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Gary L. Robertson - One of the best experts on this subject based on the ideXlab platform.
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CLINICAL STUDY
2015Co-Authors: Jonas Rutishauser, Mary Beth Gaskill, Thomas J Kotlar, Gary L. RobertsonAbstract: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 gen
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Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus.
Clinical endocrinology, 2004Co-Authors: Jane Christensen, Charlotte Siggaard, Thomas J. Corydon, Gary L. Robertson, Niels Gregersen, Lars Bolund, Søren RittigAbstract:Summary objective and study design Two different mutations in the arginine vasopressin (AVP) gene associated with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) predict Y21H (AVP2) and V67A (NP36) amino acid substitutions of the AVP prohormone. They are unique in that they change, respectively, the AVP moiety and a region of the Neurophysin II domain not so far affected by any mutations. To test whether they affect the cellular handling of the AVP prohormone in a similar manner to previously investigated mutations, they were examined by heterologous expression in cell lines. results Both mutations resulted in significantly reduced amounts of immunoreactive AVP in the cell culture medium as determined by radioimmunoassay analysis. Metabolic labelling combined with immunoprecipitation demonstrated that processing and secretion of the mutant prohormones was reduced but not prevented. Finally, confocal laser scanning microscopy showed that normal AVP prohormone and/or its processed products were localized in the tips of the cellular processes, whereas both mutant prohormones were accumulated in the endoplasmic reticulum (ER) and in the case of the V67A prohormone, also in perinuclear structures outside the ER. conclusion Both mutations result in reduced AVP prohormone processing and secretion probably due to retention in the ER. This supports, at least partly, the hypothesis that the mutations lead to the production of a mutant hormone precursor that fails to fold and/or dimerize properly and, as a consequence, is retained by the ER protein quality control machinery. Perinuclear accumulation of the V67A prohormone outside the ER indicates that additional mechanisms could be involved.
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autosomal dominant neurohypophyseal diabetes insipidus due to substitution of histidine for tyrosine2 in the vasopressin moiety of the hormone precursor
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Søren Rittig, Charlotte Siggaard, Niels Gregersen, Metin Ozata, Ilhan Yetkin, E B Pedersen, Gary L. RobertsonAbstract: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 magn...
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clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Charlotte Siggaard, Thomas J. Corydon, Gary L. Robertson, Niels Gregersen, Lars Bolund, Søren Rittig, Per Hove Andreasen, T G Jensen, Brage S Andresen, E B PedersenAbstract:The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by postnatal onset of polyuria and a deficient neurosecretion of the antidiuretic hormone, arginine vasopressin (AVP). Since 1991, adFNDI has been linked to 31 different mutations of the gene that codes for the vasopressin-Neurophysin II (AVP-NPII) precursor. The aims of the present study were to relate the clinical phenotype to the specific genotype and to the molecular genetic effects of the most frequently reported adFNDI mutation located at the cleavage site of the signal peptide of AVP-NPII [Ala(-1)Thr]. Genetic analysis and clinical studies of AVP secretion, urinary AVP, and urine output were performed in 16 affected and 16 unaffected family members and 11 spouses of a Danish adFNDI kindred carrying the Ala(-1)Thr mutation. Mutant complementary DNA carrying the same mutation was expressed in a neurogenic cell line (Neuro2A), and the cellular effects were studied by Western blotting, immunocytochemistry, and AVP measurements. The clinical studies showed a severe progressive deficiency of plasma and urinary AVP that manifested during childhood. The expression studies demonstrated that the Ala(- 1)Thr mutant cells produced 8-fold less AVP than wild-type cells and accumulated excessive amounts of 23-kDa 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). These results provide independent confirmation that this Ala(-1)Thr mutation produces adFNDI 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.
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familial neurohypophyseal diabetes insipidus associated with a signal peptide mutation
The Journal of Clinical Endocrinology and Metabolism, 1993Co-Authors: J F Mcleod, Mary Beth Gaskill, L Kovacs, S Rittig, G S Bradley, Gary L. RobertsonAbstract: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...
Annalisa Calcagno - One of the best experts on this subject based on the ideXlab platform.
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early onset central diabetes insipidus is associated with de novo arginine vasopressin Neurophysin II or wolfram syndrome 1 gene mutations
European Journal of Endocrinology, 2015Co-Authors: Silverio Perrotta, Natascia Di Iorgi, Fulvio Della Ragione, Saverio Scianguetta, Adriana Borriello, Anna Elsa Maria Allegri, Marcella Ferraro, Claudia Santoro, Flavia Napoli, Annalisa CalcagnoAbstract:Objective: Idiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin– Neurophysin II (AVP–NPII (AVP)) or wolframin (WFS1) genes. Design and methods: Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia. Results: Two patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322GOT) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997AOG), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome. Conclusions: Early-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.
Esther Breslow - One of the best experts on this subject based on the ideXlab platform.
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identification and observation of alkyl proton resonances of the amino terminal residues of bovine Neurophysins evidence for conformational differences between Neurophysin i and Neurophysin II
International Journal of Peptide and Protein Research, 2009Co-Authors: Susan T. Lord, Esther BreslowAbstract:Analysis of the 220 MHz proton magnetic resonance spectra of bovine Neurophysins-I and -II and of the effects of pH and succinylation of these spectra has allowed identification of the -CH3 proton resonances of the amino-terminal alanine of both proteins and of the -CH3 resonances of methionine-2 of Neurophysin-II. The alanine -CH3 resonance of Neurophysin-I is a sharp doublet at all pH values between 1 and 10.5 indicating relatively few restrictions on its mobility. By contrast, the -CH3 resonances of the amino-terminal alanine and methionine-2 of Neurophysin-II undergo pH-dependent changes in broadening compatible with the formation of an intramolecular salt-bridge at neutral pH between the protonated alpha-amino and an unprotonated side chain carboxyl. The results suggest that differeces in the properties of the two proteins are partially mediated by conformational differences involving their amino-terminal sequences. The potential usefulness of the amino-terminal resonances as n.m.r. 'reporter' signals is additionally demonstrated by studies of the effects of spin labels on the Neurophysin-I amino-terminal alanine resonance; these studies place the amino-terminus of Neurophysin-I approximately 14 A from residue 3 of peptides bound to the strong Neurophysin hormone-binding site.
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Contributions of the interdomain loop, amino terminus, and subunit interface to the ligand-facilitated dimerization of Neurophysin: crystal structures and mutation studies of bovine Neurophysin-I.
Protein Science, 2006Co-Authors: Hunjoong Lee, Esther BreslowAbstract:Current evidence indicates that the ligand-facilitated dimerization of Neurophysin is mediated in part by dimerization-induced changes at the hormone binding site of the unliganded state that increase ligand affinity. To elucidate other contributory factors, we investigated the potential role of Neurophysin's short interdomain loop (residues 55–59), particularly the effects of loop residue mutation and of deleting amino-terminal residues 1–6, which interact with the loop and adjacent residues 53–54. The Neurophysin studied was bovine Neurophysin-I, necessitating determination of the crystal structures of des 1–6 bovine Neurophysin-I in unliganded and liganded dimeric states, as well as the structure of its liganded Q58V mutant, in which peptide was bound with unexpectedly increased affinity. Increases in dimerization constant associated with selected loop residue mutations and with deletion of residues 1–6, together with structural data, provided evidence that dimerization of unliganded Neurophysin-I is constrained by hydrogen bonding of the side chains of Gln58, Ser56, and Gln55 and by amino terminus interactions, loss or alteration of these hydrogen bonds, and probable loss of amino terminus interactions, contributing to the increased dimerization of the liganded state. An additional intersubunit hydrogen bond from residue 81, present only in the liganded state, was demonstrated as the largest single effect of ligand binding directly on the subunit interface. Comparison of bovine Neurophysins I and II indicates broadly similar mechanisms for both, with the exception in Neurophysin II of the absence of Gln55 side chain hydrogen bonds in the unliganded state and a more firmly established loss of amino terminus interactions in the liganded state. Evidence is presented that loop status modulates dimerization via long-range effects on Neurophysin conformation involving neighboring Phe22 as a key intermediary.
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the behavior of the active site salt bridge of bovine Neurophysins as monitored by 15n nmr spectroscopy and chemical substitution relationship to biochemical properties
Biochemistry, 1996Co-Authors: Changsheng Zheng, Sean M Cahill, Esther BreslowAbstract:The active site of liganded Neurophysin contains a salt bridge that involves the side chains of Arg-8 and Glu-47 of the protein and the α-amino group of bound hormone or related peptide. The extent to which the Arg-8−Glu-47 salt bridge persists in the absence of peptide, or to which the environment of Arg-8 in the unliganded state differs in monomers and dimers, is relevant to an understanding of allosteric mechanism in this system. In the present study, the behavior of the salt bridge was investigated by 15N NMR and chemical replacement of Arg-8. Bovine Neurophysin-I was converted to its des 1−8 derivative, and Arg-8 was replaced by 15N-substituted Arg or by other residues using chemical semisynthesis. The relative abilities of different amino acids to restore peptide affinity to the des 1−8 protein were in good accord with the view of the salt bridge in the liganded state obtained from crystals of bovine Neurophysin-II complexes. In the unliganded state, comparison of the 15N and proton NMR signals from...
Søren Rittig - One of the best experts on this subject based on the ideXlab platform.
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Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus.
Clinical endocrinology, 2004Co-Authors: Jane Christensen, Charlotte Siggaard, Thomas J. Corydon, Gary L. Robertson, Niels Gregersen, Lars Bolund, Søren RittigAbstract:Summary objective and study design Two different mutations in the arginine vasopressin (AVP) gene associated with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) predict Y21H (AVP2) and V67A (NP36) amino acid substitutions of the AVP prohormone. They are unique in that they change, respectively, the AVP moiety and a region of the Neurophysin II domain not so far affected by any mutations. To test whether they affect the cellular handling of the AVP prohormone in a similar manner to previously investigated mutations, they were examined by heterologous expression in cell lines. results Both mutations resulted in significantly reduced amounts of immunoreactive AVP in the cell culture medium as determined by radioimmunoassay analysis. Metabolic labelling combined with immunoprecipitation demonstrated that processing and secretion of the mutant prohormones was reduced but not prevented. Finally, confocal laser scanning microscopy showed that normal AVP prohormone and/or its processed products were localized in the tips of the cellular processes, whereas both mutant prohormones were accumulated in the endoplasmic reticulum (ER) and in the case of the V67A prohormone, also in perinuclear structures outside the ER. conclusion Both mutations result in reduced AVP prohormone processing and secretion probably due to retention in the ER. This supports, at least partly, the hypothesis that the mutations lead to the production of a mutant hormone precursor that fails to fold and/or dimerize properly and, as a consequence, is retained by the ER protein quality control machinery. Perinuclear accumulation of the V67A prohormone outside the ER indicates that additional mechanisms could be involved.
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autosomal dominant neurohypophyseal diabetes insipidus due to substitution of histidine for tyrosine2 in the vasopressin moiety of the hormone precursor
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Søren Rittig, Charlotte Siggaard, Niels Gregersen, Metin Ozata, Ilhan Yetkin, E B Pedersen, Gary L. RobertsonAbstract: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 magn...
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clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Charlotte Siggaard, Thomas J. Corydon, Gary L. Robertson, Niels Gregersen, Lars Bolund, Søren Rittig, Per Hove Andreasen, T G Jensen, Brage S Andresen, E B PedersenAbstract:The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by postnatal onset of polyuria and a deficient neurosecretion of the antidiuretic hormone, arginine vasopressin (AVP). Since 1991, adFNDI has been linked to 31 different mutations of the gene that codes for the vasopressin-Neurophysin II (AVP-NPII) precursor. The aims of the present study were to relate the clinical phenotype to the specific genotype and to the molecular genetic effects of the most frequently reported adFNDI mutation located at the cleavage site of the signal peptide of AVP-NPII [Ala(-1)Thr]. Genetic analysis and clinical studies of AVP secretion, urinary AVP, and urine output were performed in 16 affected and 16 unaffected family members and 11 spouses of a Danish adFNDI kindred carrying the Ala(-1)Thr mutation. Mutant complementary DNA carrying the same mutation was expressed in a neurogenic cell line (Neuro2A), and the cellular effects were studied by Western blotting, immunocytochemistry, and AVP measurements. The clinical studies showed a severe progressive deficiency of plasma and urinary AVP that manifested during childhood. The expression studies demonstrated that the Ala(- 1)Thr mutant cells produced 8-fold less AVP than wild-type cells and accumulated excessive amounts of 23-kDa 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). These results provide independent confirmation that this Ala(-1)Thr mutation produces adFNDI 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.
John A. Phillips - One of the best experts on this subject based on the ideXlab platform.
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heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding ala 1 val in the signal peptide of the arginine vasopressin Neurophysin II copeptin precursor
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: David R Repaske, Rita Medlej, Ebru K Gultekin, M R S Krishnamani, George Halaby, James W Findling, John A. PhillipsAbstract:Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of diabetes insipidus due to progressive vasopressin deficiency with onset typically at 1–6 yr of age. Affected individuals demonstrate specific degeneration of the vasopressinergic magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei and loss of the posterior pituitary bright spot on magnetic resonance imaging. The genetic locus of ADNDI is the arginine vasopressin-Neurophysin II (AVP-NPII) gene. Mutations that cause ADNDI have been found to occur both within the signal peptide of the prepro-AVP-NPII precursor and within the coding sequence for Neurophysin II, but not within the coding sequence for AVP itself. We evaluated the AVP-NPII genes in two independent families with ADNDI and identified a mutation (C280→T) in the coding sequence for the signal peptide of the prepro-AVP-NPII precursor in both families. This mutation encodes an Ala→Val substitution at the C-terminus of the signal peptide (−1...