The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants

2017 ◽  
Vol 106 (2) ◽  
pp. 167-186 ◽  
Author(s):  
Lise Bols Toustrup ◽  
Helene Kvistgaard ◽  
Johan Palmfeldt ◽  
Charlotte Kjær Bjerre ◽  
Niels Gregersen ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Signal Peptide ◽  
Age At Onset ◽  
Neuronal Cell ◽  
Large Family ◽  
Cellular Level ◽  
The Novel ◽  
The Family ◽  
Challenge Tests ◽  
Avp Gene

Background/Aim: Variability in the severity and age at onset of autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) may be associated with certain types of variants in the arginine vasopressin (AVP) gene. In this study, we aimed to describe a large family with an apparent predominant female occurrence of polyuria and polydipsia and to determine the underlying cause. Methods: The family members reported their family demography and symptoms. Two subjects were diagnosed by fluid deprivation and dDAVP challenge tests. Eight subjects were tested genetically. The identified variant along with 3 previously identified variants in the AVP gene were investigated by heterologous expression in a human neuronal cell line (SH-SY5Y). Results: Both subjects investigated clinically had a partial neurohypophyseal diabetes insipidus phenotype. A g.276_278delTCC variant in the AVP gene causing a Ser18del deletion in the signal peptide (SP) of the AVP preprohormone was perfectly co-segregating with the disease. When expressed in SH-SY5Y cells, the Ser18del variant along with 3 other SP variants (g.227G>A, Ser17Phe, and Ala19Thr) resulted in reduced AVP mRNA, impaired AVP secretion, and partial AVP prohormone degradation and retention in the endoplasmic reticulum. Impaired SP cleavage was demonstrated directly in cells expressing the Ser18del, g.227G>A, and Ala19Thr variants, using state-of-the-art mass spectrometry. Conclusion: Variants affecting the SP of the AVP preprohormone cause adFNDI with variable phenotypes by a mechanism that may involve impaired SP cleavage combined with effects at the mRNA, protein, and cellular level.

scholarly journals Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family

2008 ◽  
Vol 52 (8) ◽  
pp. 1272-1276 ◽  
Author(s):  
Maria Edna de Melo ◽  
Suemi Marui ◽  
Vinícius Nahime de Brito ◽  
Marcio Corrêa Mancini ◽  
Berenice B. Mendonca ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Sequencing Analysis ◽  
The Novel ◽  
Autosomal Dominant Disorder ◽  
Vasopressin Gene ◽  
Avp Gene

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

scholarly journals SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Pablo Ramirez, Biochemist ◽  
Elisa Vaiani ◽  
Roxana Marcela Marino, Biochemist ◽  
Natalia Isabel Perez-Garrido, Biochemist ◽  
Cintia Morales ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Conformational Changes ◽  
Signal Peptide ◽  
Structural Changes ◽  
Autosomal Dominant ◽  
Disulfide Bridge ◽  
Central Diabetes Insipidus ◽  
Novel Variant ◽  
Neurophysin Ii ◽  
Avp Gene

Abstract Central diabetes insipidus (CDI) is a disorder of water balance characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although non-hereditary causes are the most frequent, Familial CDI forms, due to heterozygous mutations in the AVP gene, have also long been recognized. Inheritance occurs mostly in an autosomal dominant manner with almost complete penetrance. The AVP gene encodes for a 164 aminoacids preprotein: the AVP preprohormone which consists of a signal peptide, AVP hormone (9 amino acidpeptide), Neurophysin II (AVP carrier), and a glycoprotein, Copeptin. The AVP preprohormone, is produced in the hypothalamus sand is targeted to the endoplasmic reticulum (ER) by the signal peptide. After cleavage and processing, the AVP hormone is packaged within protein carrier NPII and are transported by axonal trafficking to the neurohypophysis where they can be stored and secreted. Structural changes in NPII have been associated with intracellular accumulation of mutant AVP precursors that have been postulated to be cytotoxic and decreased cell viability of vasopressin-producing neuronsin the neurohypophysis. In this study we describe two index cases from two families of four-generation kindred suspected to have Familial neurohypophyseal diabetes insipidus (FNDI), with absent or barely visibleposterior pituitary by MRI. A water deprivation test was performed in both cases, resulting confirmatory for DI in case 1 while it was inconclusive in case 2. In both cases, molecular studies revealed a pathogenic variant in heterozygous state in the NPII region of the AVP gene, in case 1 we found a previously reported and well characterized variant p.Cys116Gly, cysteine at codon 116 is involved in disulfide bridge important for the secondary structure of NPII. While in case 2 we found a novel variant, p.Gly45Val, in which all in silico tools predict deletereous, whereas there are a previously reported patogenic variant at the same amino acid residueand in 3D modeling it can be observed that structural and conformational changes occur in binding bridge of NPII. We are reporting two novel non related familial CDI cases, even though lack of functional studies, the clinical phenotype in each pedigree suggest this diagnosis, and support the genetic counseling.

SISTEM SOSIAL ALA NIKLASH LUHMAN DALAM NOVEL SEPERTIGA MALAM DI MANHATTAN KARYA ARUMI E

2019 ◽  
Vol 7 (2) ◽  
pp. 49
Author(s):  
Anton Wahyudi
Keyword(s):  
Social System ◽  
System Approach ◽  
Research Method ◽  
Qualitative Method ◽  
The Novel ◽  
Original Culture ◽  
The Family ◽  
Data Source ◽  
Social System Approach ◽  
Fictional Story

The novel Sepertiga Malam di Manhattan by Arumi E is very interesting to study. This novel is a novel about the struggle of a family to get happiness. This novel is the Arumi E's 27th newest novel. The struggle in this novel is to make the family happy, expecting for the baby. Before writing the novel, Arumi E did a research in the places written in the novel to achieve a very interesting fictional story and most of this story was taken from the traveling results so it was so interesting. The objective of this research is to describe (1) the Autopoetic System in the novel Sepertiga MalamdiManhattan by Arumi E. (2) The differentiation system in the Novel Sepertiga Malamdi Manhattan by Arumi E.The research method used is in the form of a descriptive qualitative method that uses a social system approach. The method used by the researcher is the dialectical method. The data source used in this research is the novel Sepertiga Malamdi Manhattan by Arumi E, published by Gramedia publisher in 2018. The data collection in this study uses the steps of reading the novel. To collect data, the researcher use any instrument.There are two results of the study: (1) The autopoetic system in the novel Sepertiga MalamdiManhattan by Arumi E. is concerning to some characters who have their own beliefs or rules in their lives who do not want to follow the rules of others, they are more confident in their own way to success and purpose of life. (2) The system of differentiation in the novel Sepertiga Malamdi Manhattan by Arumi E. is covering the handling of changes in the environment, the characters are able to adapt to the new environment, which has a different culture from the original culture. This shows evidence of the system autopoetic and differentiation in the novel Sepertiga MalamdiManhattan by Arumi E.

Buried Narratives: Exhuming the Mother's Story in Oliver Twist

2018 ◽  
Vol 8 (3) ◽  
pp. 247-266
Author(s):  
Michelle L. Wilson
Keyword(s):  
Social Change ◽  
Maternal Inheritance ◽  
The Novel ◽  
Poor Law ◽  
The Family ◽  
The Law ◽  
First Time ◽  
Critical Consideration

Initially, Oliver Twist (1839) might seem representative of the archetypal male social plot, following an orphan and finding him a place by discovering the father and settling the boy within his inheritance. But Agnes Fleming haunts this narrative, undoing its neat, linear transmission. This reconsideration of maternal inheritance and plot in the novel occurs against the backdrop of legal and social change. I extend the critical consideration of the novel's relationship to the New Poor Law by thinking about its reflection on the bastardy clauses. And here, of course, is where the mother enters. Under the bastardy clauses, the responsibility for economic maintenance of bastard children was, for the first time, legally assigned to the mother, relieving the father of any and all obligation. Oliver Twist manages to critique the bastardy clauses for their release of the father, while simultaneously embracing the placement of the mother at the head of the family line. Both Oliver and the novel thus suggest that it is the mother's story that matters, her name through which we find our own. And by containing both plots – that of the father and the mother – Oliver Twist reveals the violence implicit in traditional modes of inheritance in the novel and under the law.

ДИАГНОСТИКА ХРОНИЧЕСКИХ ИНДУЦИРОВАННЫХ КРАПИВНИЦ

2019 ◽  
pp. 5-13
Author(s):  
E.Yu. Borzova
Keyword(s):  
Quality Of Life ◽  
Biological Therapy ◽  
Treatment Algorithm ◽  
The Novel ◽  
International Guidelines ◽  
Systemic Reactions ◽  
Significant Impairment ◽  
Challenge Tests

Хронические индуцированные крапивницы имеют важное социальноэкономическое значение вследствие риска развития системных реакций и значительного снижения качества жизни пациентов. Диагностика хронических индуцированных крапивниц основывается на анамнестических данных и проведении провокационных тестов. Современный протокол ведения больных хронической крапивницей включает применение неседативных антигистаминных препаратов. Международные согласительные документы по лечению крапивницы рекомендуют 4кратное увеличение суточной дозы неседативных антигистаминных препаратов при их неэффективности в стандартных дозах. Данные метаанализа указывают на эффективность омализумаба при хронических индуцированных крапивницах. В перспективе ожидается расширение арсенала генноинженерной биологической терапии хронических индуцированных крапивниц.Chronic inducible urticarias are characterized by the risks of systemic reactions and a significant impairment of patients quality of life. The diagnosis of chronic inducible urticarias relies on the patients history and the challenge tests. A treatment algorithm for the management of chronic inducible urticarias includes nonsedating antihistamines as a firstline treatment. The international guidelines for the management of chronic inducible urticarias recommend updosing of nonsedating antihistamines up to four fold if standard doses are not effective. The metaanalysis suggests the efficacy of omalizumab in chronic inducible urticarias. In the prospect, the novel options of biological therapy for chronic inducible urticarias are expected.

ДИАГНОСТИКА ХРОНИЧЕСКИХ ИНДУЦИРОВАННЫХ КРАПИВНИЦ

2019 ◽  
Author(s):  
E.Yu. Borzova
Keyword(s):  
Biological Therapy ◽  
Meta Analysis ◽  
Treatment Algorithm ◽  
The Novel ◽  
First Line ◽  
Systemic Reactions ◽  
Significant Impairment ◽  
Challenge Tests ◽  
First Line Treatment

Хронические индуцированные крапивницы имеют важное социально-экономическое значение вследствие риска развития системных реакций и значительного снижения качества жизни пациентов. Диагностика хронических индуцированных крапивниц основывается на анамнестических данных и проведении провокационных тестов. Современный протокол ведения больных хронической крапивницей включает применение неседативных антигистаминных препаратов. Международные согласительные документы по лечению крапивницы рекомендуют 4-кратное увеличение суточной дозы неседативных антигистаминных препаратов при их неэффективности в стандартных дозах. Данные мета-анализа указывают на эффективность омализумаба при хронических индуцированных крапивницах. В перспективе ожидается расширение арсенала генно-инженерной биологической терапии хронических индуцированных крапивниц.Chronic inducible urticarias are characterized by the risks of systemic reactions and a significant impairment of patients quality of life. The diagnosis of chronic inducible urticarias relies on the patients history and the challenge tests. A treatment algorithm for the management of chronic inducible urticarias includes nonsedating antihistamines as a first-line treatment. The international guidelines for the management of chronic inducible urticarias recommend updosing of nonsedating antihistamines up to four fold if standard doses are not effective. The meta-analysis suggests the efficacy of omalizumab in chronic inducible urticarias. In the prospect, the novel options of biological therapy for chronic inducible urticarias are expected.

Breaking Free

2017 ◽  
Author(s):  
Deirdre David
Keyword(s):  
United States ◽  
The United States ◽  
The Novel ◽  
Male Homosexuality ◽  
Domestic Life ◽  
The Family

In the mid- to late 1950s, Pamela emerged as a critically acclaimed novelist, particularly after the family returned to London. In perhaps her best-known novel, The Unspeakable Skipton, she explores the life of a paranoid writer who sponges on English visitors to Bruges. The novel was hailed for its wit and sensitive depiction of the life of a writer. She also published a fine study of a London vicar martyred in marriage to a vain and selfish wife: The Humbler Creation is remarkable for its incisive and empathetic depiction of male despair. The Last Resort sealed her distinction as a brilliant novelist of domestic life in its frank depiction of male homosexuality. While continuing to publish fiction, Pamela maintained her reputation as a deft reviewer. In 1954, she and Charles travelled to the United States—the first of many trips that were to follow.

Mansfield Park

2008 ◽  
Author(s):  
Jane Austen ◽  
Jane Stabler
Keyword(s):  
The Novel ◽  
Mansfield Park ◽  
Sexual Jealousy ◽  
The Family ◽  
The World ◽  
The Face

‘Me!’ cried Fanny … ‘Indeed you must excuse me. I could not act any thing if you were to give me the world. No, indeed, I cannot act.’ At the age of ten, Fanny Price leaves the poverty of her Portsmouth home to be brought up among the family of her wealthy uncle, Sir Thomas Bertram, in the chilly grandeur of Mansfield Park. There she accepts her lowly status, and gradually falls in love with her cousin Edmund. When the dazzling and sophisticated Henry and Mary Crawford arrive, Fanny watches as her cousins become embroiled in rivalry and sexual jealousy. As the company starts to rehearse a play by way of entertainment, Fanny struggles to retain her independence in the face of the Crawfords’ dangerous attractions; and when Henry turns his attentions to her, the drama really begins… This new edition does full justice to Austen’s complex and subtle story, placing it in its Regency context and elucidating the theatrical background that pervades the novel.

scholarly journals Delayed diagnosis of Peutz–Jeghers syndrome due to pathological information loss or mistake in family/personal history

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yu-Liang Jiang ◽  
Xiao-Dong Xu ◽  
Bai-Rong Li ◽  
En-Da Yu ◽  
Zi-Ye Zhao ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Novel Mutation ◽  
Delayed Diagnosis ◽  
Personal History ◽  
Pathological Examination ◽  
The Novel ◽  
Novel Mutations ◽  
The Family ◽  
Genetic Level ◽  
Peutz Jeghers Syndrome

Abstract Objective To report Peutz–Jeghers syndrome (PJS) cases with non-definitive clues in the family or personal history and finally diagnosed through pathological examination and STK11 gene mutation test. Clinical presentation and intervention PJS was suspected in 3 families with tortuous medical courses. Two of them had relatives departed due to polyposis or colon cancer without pathological results, and the other one had been diagnosed as hyperplastic polyposis before. Diagnosis of PJS was confirmed by endoscopy and repeated pathological examinations, and the STK11 mutation test finally confirmed the diagnosis at genetic level, during which 3 novel mutation were detected (536C > A, 373_374insA, 454_455insGGAGAAGCGTTTCCCAGTGTGCC). Conclusion Early diagnosis of PJS is important and may be based on a family history with selective features among family members, and the pathological information is the key. The novel mutations also expand the STK11 variant spectrum.

scholarly journals Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel missense mutation in AVP gene in a large Italian kindred

Endocrine ◽  
2021 ◽  
Author(s):  
Carlotta Marzocchi ◽  
Silvia Cantara ◽  
Alfonso Sagnella ◽  
Maria Grazia Castagna ◽  
Marco Capezzone
Keyword(s):  
Diabetes Insipidus ◽  
Missense Mutation ◽  
Autosomal Dominant ◽  
Three Dimensional ◽  
Rare Condition ◽  
Central Diabetes Insipidus ◽  
Disulfide Bridges ◽  
Italian Family ◽  
Avp Gene

Abstract Purpose Familial neurohypophysial diabetes insipidus (FNDI), commonly caused by autosomal dominant arginine vasopressin (AVP) mutations, is a rare condition in which vasopressin fails in regulating body’s level of water with final polyuria and polydipsia. Genetic testing in familial cases of FNDI should be carry out to ensure adequate treatments and avoid disease manifestations especially in infants. Methods In this study, we investigated three-generations of a large Italian family with clinical diagnosis of familial central diabetes insipidus for the presence of potential pathogenic mutations in the AVP gene. Results We identified a heterozygous missense mutation (c.154 T > A; p.C52S) in AVP gene in all affected members studied of a large Italian family. In silico tools were used to investigate the pathogenic role of the mutation and three-dimensional protein structure predicted that the p.C52S impairs disulfide bridges formation resulting in misfolding of the protein. Conclusions This is the first study that identified a novel missense p.C52S mutation as causative of central diabetes insipidus in a large Italian pedigree.

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