Autosomal dominant neurohypophyseal diabetes insipidus in a Swiss family, caused by a novel mutation (C59Delta/A60W) in the neurophysin moiety of prepro-vasopressin-neurophysin II (AVP-NP II).
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OBJECTIVE: To study clinical, morphological and molecular characteristics in a Swiss family with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). PARTICIPANTS AND METHODS: A 15-month-old girl presenting with symptoms of polydipsia and polyuria was investigated by water deprivation test. Evaluation of the family revealed three further family members with symptomatic vasopressin-deficient diabetes insipidus. T1-weighted magnetic resonance images of the posterior pituitary were taken in two affected adult family members and molecular genetic analysis was performed in all affected individuals. RESULTS: The water deprivation test in the 15-month-old child confirmed the diagnosis of vasopressin-deficient diabetes insipidus and the pedigree was consistent with autosomal dominant inheritance. The characteristic bright spot of the normal vasopressin-containing neurophypophysis was absent in both adults with adFNDI. Direct sequence analysis revealed a new deletion (177-179DeltaCGC) in exon 2 of the AVP-NP II gene in all affected individuals. At the amino acid level, this deletion eliminates cysteine 59 (C59Delta) and substitutes alanine 60 by tryptophan (A60W) in the AVP-NP II precursor; interestingly, the remainder of the reading frame remains unchanged. According to the three-dimensional structure of neurophysin, C59 is involved in a disulphide bond with C65. CONCLUSIONS: Deletion of C59 and substitution of A60W in the AVP-NP II precursor is predicted to disrupt one of the seven disulphide bridges required for correct folding of the neurophysin moiety and thus disturb the function of neurophysin as the vasopressin transport protein. These data are in line with the clinical and morphological findings in the reported family with adFNDI. (+info)
Hyperintensity of posterior pituitary on MR T1WI in a boy with central diabetes insipidus caused by missense mutation of neurophysin II gene.
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We present a 10-year old boy with central diabetes insipidus (CDI) showing hyperintensity in a normal-sized posterior pituitary on magnetic resonance (MR) T1-weighted image (T1WI). He complained of nocturnal enuresis and polyuria. Daily urine volume increased to 4 to 5 L, and AVP plasma level was very low. Polymerase chain reaction (PCR)-amplified exons of the arginine vasopressin (AVP)-neurophysin (NP) II gene were sequenced. Nucleotide-1884 guanine in Exon 2 was substituted with thymine, which induced a substitution of glycine for valine at amino acid position 65 in the NP II moiety. However, MR imaging showed hyperintensity in the posterior pituitary on T1WI. These results suggest that the MR findings of the posterior pituitary in CDI may vary. (+info)
Isolation, assay, and secretion of individual human neurophysins.
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Human neurophysin was isolated from acetone-dried human posterior pituitaries and separated into two major neurophysin peptides by ion exchange chromatography and into four major peptides by preparative disk gel electrophoresis. Antisera raised in rabbits distinguished only two specific antigenic sites on the isolated neurophysin peptides. Individual sensitive and specific radioimmunoassays for two human neurophysins were developed. These assays were used to measure each neurophysin in unextracted human plasma. The two neurophysins are secreted independently in man. One assay measures a neurphysin that is specifically secreted in response to estrogen administration, estrogen-stimulated neurophysin (ESN). The other assay measures a neurophysin that is specifically secreted in response to cigarette smoking, nicotine-stimulated neurophysin (NSN). The mean ESN is 1.1 ng/ml plus or minus 0.7 SD in women and 1.0 ng/ml plus or minus 0.7 SD in men. The mean NSN is 0.9 ng/ml plus or minus 0.2 SD in women and 0.6 ng/ml plus or minus 0.3 SD in men. It is proposed that these may prove to be a specific human "oxytocinneurophysin," ESN, and a human "vasopressin-neurophysin," NSN. (+info)
Kinetics of precursor cleavage at the dibasic sites. Involvement of peptide dynamics.
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The presence in the P'1 position relative to the LysArg doublet of either Phe, Tyr or Trp residues affects only pro-OT/Np(7-15) flexibility. This has a measurable effect on the dynamics of the peptide. Since the same modifications have a major influence on the K(m) and V(max) values of the peptide cleavage, these kinetic parameters should depend on the peptide substrate motions. Therefore, the primary kinetic contribution of substrate cleavage should arise from substrate dynamics rather than from the enzyme. (+info)
Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene.
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OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected. (+info)
The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei.
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The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are implicated in the photic entrainment of circadian rhythms in the suprachiasmatic nuclei (SCN). We now report that mice carrying a null mutation of the VPAC(2) receptor for VIP and PACAP (Vipr2(-/-)) are incapable of sustaining normal circadian rhythms of rest/activity behavior. These mice also fail to exhibit circadian expression of the core clock genes mPer1, mPer2, and mCry1 and the clock-controlled gene arginine vasopressin (AVP) in the SCN. Moreover, the mutants fail to show acute induction of mPer1 and mPer2 by nocturnal illumination. This study highlights the role of intercellular neuropeptidergic signaling in maintenance of circadian function within the SCN. (+info)
Oxytocin synthesis and oxytocin receptor expression by cell lines of human small cell carcinoma of the lung stimulate tumor growth through autocrine/paracrine signaling.
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The objective of the present work was to investigate the existence of an oxytocin (OT)-mediated autocrine/paracrine signaling upon small cell carcinoma of the lung (SCCL) cell growth. In that view, OT receptor (OTR) expression, concomitant with OT synthesis and secretion, was evidenced on three different SCCL cell lines (DMS79, H146, and H345) and related to the vasopressin (VP) system. Specific OT, VP, OTR, V1a VP receptor (V1aR), and V1b/V3 VP receptor (V1bR/V3R) transcripts were identified by reverse transcription-PCR in all cell lines studied. Binding of 125I-(d(CH2)(5)(1), Tyr(Me)(2),Thr(4),Orn(8),Tyr(9)-NH2)-vasotocin (OVTA) was observed on all SCCL cell lines, with a K(d) (dissociation constant) ranging from 0.025-0.089 nM, depending on the cell line and the analytical method. Selectivity of 125I-OVTA binding was confirmed by displacement curves obtained with various OTR and VP receptor agonists and antagonists (OT, OVTA, L-371,257, VP, F180). Immunocytochemistry identified cellular OT and VP, and peptide secretion was measured in supernatants of SCCL cultures. [3H]Thymidine incorporations, applied on H345 cells, demonstrated a dose-dependent mitogenic effect of exogenous OT (1 and 100 nM) that was abolished by the OTR antagonist OVTA. A decrease of proliferation was also observed with OVTA alone, showing a functional mitogenic effect of tumor-derived OT. Taken together, these observations demonstrate the existence of a functional OT-mediated autocrine/paracrine signaling actively implicated in growth and development of SCCL tumors. Furthermore, these findings point to the potential of OT antagonists for development as therapeutic agents for the treatment of SCCL. (+info)
Co-operative binding of oxytocin to bovine neurophysin II.
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The interaction of oxytocin with bovine neurophysin II in 0.1 M-sodium phosphate, pH 5.8, was investigated by equilibrium-dialysis and sedimentation studies. Sigmoidality of the binding curve is attributed to isomerization, either hormone-induced or pre-existing, with preferential binding of oxytocin to one isomeric state. Results are consistent with a binding equation of the form r = (2P[S]+2PQ[S]2)/(1+2P[S]+PQ[S]2) and values of 0.7 X 10(5)M-1 and 1.3 X 10(5)M-1 for P and Q respectively. The significance of these two parameters in relation to current theories of allostery is also discussed. (+info)