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SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene
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 muta...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207637/ http://dx.doi.org/10.1210/jendso/bvaa046.1794 |
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author | Ramirez, Biochemist, Pablo Vaiani, Elisa Marino, Biochemist, Roxana Marcela Perez-Garrido, Biochemist, Natalia Isabel Morales, Cintia Rubio, Betty Rivarola, Marco A Belgorosky, Alicia |
author_facet | Ramirez, Biochemist, Pablo Vaiani, Elisa Marino, Biochemist, Roxana Marcela Perez-Garrido, Biochemist, Natalia Isabel Morales, Cintia Rubio, Betty Rivarola, Marco A Belgorosky, Alicia |
author_sort | Ramirez, Biochemist, Pablo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7207637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72076372020-05-13 SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene Ramirez, Biochemist, Pablo Vaiani, Elisa Marino, Biochemist, Roxana Marcela Perez-Garrido, Biochemist, Natalia Isabel Morales, Cintia Rubio, Betty Rivarola, Marco A Belgorosky, Alicia J Endocr Soc Pediatric Endocrinology 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. Oxford University Press 2020-05-08 /pmc/articles/PMC7207637/ http://dx.doi.org/10.1210/jendso/bvaa046.1794 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Pediatric Endocrinology Ramirez, Biochemist, Pablo Vaiani, Elisa Marino, Biochemist, Roxana Marcela Perez-Garrido, Biochemist, Natalia Isabel Morales, Cintia Rubio, Betty Rivarola, Marco A Belgorosky, Alicia SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene |
title | SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene |
title_full | SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene |
title_fullStr | SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene |
title_full_unstemmed | SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene |
title_short | SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene |
title_sort | sat-093 two cases of autosomal dominant familial central diabetes insipidus: a novel variant in neurophysin ii region of avp gene |
topic | Pediatric Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207637/ http://dx.doi.org/10.1210/jendso/bvaa046.1794 |
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