomal dominant | 3 |
The arginine vasopressin (AVP) gene encodes prepro-AVP, which consists of a signal peptide, AVP, neurophysin II (NPII), and a glycoprotein, copeptin (summary by Mahoney et al., 2002).
Land et al. (1982) sequenced a cDNA clone that encoded bovine arginine vasopressin-neurophysin II (AVP-NpII) precursor.
Sachs et al. (1969) suggested that arginine vasopressin and its corresponding neurophysin are synthesized in the form of a common precursor which is cleaved by proteolysis to yield the biologically functional peptides. Rats with hereditary diabetes insipidus are deficient in synthesis of both arginine vasopressin and one species of neurophysin (Sunde and Sokol, 1975). Both of the nonapeptide hormones arginine vasopressin and oxytocin (OXT; 167050) are synthesized in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus together with their respective 'carrier' proteins, the neurophysins (Brownstein et al., 1980). Vasopressin and oxytocin are produced by separate populations of magnocellular neurons in both nuclei. Together with the neurophysins they are packaged into neurosecretory vesicles and transported axonally to the nerve endings in the neurohypophysis, where they are either stored or secreted into the bloodstream. In addition to having 9 amino acids, each has a disulfide bond between the cysteines at positions 1 and 6. Ganz et al. (1989) provided evidence that the hormone regulates pH in the presence of bicarbonate by stimulating 3 acid-base transport systems.
Gabreels et al. (1998) showed 7B2 (173120) immunoreactivity in the supraoptic nucleus or the paraventricular nucleus in only 3 of 5 Prader-Willi syndrome (PWS) patients. In contrast with 5 other PWS patients, the neurons in the hypothalamic SON and PVN of the two 7B2-immunonegative PWS patients also failed to show any reaction using 2 antibodies directed against processed vasopressin (VP). On the other hand, even these 2 cases reacted normally with 5 antibodies that recognize different parts of the VP precursor. This finding pointed to a processing defect. The same patients had no PC2 (162151) immunoreactivity in the SON or PVN, whereas PC1 (162150) immunoreactivity was only slightly diminished. The authors concluded that in the VP neurons of 2 PWS patients, the amounts of 7B2 and PC2 present are greatly reduced, resulting in diminished VP precursor processing.
The PVN and the SON in the rat contain estrogen-regulated oxytocin and arginine-vasopressin systems, but little or no estrogen receptor-alpha (133430). Using estradiol-treated ovariectomized young adult Sprague-Dawley rats and dual-labeled immunocytochemistry, Alves et al. (1998) showed that OXT-ir (OXT-immunoreactivity) colocalized with ESR-beta (601663)-ir in the parvicellular subnuclei of PVN but there was little AVP-/ESR-beta-ir. In contrast, in the SON, most nuclear ESR-beta-ir colocalized with AVP-ir, whereas few OXT-/ESR-beta-ir dual-labeled cells were observed. These results suggested that estrogen can directly modulate specific OXT and AVP systems through an ESR-beta-mediated mechanism, in a tissue specific manner.
Growth hormone (GH; 139250) secretagogues (GHSs) act via specific receptors in the hypothalamus and the pituitary gland to release GH (see 601898). GHSs also stimulate the hypothalamo-pituitary-adrenal (HPA) axis via central mechanisms probably involving corticotropin-releasing hormone (CRH; 122560) or AVP. Korbonits et al. (1999) studied the effects of the GHS hexarelin, CRH, and desmopressin, an AVP analog, on stimulation of the HPA axis in 15 healthy young male volunteers. They concluded that the effect of GHSs on the HPA axis does not involve CRH, but may occur through the stimulation of AVP release.
Tobin et al. (2010) reported that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats, and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. Tobin et al. (2010) concluded that social information is processed in part by a vasopressin system intrinsic to the olfactory system.
Vasopressin is synthesized as a much larger precursor which includes--besides the hormone--its carrier protein, neurophysin, and a glycoprotein. The functional domains of the protein precursor are coded by 3 exons separated by 2 introns. The first exon encodes the hormone, the second most of the carrier protein, and the third the glycoprotein (summary by Schmale et al., 1984).
Sausville et al. (1985) found that the genes for prepro-arginine-vasopressin-neurophysin II (AVP) and prepro-oxytocin-neurophysin I (OXT; 167050) have a similar intron-exon structure, are linked (on chromosome 20) with 12 kb intervening DNA, and are transcribed from opposite DNA strands. In a human small cell lung cancer (182280) cell line, they found that the first but not the second strand was actively transcribed.
The structural gene for AVP was assigned to chromosome 20 by means of a gene probe in somatic cell hybrids (Riddell et al., 1985); the gene probe was for arginine vasopressin/neurophysin II.
By use of a RFLP located near the ARVP/OXT complex, Summar et al. (1990) accumulated linkage data showing that the AVP and OXT genes are located on the distal short arm of chromosome 20 about 15 cM toward the telomere from the D20S5 locus, which is located near the middle of the short arm of 20p12.21. Thus, the location of the gene can be stated as 20pter-p12.21. The mapping of the neighboring gene OXT to 20p13 by both isotopic and fluorescence in situ hybridization (Rao et al., 1992) means that AVP is also in band 20p13.
In the mouse, Marini et al. (1993) noted that Avp and Oxt are separated by only 3.5 kb of intergenic sequence. By interspecific backcross analysis, they mapped this pair of genes to mouse chromosome 2.
Ito et al. (1991) showed that central diabetes insipidus (125700) was caused by a gly57-to-ser substitution (192340.0001) of the AVP gene in 2 patients.
Rittig et al. (1996) identified 13 new mutations in the AVP gene in 17 unrelated kindreds with familial neurohypophyseal diabetes insipidus. They sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the site of mutation in each case. Four of the mutations had been described previously. There were 2 missense mutations that altered the cleavage region of the signal peptide, 7 missense mutations in exon 2, which codes for the conserved portion of the protein, 1 nonsense mutation in exon 2, and 3 nonsense mutations in exon 3. The affected individuals were heterozygous for the mutations as expected in this autosomal dominant disorder.
Repaske et al. (1996) examined the AVP gene in 3 unrelated kindreds with autosomal dominant neurohypophyseal diabetes insipidus. They identified 3 different mutations, each of which represented a recurrence of a previously described mutation. All 3 were transitions; 2 occurred in the NPII moiety and 1 in the last amino acid at the C terminus of the signal peptide. To determine if these apparent recurrent mutations arose independently rather than from ancestral founder mutations, Repaske et al. (1996) examined family origins, polymorphic markers on chromosome 20 in close proximity to AVP, and/or the occurrence of a de novo mutation in these 3 families and compared the data to 4 previously reported families. The results suggested that the mutations probably arose independently in 2 of the 3 families but that 1 family may share an ancestral founder mutation with a previously reported family.
Christensen et al. (2004) screened for mutations in the AVP gene in 1 or more affected members of 15 unrelated kindreds in which diabetes insipidus appeared to be segregating. In each of 6 kindreds, they identified a unique novel mutation, 2 in the translation initiation codon of the AVP pre-prohormone signal peptide and 4 that predict substitutions in the NPII moiety of the AVP prohormone. In the other 9 kindreds, 7 different previously described mutations were identified. Christensen et al. (2004) suggested that mutations in the AVP gene causing familial central diabetes insipidus affect amino acid residues known or presumed to be important for the proper folding and/or dimerization of the NPII moiety of the AVP prohormone.
Ito et al. (1997) expressed wildtype and different mutant AVP genes in neuro2A neuroblastoma cells. When cells were treated with valproic acid to induce neuronal differentiation, each of the mutants caused reduced viability. Metabolic labeling revealed diminished intracellular trafficking of mutant AVP precursors and confirmed inefficient secretion of immunoreactive AVP. Immunofluorescence studies demonstrated marked accumulation of mutant AVP precursors within the endoplasmic reticulum. These studies suggested that the cellular toxicity in familial neurohypophyseal diabetes insipidus may be caused by the intracellular accumulation of mutant precursor proteins.
To elucidate the mechanism of neurohypophyseal diabetes insipidus, Nijenhuis et al. (1999) stably expressed 5 vasopressin prohormones with a mutation in the neurophysin moiety in 2 neuroendocrine cell lines. The mutations studied included G57S (192340.0001) and G65V (192340.0008). Metabolic labeling demonstrated that the processing and secretion of all 5 mutants was impaired, albeit to different extents, the impairment being greatest in G65V and least in G57S. Persisting endoglycosidase H sensitivity showed that these defects were associated with retention of mutant prohormone in the endoplasmic reticulum. Mutant prohormones that partially passed the endoplasmic reticulum were normally targeted to the regulated secretory pathway. This also included mutants with mutations in residues involved in binding of vasopressin to neurophysin, a process implicated in targeting of the prohormone. To mimic the high expression in vasopressin-producing neurons, mutant vasopressin prohormones were transiently expressed in one of the 2 neuroendocrine cell lines. Immunofluorescence displayed formation of large accumulations of mutant prohormone in the endoplasmic reticulum, accompanied by redistribution of an endoplasmic reticulum marker. The data suggested that prolonged perturbation of the endoplasmic reticulum eventually leads to degeneration of neurons expressing mutant vasopressin prohormones, explaining the dominant nature of the disease.
Christensen et al. (2004) compared the cellular handling of the recessive P26L (see 192340.0016) and dominant Y21H (see 192340.0018) prohormones and demonstrated that the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. The authors determined that their results provided an important negative control in support of the hypothesis that autosomal dominant inheritance of familial neurohypophyseal diabetes insipidus is caused by mutations in the AVP gene that alter amino acids important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.
A single-nucleotide deletion is found in the second exon in the Brattleboro rat with diabetes insipidus (Schmale et al., 1984). Diabetes insipidus in the Brattleboro rat is autosomal recessive (Valtin et al., 1965); in man, a recessive form is probably a rarity (see 125800). In studies of the homozygous (di/di) Brattleboro rat with severe diabetes insipidus, Evans et al. (1994) found evidence indicating that nondividing neurons can be subject to somatic mutations at high frequency. They reported specific frameshift mutations occurring in postmitotic neurons. The mutations were identified in vasopressin transcripts in magnocellular neurons of the homozygous rats and consisted predominantly of a GA deletion in GAGAG motifs. Immunocytochemistry provided evidence for similar events in wildtype rats. However, the diseased state of the Brattleboro rat, resulting in a permanent activation of vasopressin neurons, enhanced the mutation rate.
In Alzheimer disease (AD; 104300) and Down syndrome (190685) patients, van Leeuwen et al. (1998) demonstrated the cellular colocalization of truncated forms of ubiquitin-B (UBB; 191339) and beta-amyloid precursor protein (APP; 104760) and involvement with a similar type of mutation operating at the transcriptional level or by posttranscriptional editing of RNA. They suggested that transcript mutation may be a widely occurring phenomenon. The frequently mutated motif in exon 9 of the APP gene transcript (GAGAGAGA) is an extended version of the GAGAG motif of the AVP transcript that is frequently involved in a GA dinucleotide deletion in the homozygous Brattleboro rat.
In 2 patients with central diabetes insipidus (125700) from a pedigree consistent with autosomal dominant inheritance, Ito et al. (1991) used PCR to amplify fragments including the promoter region and all coding regions from genomic DNA. Direct sequencing showed that 1 of the 2 ARVP genes contained a G-to-A transition at nucleotide 1859 in the second exon, resulting in substitution of serine for glycine at amino acid position 57 in the neurophysin II moiety of the gene. Ito et al. (1991) also sequenced the AVP-NPII gene in 10 patients with idiopathic central diabetes insipidus, of whom 5 had juvenile onset. No difference in sequence was found compared with normal subjects. Autoimmunity has been proposed as one cause of idiopathic diabetes insipidus (Scherbaum and Bottazzo, 1983).
In a Dutch family in which autosomal dominant diabetes insipidus (125700) could be traced back for 5 generations, Bahnsen et al. (1992) identified a G-to-T transversion within the neurophysin-encoding exon B, which converted a highly conserved glycine (gly17 of neurophysin) to a valine residue.
Olias et al. (1996) examined whether this point mutation affects the processing and transport of the vasopressin-neurophysin precursor. They stably expressed the normal and mutant vasopressin cDNAs under the control of the cytomegalovirus promoter in the mouse pituitary cell line AtT20. The mutant precursor was synthesized, but processing and secretion were dramatically reduced compared to the normal. The mutant neurophysin staining was restricted to the endoplasmic reticulum and never reached the trans-Golgi network, whereas the normal neurophysin concentrated in the tips of the cell processes where secretory granules accumulate. These results suggested that the mutation alters the conformation of the precursor, impairs its intracellular transport, and triggers its retention.
In 23 individuals with central diabetes insipidus (125700) spanning 4 generations of a Japanese family, Ito et al. (1993) discovered a G-to-A transition at nucleotide 279 in exon 1 of the ARVP gene, causing substitution of thr (ACG) for ala (GCG) at -1 position (A-1T), the carboxy end, of the signal peptide of prepro-VP. They suggested that insufficient processing of prepro-VP produced by the mutant allele is involved in the pathogenesis of diabetes insipidus in this family. A similar defect in cleavage by signal peptidase occurs in factor X (Santo Domingo) with resulting bleeding diathesis (613872.0005). Similarly, a point mutation in the signal peptide-encoding region of the PTH gene has been demonstrated as the cause of familial isolated hypoparathyroidism (168450.0001). Precisely the same mutation was found by McLeod et al. (1993) in a Caucasian American kindred with 14 affected members. The mutation was also found in 2 infants in whom AVP was normal when tested at 6 and 9 months of age. This led McLeod et al. (1993) to hypothesize that a mutation in exon 1 of the AVP-neurophysin-II gene causes neurohypophyseal diabetes insipidus by making an abnormally processed precursor that gradually destroys vasopressinergic neurons. Krishnamani et al. (1993) found the same mutation in 15 members of a 4-generation family, some members of which were reported by Doherty-Fuller and Copeland (1988).
Siggaard et al. (1999) carried out genetic analysis and clinical studies of AVP secretion, urinary AVP, and urine output in 16 affected and 16 unaffected family members and 11 spouses of a Danish kindred with neurohypophyseal diabetes insipidus who carried the A-1T mutation. Mutant cDNA carrying the same mutation was expressed in a neurogenic cell line, and the cellular effects were studied by Western blot analysis, immunocytochemistry, and AVP measurements. Clinical studies showed a severe progressive deficiency of plasma and urinary AVP that manifested during childhood. Expression studies demonstrated that the A-1T mutant cells produced 8-fold less AVP than wildtype cells and accumulated excessive amounts of 23-kD NPII protein corresponding to uncleaved prepro-AVP-NPII. Furthermore, a substantial portion of the intracellular AVP-NPII precursor appeared to be colocalized with an endoplasmic reticulum antigen (Grp78). The authors concluded that the A-1T mutation produces neurohypophyseal diabetes insipidus by directing the production of a mutant preprohormone that accumulates in the endoplasmic reticulum, because it cannot be cleaved from the signal peptide and transported to neurosecretory vesicles for further processing and secretion.
In a family with central diabetes insipidus (125700) in an autosomal dominant pedigree pattern, Yuasa et al. (1993) demonstrated a 3-bp deletion (AGG) out of 2 consecutive AGG sequences (nucleotides 1824-1829) in 1 AVP allele. Cosegregation of the mutation with the DI phenotype in the family was confirmed by restriction enzyme analyses. The mutation was predicted to yield an abnormal AVP precursor lacking glu47 (E47) in its neurophysin-II moiety. Since glu47 (E47) is essential for NP molecules to form a salt bridge with AVP, the function of NP as a carrier protein for AVP would be impaired. As a result, AVP probably undergoes accelerated proteolytic degradation.
To determine whether the clinical course of autosomal dominant NDI is compatible with the hypothesis that the neuropathologic findings are attributable to a progressive loss of magnocellular neurons beginning in early life, Mahoney et al. (2002) performed posterior pituitary magnetic resonance imaging (MRI) and water deprivation tests, including plasma adrenocorticotropin (ACTH) measurements, on 17 affected members of a kindred with the delta-E47 neurophysin mutation whose ages ranged from 3 months to 54 years. Nine adult unaffected members aged 20 to 56 years underwent these tests as controls. All 6 children undergoing MRI demonstrated a posterior pituitary hyperintense signal (PPHS). Eight of 9 affected adults showed an absent or barely visible PPHS, whereas 8 of 9 age-matched unaffected adults produced a normal size PPHS. During water deprivation tests, infants concentrated their urine normally, and a 3-month-old infant produced a high plasma AVP level of 15.7 pmol/liter. By school age, affected children were no longer able to concentrate their urine or prevent hypernatremia. Affected adults became dehydrated; their median plasma AVP level was less than 1.0 pmol/liter, but their median fasting plasma ACTH was 2-fold greater than the level of unaffected adults (10.0 vs 5.0 pmol/liter; P = 0.008). The authors concluded that autosomal dominant NDI is a progressive disease associated with chronic loss of the magnocellular neurons that supply AVP to the posterior pituitary but preservation of the parvocellular neurons that supply AVP and corticotropin-releasing hormone (CRH; 122560) to the median eminence and stimulate ACTH production during hypernatremia.
In a Japanese pedigree with familial central diabetes insipidus (125700), Nagasaki et al. (1995) demonstrated a TGC-to-TGA transition at nucleotide position 1891 that generated a cys67-to-ter (C67X) change. As the premature termination eliminated part of the COOH domain of the NPII moiety and the glycoprotein moiety, the conformation of the protein was probably markedly changed. A history of diabetes insipidus was obtained in 3 members of the family spanning 3 generations.
Russell et al. (2003) established a murine knockin model of the human C67X mutation. Heterozygous mice exhibited polyuria and polydipsia by 2 months of age, and these features of diabetes insipidus progressively worsened with age. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of wildtype and mutant AVP precursors within the cell bodies. This murine model recapitulated many features of the human disorder and demonstrated that expression of the mutant AVP precursor leads to progressive neuronal cell loss, a 'dominant-negative' effect.
In a Japanese kindred with familial central diabetes insipidus (125700), Nagasaki et al. (1995) identified a G-to-T transversion at nucleotide 1874 of AVP which substituted polar trp (TGG) for hydrophobic gly62 (GGG). Symptoms of diabetes insipidus were present in 10 members of the family spanning 3 generations.
Rutishauser et al. (1996) identified a novel single base deletion (G227) in the translation initiation codon of the AVP signal peptide in a 3-generation kindred with familial neurohypophyseal diabetes insipidus (125700). The mutation deletes nucleotide 227, the third base of the initiation codon (ATG), and this may cause alternative use of an ATG which is 4 triplets downstream. Magnetic resonance imaging (MRI) studies showed the 'bright spot' that is characteristic of the posterior pituitary in 2 unaffected family members whereas this was absent in all 4 affected family members studied. This absence may reflect the deficient posterior pituitary function.
In a Japanese family with familial neurohypophyseal diabetes insipidus (125700), Ueta et al. (1996) found a G-to-T transversion of nucleotide 1884 in exon 2, resulting in a gly65-to-val substitution in the AVP gene. (Note: the authors stated incorrectly in the abstract that the substitution was 'glycine (Gly) for valine (Val)'.) To examine the presence of this mutation in affected subjects, they designed 2 mutated primers: by PCR amplification, 1 of the primers induced a new endonuclease restriction site in the PCR fragment from normal persons, while the other induced a different endonuclease restriction site from patients with the mutation. Subsequently, restriction analysis of PCR fragments and sequencing of genomic DNA indicated that affected subjects were heterozygous for normal and mutant alleles.
Repaske et al. (1997) identified a C-to-T transition in exon 1 of the AVP gene causing an ala280-to-val substitution in the coding sequence for the C terminus of the signal peptide (-1 amino acid) of the prepro-AVP-NPII precursor in 2 independent families with autosomal dominant neurohypophyseal diabetes insipidus (125700). This mutation predicts the complete inability of signal peptidase to cleave the signal peptide from the preproprecursor and supports the hypothesis that the progressive neurodegeneration that underlies neurohypophyseal diabetes insipidus is caused by accumulation of malprocessed precursor. Considerable heterogeneity in the age of onset (1 to 28 years of age) and the severity of diabetes insipidus among affected members of these 2 families suggested that additional factors modulate the rate and extent of progression of the neurodegeneration that results from this specific mutation.
Heppner et al. (1998) found the same mutation in 2 children of an affected father. Both children had onset of symptoms by 1 year of age.
In a girl with familial central diabetes insipidus (125700) who presented at 9 months of age, and in her similarly affected younger brother and father, Gagliardi et al. (1997) identified a 1758G-T transversion in the AVP gene, resulting in a gly23-to-val substitution in NPII. T1-weighted magnetic resonance imaging of the father's pituitary gland showed an attenuated posterior pituitary bright spot. The authors concluded that studies of this mutation may be useful in developing models of dominantly inherited neurodegeneration because the early age of onset of symptoms suggests that this mutation may be particularly deleterious to the magnocellular neuron.
In all affected individuals of a Spanish kindred with familial neurohypophyseal diabetes insipidus, Calvo et al. (1999) identified heterozygosity for a G-to-A transition at nucleotide 1757 of the AVP gene, resulting in a gly23-to-arg substitution in the NPII domain. The substitution was confirmed by restriction endonuclease analysis. Additionally, one of the asymptomatic relatives, an 8-month-old girl, was identified as being heterozygous for the same mutation and developed the disease 3 months later.
In a family with central diabetes insipidus (125700), Heppner et al. (1998) found a G-to-C change at nucleotide 1757, predicting the substitution of glycine by arginine at position 23. All 3 affected children who were studied developed polydipsia and polyuria at the age of 6 to 9 months, when treatment was started.
Calvo et al. (1998) analyzed 2 families with familial neurohypophyseal diabetes insipidus (125700). In 1 family, affected individuals had a novel nonsense mutation in exon 3 of the AVP gene, consisting in a G-to-T transversion at nucleotide 2101, which produces a stop signal in codon 82 (glu) of NPII. The premature termination eliminates part of the C-terminal domain of NPII, including a cysteine residue in position 85, which may be involved in correct folding of the prohormone. In the second family, heterozygosity for a 279G-A transition resulting in a change of alanine to threonine at position -1 of the signal peptide (192340.0003) was observed in all affected individuals.
Grant et al. (1998) identified 2 novel mutations of the AVP gene in 2 kindreds with familial diabetes insipidus (125700). In each kindred, the inheritance of the diabetes insipidus phenotype was consistent with an autosomal dominant mode of inheritance. The proband and 2 other members of 1 kindred were heterozygous for a C-to-T transition at nucleotide 1857, predicting a ser-to-phe substitution at residue 56 of the vasopressin-related neurophysin peptide encoded by the mutant allele. The proband of the other kindred was heterozygous for a G-to-A transition at nucleotide 1873, predicting a cys-to-tyr substitution at residue 61 (192340.0015) of the vasopressin-related neurophysin peptide encoded by the mutant allele.
See 192340.0014 and Grant et al. (1998).
In a consanguineous Palestinian family with neurohypophyseal diabetes insipidus (125700), Willcutts et al. (1999) identified a C-to-T transition at nucleotide 301 (C301T) in exon 1 of the AVP gene, replacing proline-7 of mature AVP with leucine (Leu-AVP). All 3 affected children were homozygous for the mutation, and the parents were heterozygous. The authors determined that Leu-AVP is a weak agonist with approximately 30-fold reduced binding to the human V2 receptor. Serum Leu-AVP levels were elevated in all 3 children and further increased during water deprivation to as high as 30 times normal, as measured by radioimmunoassay. The youngest child (2 years old) was only mildly affected, but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting to the authors that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children.
Christensen et al. (2004) investigated the cellular handling of the P26L prohormone (P7L in the mature AVP protein) by heterologous expression in neurogenic and neuronal cell lines. Secretion of P26L prohormone was unaffected compared to wildtype prohormone. Confocal laser scanning microscopy showed localization of the P26L prohormone and/or processed products in secretory granules in the cellular processes. Christensen et al. (2004) concluded that the recessive P26L mutation does not seem to affect intracellular trafficking but rather the final processing of the AVP prohormone.
In a Dutch family in which familial neurohypophyseal diabetes insipidus (125700) had been diagnosed, Abbes et al. (2000) identified a cysteine (TGC)-to-glycine (GGC) substitution at codon 116 of the AVP gene. Nijenhuis et al. (2001) analyzed the intracellular transport of the mutant vasopressin prohormone in stably transfected cell lines that contained a regulated secretory pathway. Nijenhuis et al. (2001) referred to the mutation as NP85C-G. In 2 children from this kindred they found that growth retardation was an important early sign that responded to substitution therapy with 1-desamino-8-D-arginine vasopressin. To obtain clues about the basis for the dominant inheritance of familial neurohypophyseal diabetes insipidus, they analyzed the trafficking and processing of the mutant vasopressin prohormone in cell lines by metabolic labeling and immunoprecipitation. The mutant vasopressin prohormone was retained in the endoplasmic reticulum and thus was not processed to vasopressin. The defect was not caused by dimerization of the vasopressin prohormone via its unpaired cysteine residue. High-level expression of the mutant vasopressin prohormone in cell lines resulted in strong accumulation in the endoplasmic reticulum and an altered morphology of this organelle. The authors hypothesized that disturbance of the endoplasmic reticulum results in dysfunction and ultimately cell death of the cells expressing the mutant prohormone.
Rittig et al. (2002) reported a 3-generation Turkish kindred in which severe familial neurohypophyseal diabetes insipidus (125700) cosegregated with a novel missense mutation in the part of the AVP-NPII gene encoding the AVP moiety. A heterozygous T-to-C transition at position 285 in the genomic sequence predicted a tyr2-to-his (Y2H) substitution. Like other mutations in the AVP gene that result in diabetes insipidus, this substitution was expected to impair folding and processing of the precursor, in this case by interfering with normal binding of the AVP and NPII moieties. It was 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.
Christensen et al. (2004) investigated the cellular handling of the Y21H prohormone (Y2H in the mature AVP protein) by heterologous expression in neurogenic and neuronal cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum.
In an Asian American family in which diabetes insipidus (125700) appeared to be segregating, Christensen et al. (2004) identified a 1797T-C transition in the AVP gene that predicted a val67-to-ala substitution (V67A). The authors noted that the mutation affects a region of NPII unaffected by known AVP mutations and produces only a minor change in the protein. They also noted that the inheritance pattern was atypical and suggested incomplete penetrance. The proband apparently inherited the disease through his affected mother, although allegedly neither of his maternal grandparents had a history of polyuria, but a brother of the maternal grandmother was affected.
In an American kindred with autosomal dominant neurohypophyseal diabetes insipidus (125700), Wahlstrom et al. (2004) identified deletion of 3 nucleotides in exon 1 of the AVP gene, either CTT or TTC, resulting in deletion of the phenylalanine at codon 3 (F3del). The index patient was a 78-year-old man noted to have hypotonic polyuria after a surgical procedure. He had experienced polyuria and polydipsia since childhood but had avoided medical attention by assiduously maintaining access to water at all times. His family had recognized that some members required large volumes of water, and to accommodate these individuals (known in the family as 'water dogs'), a number of extra wells had been dug on the family farm. Neuro 2A cells stably transfected with the mutant AVP-NP construct showed increased rates of apoptosis as assessed by flow cytometric methods. These observations supported the concept that cellular toxicity of abnormal AVP-NP gene products underlies the development of ADNDI, and the data further demonstrated that mutations affecting the AVP moiety can result in initiation of these pathologic processes.
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