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Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor

Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to re...

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Autores principales: Moffitt, Bridgette A., Sarasua, Sara M., Ivankovic, Diana, Ward, Linda D., Valentine, Kathleen, Bennett, William E., Rogers, Curtis, Phelan, Katy, Boccuto, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956088/
https://www.ncbi.nlm.nih.gov/pubmed/36833418
http://dx.doi.org/10.3390/genes14020490
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author Moffitt, Bridgette A.
Sarasua, Sara M.
Ivankovic, Diana
Ward, Linda D.
Valentine, Kathleen
Bennett, William E.
Rogers, Curtis
Phelan, Katy
Boccuto, Luigi
author_facet Moffitt, Bridgette A.
Sarasua, Sara M.
Ivankovic, Diana
Ward, Linda D.
Valentine, Kathleen
Bennett, William E.
Rogers, Curtis
Phelan, Katy
Boccuto, Luigi
author_sort Moffitt, Bridgette A.
collection PubMed
description Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials.
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spelling pubmed-99560882023-02-25 Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor Moffitt, Bridgette A. Sarasua, Sara M. Ivankovic, Diana Ward, Linda D. Valentine, Kathleen Bennett, William E. Rogers, Curtis Phelan, Katy Boccuto, Luigi Genes (Basel) Article Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials. MDPI 2023-02-15 /pmc/articles/PMC9956088/ /pubmed/36833418 http://dx.doi.org/10.3390/genes14020490 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Moffitt, Bridgette A.
Sarasua, Sara M.
Ivankovic, Diana
Ward, Linda D.
Valentine, Kathleen
Bennett, William E.
Rogers, Curtis
Phelan, Katy
Boccuto, Luigi
Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
title Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
title_full Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
title_fullStr Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
title_full_unstemmed Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
title_short Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
title_sort stratification of a phelan–mcdermid syndrome population based on their response to human growth hormone and insulin-like growth factor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9956088/
https://www.ncbi.nlm.nih.gov/pubmed/36833418
http://dx.doi.org/10.3390/genes14020490
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