Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial central diabetes insipidus is an autosomal dominant disease caused by a deficiency of arginine vasopressin (AVP). We previously reported three distinct mutations in the AVP gene in Japanese familial central diabetes insipidus pedigrees that result in a substitution of Ser for Gly57 in the neurophysin-II (NPII) moiety of the AVP precursor, a substitution of Thr for Ala at the COOH-terminus of the signal peptide, and a deletion of Glu47 in the NPII moiety. In this study, we analyzed the AVP gene in two pedigrees by direct sequencing of the polymerase chain reaction-amplified DNA and found two novel mutations in exon 2, which encodes the central part of the NPII moiety of the precursor. The mutation in one pedigree was a C to A transition at nucleotide position 1891, which replaces Cys67 (TGC) with stop codon (TGA). As the premature termination eliminates part of the COOH domain of the NPII moiety and the glycoprotein moiety, the conformation of the truncated protein is likely to be markedly different from that of normal precursor. In another pedigree, a G to T transversion was detected at nucleotide position 1874, which substitutes polar Trp (TGG) for hydrophobic Gly62 (GGG). It is possible that mutated NPII molecules, as a consequence of a conformational change, cannot bind AVP or self-associate to form higher oligomer complexes. Interestingly, all mutations we have identified to date, with the exception of the signal peptide mutation, are located in exon 2, suggesting the importance of the highly conserved central part of the NPII molecules and/or the NPII moiety in the precursor for AVP synthesis.
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PMID:Two novel mutations in the coding region for neurophysin-II associated with familial central diabetes insipidus. 771 10

The molecular basis of autosomal dominant neurohypophyseal diabetes insipidus, a hereditary deficiency of vasopressin, was determined by nucleotide sequence analysis of the arginine vasopressin-neurophysin-II gene. A C-->T mutation at nucleotide 1761 was detected in one allele of this gene in each affected individual in three generations of one family. This mutant gene encodes a normal arginine vasopressin peptide, but predicts a substitution of leucine for proline at amino acid 24 of neurophysin-II, the arginine vasopressin carrier protein. This mutation was not detected 50 control individuals, thus demonstrating that it is not a common silent genetic polymorphism. The disease arose in the second generation of the studied family, and the chromosome 20 carrying this new mutation was identified by polymorphic CA microsatellite haplotype analysis. The first affected individual inherited this chromosome segment from her mother, who had neither the disease nor this mutation in her somatic cell DNA. Third generation individuals who subsequently inherited this mutation were affected. These data demonstrate that this amino acid substitution in neurophysin-II causes the disease. Two possibilities to explain the mechanism by which clinical deficiency of arginine vasopressin develops even in the presence of one normal arginine vasopressin-neurophysin-II allele are discussed.
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PMID:A de novo mutation in the coding sequence for neurophysin-II (Pro24-->Leu) is associated with onset and transmission of autosomal dominant neurohypophyseal diabetes insipidus. 804 58

The arginine vasopressin (AVP) gene was sequenced in a pedigree with familial central diabetes insipidus (DI). When polymerase chain reaction-amplified DNAs from affected subjects were subjected to polyacrylamide gel electrophoresis, fragments including exon 2 displayed two additional, slower migrating bands. These extra bands represented DNA heteroduplexes, indicating that there was a deletion or insertion mutation in exon 2. As the region with such a mutation was identified by direct sequence analysis, polymerase chain reaction-amplified fragments including the region were subcloned and sequenced. A 3-basepair deletion (AGG) out of two consecutive AGG sequences (nucleotides 1824-1829) was identified in one of two alleles. The cosegregation of the mutation with the DI phenotype in the family was confirmed by restriction enzyme analyses. This mutation should yield an abnormal AVP precursor lacking Glu47 in its neurophysin-II (NP) moiety. Since Glu47 is essential for NP molecules to form a salt bridge with AVP, it is very likely that the function of NP as a carrier protein for AVP would be impaired. We suggest that AVP would undergo accelerated proteolytic degradation, and this mechanism would be involved in the pathogenesis of DI in this pedigree.
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PMID:Glu-47, which forms a salt bridge between neurophysin-II and arginine vasopressin, is deleted in patients with familial central diabetes insipidus. 837 Jun 80

In the homozygous Brattleboro rat (di/di) a single base deletion in the vasopressin (VP) gene causes diabetes insipidus, resulting in the synthesis of a VP precursor with a different C-terminus. We reported previously that a small number of post-mitotic VP neurons in di/di rats undergo a switch to a heterozygous phenotype, suggesting the existence of VP mRNAs with a restored reading frame coding for a normal VP precursor. In the present study we report that the increase in the number of these revertant cells declines after 79 weeks of age. Furthermore, we provide evidence that the neurophysin (NP) moiety in solitary neurons is different from normal NP. Comparing the immunoreactivities of two different NP antibodies we deduced that the restoration of the reading frame may take place downstream of the deletion between amino acids 75 and 93 of the VP-NP.
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PMID:Differential neurophysin immunoreactivities in solitary magnocellular neurons of the homozygous Brattleboro rat indicate an altered neurophysin moiety. 817 71

Recent progress in the diagnosis and treatment of diabetes insipidus (DI) is reviewed. Response of plasma vasopressin (AVP) to 5% hypertonic saline can be a new indicator of the capacity of AVP response to osmotic stimuli. Marked progress in the imaging analysis by computed tomography and magnetic resonance imaging (MRI) has made it possible to evaluate hypothalamic-pituitary lesions in detail. Especially, signal intensity on T1-weighted MR image of neurohypophysis is suggested to reflect its function. Sequencing analysis of genes encoding AVP-neurophysin precursor or AVP receptor is expected to be a most useful method for the diagnosis of inherited DI. Intranasal administration of DDAVP (1-deamino-8-D-AVP) is recommended as a standard therapy for DI.
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PMID:[Recent progress in the diagnosis and treatment of diabetes insipidus]. 825 49

We studied the pathophysiology, natural history, and genetic basis of familial neurohypophyseal diabetes insipidus (FNDI) in a caucasian kindred. Twelve members had polyuria and a deficiency of plasma vasopressin (AVP), which progressed in severity over time. Another had normal urine volumes and plasma AVP when first tested at age 3 yr, but developed severe FNDI a year later. For unknown reasons, one man had a normal urine volume despite severe AVP deficiency and a history of polyuria in the past. When the AVP-neurophysin-II gene was amplified and sequenced, exon 2/3 was normal, but 7 of 12 clones of exon 1 contained a base substitution (G-->A) predicting a substitution of threonine for alanine at the -1 position of the signal peptide. Restriction analysis found the mutation in all 14 affected members, but in none of the 41 controls or 19 adult members with normal urine volumes and plasma or urinary AVP (lod score = 5.7). The mutation was also found in 2 infants in whom AVP was normal when tested at 6 and 9 months of age. We hypothesize that a mutation in exon 1 of the AVP-neurophysin-II gene causes FNDI in this kindred by making an abnormally processed precursor that gradually destroys vasopressinergic neurons.
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PMID:Familial neurohypophyseal diabetes insipidus associated with a signal peptide mutation. 837 Jun 80

Neurophysin is an allosteric protein in which peptide binding and self-association are positively linked. Reaction of neurophysin with succinic anhydride led to a large decrease in peptide affinity assignable to succinylation of a serine or threonine hydroxyl group. To identify the residue involved, acetimidated protein was reacted with [14C]succinic anhydride and the active and inactive components were separated by affinity chromatography. Performic acid oxidation and tryptic and Asp-N mapping of the two components, followed by automated Edman degradation, allowed identification of the critical residue as Ser-56. This residue is not a direct participant in peptide binding and is distant from the subunit interface of the dimer, but it is immediately adjacent to the site of one of the known mutations associated with familial diabetes insipidus. Examination in solution of the peptide affinity of neurophysin succinylated at Ser-56 indicated a binding affinity approximately 1/20th that of the native protein or of protein succinylated at other residues, and a loss of the normal dependence of binding affinity on protein concentration. Under the same buffer conditions, loss of the concentration dependence of binding, in addition to the previously demonstrated loss of binding affinity, also accompanied excision of residues 1-8, an effect attributed to the loss of binding site residue Arg-8. However, in contrast to the effects of succinylation on native neurophysin, only minor effects of succinylation on the binding affinity of the des-1-8 protein were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of allosteric interactions in neurophysin induced by succinylation of serine-56 or cleavage of residues 1-8. 839 21

The human hypothalamus is involved in a wide range of functions in the developing, adult and aging subject and is responsible for a large number of symptoms of neuroendocrine, neurological and psychiatric diseases. In the present review some prominent hypothalamic nuclei are discussed in relation to normal development, sexual differentiation, aging and a number of neuropathological conditions. The suprachiasmatic nucleus, the clock of the brain, shows seasonal and circadian variations in its vasopressin neurons. During normal aging, but even more so in Alzheimer's disease, the number of these neurons decreases. In homosexual men this nucleus is larger than in heterosexual men. The difference between the sexually dimorphic nuclei of men and women arises between the ages of 2-4 to puberty. In adult men this nucleus is twice as large as in adult women. In the process of aging, a sex-dependent decrease in cell number occurs. The vasopressin and oxytocin cells of the supraoptic and paraventricular nucleus are present in adult numbers as early as mid-gestation. Lower oxytocin neuron numbers are found in Prader-Willi syndrome, AIDS and Parkinson's disease. Familial hypothalamic diabetes insipidus is based upon a point mutation in the vasopressin-neurophysin-glycopeptide gene. Parvicellular corticotropin-releasing hormone-containing neurons in the paraventricular nucleus increase in number and are activated during the course of aging. In post-menopausal women, the infundibular or arcuate nucleus contains hypertrophic neurons containing oestrogen receptors. These neurons may be involved in the initiation of menopausal flushes. The nucleus tuberalis lateralis may be involved in feeding behaviour and metabolism. In Huntington's disease the majority of its neurons is lost; in Alzheimer's disease it shows very strong cytoskeletal alterations. Tuberomammillary nucleus neurons contain, e.g., histamine or galanine, and project to the cortex. Strong cytoskeletal changes, as well as plaques and tangles are found in this nucleus in Alzheimer's disease. The various hypothalamic nuclei are probably involved in many functions and symptoms of which only a minority has been revealed.
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PMID:Functional neuroanatomy and neuropathology of the human hypothalamus. 851 84

Surgical pituitary stalk compression (PSC) causes neural lobe denervation and development of ectopic magnocellular terminals in the external zone of the median eminence, resulting in shunting of magnocellular vasopressin (VP) and oxytocin (OT) to the pituitary portal circulation. To determine the effects of PSC on hypothalamic and pituitary function, VP and CRH receptors and POMC messenger RNA (mRNA) in the pituitary, and CRH, VP, and OT mRNA levels in the PVN were examined in 7-day PSC and sham-operated rats. Immunohistochemical staining revealed marked accumulation of immunoreactive VP in the swollen pituitary stalk and the external zone of the distal median eminence of PSC rats. Plasma ACTH and corticosterone levels were significantly increased by PSC, an effect that was attenuated by minipump infusion of desamino-[D-Arg8]-vasopressin (DDAVP) given to correct the diabetes insipidus. [3H]VP binding to anterior pituitary membranes from PSC rats was reduced by 50% compared to that in sham-operated controls, but VP V1b receptor mRNA levels measured by in situ hybridization were unchanged. Pituitary CRH receptors measured by binding autoradiography and CRH receptor mRNA levels did not change after PSC. POMC mRNA was unchanged in the anterior pituitary lobe, but markedly increased in the intermediate lobe of PSC rats, with or without DDAVP infusion. In the hypothalamic supraoptic and paraventricular nuclei, PSC resulted in reduction of VP mRNA (-83%) and OT mRNA (-38%) levels, probably reflecting retrograde degeneration of magnocellular neurons. This decrease was more pronounced for VP mRNA than for OT mRNA CRH mRNA levels in parvicellular cells of the paraventricular nuclei of PSC rats were reduced by 55%. Correction of the diabetes insipidus by DDAVP treatment further decreased hypothalamic VP mRNA levels, but restored CRH mRNA to control levels. The data show that continuous exposure of the pituitary to high VP levels from ectopic magnocellular fibers in the median eminence results in VP, but not CRH, receptor loss. Pituitary VP receptor down-regulation and decreased hypothalamic CRH expression are likely to contribute to the reduced corticotroph responsiveness to VP reported in this experimental model.
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PMID:Hypothalamic-pituitary corticotroph function after shunting of magnocellular vasopressin and oxytocin to the hypophyseal portal circulation. 859 5

Constitutive nitric oxide synthase (cNOS) was immunolocalized to study its role in osmotic regulation. Immunoreactivity was observed in all major hypothalamic osmoregulatory structures, the organum vasculosum laminae terminalis, subfornical organ, median preoptic nucleus, and supraoptic and paraventricular nuclei. These nuclei were compared in normal Long-Evans rats and homozygous Brattleboro rats with hereditary hypothalamic diabetes insipidus and in normal mice and mice with hereditary nephrogenic diabetes insipidus. About 50% of supraoptic neurons in Long-Evans rats and 90% in Brattleboro rats were cNOS immunopositive; a qualitatively similar difference occurred in the paraventricular nucleus. Mice with hereditary nephrogenic diabetes insipidus also showed a greater proportion of cNOS-positive supraoptic neurons (50%) than normal mice (20%). However, the number of cNOS-positive cells in the organum vasculosum laminae terminalis, subfornical organ, and median preoptic nucleus dis not differ significantly between diabetic and normal animals. The similar changes in cNOS in two mutant strains in which the only common feature is chronic osmotic stimulation shows that differences in vasopressin and oxytocin are not involved in the regulation of cNOS. The results suggest strongly that cNOS is involved in long term modulation of the hypothalamo-neurohypophysial system and, hence, body water and electrolyte homeostasis, and that cNOS is itself regulated by body osmotic status.
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PMID:Constitutive nitric oxide synthase in hypothalami of normal and hereditary diabetes insipidus rats and mice: role of nitric oxide in osmotic regulation and its mechanism. 861 10


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