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Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency
CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report t...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686656/ https://www.ncbi.nlm.nih.gov/pubmed/29188236 http://dx.doi.org/10.1210/js.2016-1119 |
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author | Vairamani, Kanimozhi Merjaneh, Lina Casano-Sancho, Paula Sanli, Merve Emecen David, Alessia Metherell, Louise A. Savage, Martin O. Sánchez del Pozo, Jaime Backeljauw, Philippe F. Rosenfeld, Ron G. Aisenberg, Javier Dauber, Andrew Hwa, Vivian |
author_facet | Vairamani, Kanimozhi Merjaneh, Lina Casano-Sancho, Paula Sanli, Merve Emecen David, Alessia Metherell, Louise A. Savage, Martin O. Sánchez del Pozo, Jaime Backeljauw, Philippe F. Rosenfeld, Ron G. Aisenberg, Javier Dauber, Andrew Hwa, Vivian |
author_sort | Vairamani, Kanimozhi |
collection | PubMed |
description | CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. OBJECTIVE: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. RESULTS: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. CONCLUSION: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients. |
format | Online Article Text |
id | pubmed-5686656 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-56866562017-11-27 Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency Vairamani, Kanimozhi Merjaneh, Lina Casano-Sancho, Paula Sanli, Merve Emecen David, Alessia Metherell, Louise A. Savage, Martin O. Sánchez del Pozo, Jaime Backeljauw, Philippe F. Rosenfeld, Ron G. Aisenberg, Javier Dauber, Andrew Hwa, Vivian J Endocr Soc Clinical Research Articles CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. OBJECTIVE: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. RESULTS: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. CONCLUSION: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients. Endocrine Society 2017-03-08 /pmc/articles/PMC5686656/ /pubmed/29188236 http://dx.doi.org/10.1210/js.2016-1119 Text en Copyright © 2017 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is published under the terms of the Creative Commons Attribution-Non Commercial License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Clinical Research Articles Vairamani, Kanimozhi Merjaneh, Lina Casano-Sancho, Paula Sanli, Merve Emecen David, Alessia Metherell, Louise A. Savage, Martin O. Sánchez del Pozo, Jaime Backeljauw, Philippe F. Rosenfeld, Ron G. Aisenberg, Javier Dauber, Andrew Hwa, Vivian Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency |
title | Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency |
title_full | Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency |
title_fullStr | Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency |
title_full_unstemmed | Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency |
title_short | Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency |
title_sort | novel dominant-negative gh receptor mutations expands the spectrum of ghi and igf-i deficiency |
topic | Clinical Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686656/ https://www.ncbi.nlm.nih.gov/pubmed/29188236 http://dx.doi.org/10.1210/js.2016-1119 |
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