Signal Peptide and Neurophysin II Gene Mutations in Hereditary Central Diabetes Insipidus

Physiology ◽  
1997 ◽  
Vol 12 (2) ◽  
pp. 67-71
Author(s):  
J Rutishauser ◽  
ER Froesch
Keyword(s):  
Diabetes Insipidus ◽  
Antidiuretic Hormone ◽  
Signal Peptide ◽  
Gene Mutations ◽  
Central Diabetes Insipidus ◽  
Carrier Protein ◽  
Gene Encoding ◽  
Precursor Processing ◽  
The Impact ◽  
Neurophysin Ii

Recent studies on the molecular background of central diabetes insipidus have identified several mutations in the gene encoding antidiuretic hormone and its carrier protein neurophysin II. This article discusses the impact of such mutations on precursor processing and transport in neuronal cells.

scholarly journals Identification of Mutations of the Arginine Vasopressin-Neurophysin II Gene in Two Kindreds with Familial Central Diabetes Insipidus

1998 ◽  
Vol 83 (2) ◽  
pp. 693-696 ◽  
Author(s):  
Christina Heppner ◽  
Jörg Kotzka ◽  
Catharina Bullmann ◽  
Wilhelm Krone ◽  
Dirk Müller-Wieland
Keyword(s):  
Diabetes Insipidus ◽  
Missense Mutation ◽  
Signal Peptide ◽  
Arginine Vasopressin ◽  
Family Members ◽  
Central Diabetes Insipidus ◽  
Nucleotide Position ◽  
Coding Region ◽  
Control Subjects ◽  
Neurophysin Ii

Familial central diabetes insipidus is transmitted as an autosomal dominant trait with almost complete penetrance. Twenty-three different mutations of the arginine vasopressin-neurophysin II gene have been reported to date, located within the signal peptide-, the arginine vasopressin-, or the neurophysin II-coding region. In the present study two kindreds with familial central diabetes insipidus were examined. The entire coding region of the arginine vasopressin-neurophysin II gene of one affected subject of each family was amplified by PCR and subcloned into a pUC 18 plasmid, and six positive clones were sequenced. After identification of the mutation, direct sequencing was performed on the respective sequence of family members and 28 healthy control subjects. In family A, a missense mutation (C→T) at nucleotide position 280 was detected, predicting the substitution of alanine by valine at position −1 of the signal peptide. All affected subjects were heterozygote for the mutation, whereas none of the unaffected family members or control subjects displayed the mutant sequence. In family B, a missense mutation within the neurophysin II-coding sequence was identified (nucleotide 1757, G→C), predicting the substitution of glycine by arginine at position 23. Again, affected family members were found to be heterozygote for the mutation, which was not observed in unaffected family members or in control subjects. Although the mutation of family A was recently described in 3 other kindreds as well, the mutation within the neurophysin II-coding region represents a novel mutation of the AVP-NP II gene.

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.

scholarly journals Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lixia Wang ◽  
Weihong Guo ◽  
Chunyun Fang ◽  
Wenli Feng ◽  
Yumeng Huang ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Nephrogenic Diabetes Insipidus ◽  
Functional Characterization ◽  
Gene Mutations ◽  
Biochemical Properties ◽  
Vasopressin Receptor ◽  
Inherited Disease ◽  
Loss Of Function ◽  
Gene Encoding

AbstractX-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly “rescue” I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI.

scholarly journals Pengelolaan Central Diabetes Insipidus Pasca Cedera Kepala Berat

2019 ◽  
Vol 8 (2) ◽  
pp. 99-104
Author(s):  
Bona Akhmad Fithrah ◽  
Marsudi Rasman ◽  
Siti Chasnak Saleh
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Diabetes Insipidus ◽  
Antidiuretic Hormone ◽  
Central Diabetes Insipidus ◽  
Young Generation ◽  
Posterior Pituitary ◽  
Challenging Problem ◽  
Mortality And Morbidity ◽  
Post Traumatic

Cedera otak traumatika adalah salah satu penyebab kematian dan kesakitan tersering pada kelompok masyarakat muda. Hasil akhir dari cedera kepala berat dapat menyebabkan gangguan kognitif, perilaku, psikologi dan sosial. Salah satu konsekuensi dari cedera kepala berat adalah terjadinya disfungsi hormonal baik dari hipofise anterior maupun posterior. Angka kejadian disfungsi hormonal ini sekitar 20-50%. Salah satu yang paling menantang dan sering terjadi adalah diabetes insipidus (DI) dan Syndrome inappropriate antidiuretic hormone (SIADH). Angka kejadian diabetes insipidus pasca cedera kepala diduga sebesar 1-2,9% dengan berbagai tingkatannya. Pada beberapa kasus bersifat sementara tapi beberapa kasus terjadi bersifat menetap. Pada laporan kasus ini akan dibawakan sebuah kasus diabetes insipidus pasca cedera kepala berat. Pasien mengalami cedera kepala berat, hingga dilakukan decompressive craniectomi dan trakeostomi. Untuk perawatan lanjutan pasien dirujuk ke Jakarta. Saat menjalani terapi lanjutan ini pasien terdiagnosis diabetes insipidus Pada kasus ini diabetes insipidus tidak timbul langsung setelah cedera kepala tetapi baru timbul lebih kurang satu bulan setelah cedera kepala. Diabetes insipidus dikelola dengan menggunakan desmopressin spray dan oral disamping mengganti cairan yang hilang. Pada kasus ini desmopressin sempat di stop sebelum akhirnya diberikan terus menerus dan pasien diterapi sebagai diabetes insipidus yang menetap. Managing Central Diabetes Insipidus in Post Severe Head Injury PatientAbstractTraumatic brain injury is the cause of mortality and morbidity in society mostly in male-young generation. The last outcome of traumatic brain injury might be deficit in cognitive, behavioral, psychological and social. the consequences of traumatic brain injury might be hormonal disfunction from anterior and posterior pituitary. The incidence around 20-50%. The most challenging problem is diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone (SIADH). The incident of post traumatic diabetes insipidus around 1-2,9% with several degree. In certain case its only occurred transiently but some report it could be permanent. In this case report will find one case post traumatic diabetes insipidus. This pasien had severe traumatic brain injury and underwent decompressive craniectomy and tracheostomy. For further therapy patient was referred to Jakarta. In this further treatment patient diagnosed with diabetes insipidus. Diabetes insipidus doesn’t occurred since the first day of injury but occurred almost one month after. Diabetes insipidus managed with desmopressin spray and oral beside replace water loss. For a few days desmopressin stop but diabetes insipidus occurred again so desmopressin given daily both spray and oral and the patient had therapy as diabetes insipidus permanent. 

scholarly journals Coexistence of central diabetes insipidus and salt wasting: the difficulties in diagnosis, changes in natremia, and treatment.

1996 ◽  
Vol 7 (12) ◽  
pp. 2527-2532
Author(s):  
S Laredo ◽  
K Yuen ◽  
B Sonnenberg ◽  
M L Halperin
Keyword(s):  
Diabetes Insipidus ◽  
Antidiuretic Hormone ◽  
Urine Volume ◽  
Extracellular Fluid ◽  
Central Diabetes Insipidus ◽  
High Rate ◽  
Salt Wasting ◽  
Positive Balance ◽  
Clinical Tools ◽  
Negative Balance

Both central diabetes insipidus (DI) and a high rate of excretion of sodium (Na) and chloride (Cl) contributed to the development of polyuria and dysnatremia in two patients during the acute postoperative period after neurosurgery. To minimize difficulties in diagnosis and projections for therapy, two available (but not often used) clinical tools were helpful. First, the osmole excretion rate early on revealed the co-existence of central DI and an osmotic diuresis. The osmoles excreted were largely Na salts; after antidiuretic hormone acted, this electrolyte diuresis caused the urine flow rate to be much higher than otherwise anticipated. Interestingly, part of this saline diuresis occurred when the extracellular fluid volume was contracted. The tool to explain the basis for the dysnatremias was a tonicity balance. Hypernatremia, which developed before treatment of central DI, was primarily a result of a positive balance for Na rather than a large negative balance for water. Moreover, hyponatremia that developed once antidiuretic hormone acted was primarily a result of a negative balance for Na; the urine volume was large and its Na concentration was hypertonic. To prevent a further decline in the plasma Na concentration, either the Na concentration in the urine should be decreased by provision of urea or a loop diuretic while replacing all unwanted water and electrolyte losses; alternatively, the fluid infused should have a similar Na concentration and volume as the urine (infuse hypertonic saline).

scholarly journals Efficacy of Deep Brain Stimulation in a Patient with Genetically Confirmed Chorea-Acanthocytosis

2019 ◽  
Vol 11 (2) ◽  
pp. 199-204
Author(s):  
Alby Richard ◽  
Joey Hsu ◽  
Patricia Baum ◽  
Ron Alterman ◽  
David K. Simon
Keyword(s):  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Early Adulthood ◽  
Gene Mutations ◽  
Gene Encoding ◽  
Laboratory Findings ◽  
Current State ◽  
Monopolar Stimulation ◽  
The Impact ◽  
Deep Brain

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disease due to mutation of the VPS13A gene encoding the protein chorein. ChAc is a slowly progressive disorder that typically presents in early adulthood, and whose clinical features include chorea and dystonia with involuntary lip, cheek, and tongue biting. Some patients also have seizures. Treatment for ChAc is symptomatic. A small number of ChAc patients have been treated with bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi), and we now present an additional case. Patient chart, functional measures, and laboratory findings were reviewed from the time of ChAc diagnosis until 6 months after DBS surgery. Here, we present a case of ChAc in a 31-year-old male positive for VPS13A gene mutations who presented with chorea, tongue biting, dysarthria, weight loss, and mild cognitive dysfunction. DBS using monopolar stimulation with placement slightly lateral to the GPi was associated with significant improvement in chorea and dysarthria. This case adds to the current state of knowledge regarding the efficacy and safety of bilateral GPi-DBS for symptomatic control of drug-resistant hyperkinetic movements seen in ChAc. Controlled trials are needed to better assess the impact and ideal target of DBS in ChAc.

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