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Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism

OBJECTIVE: To identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease. METHODS: We performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy. RESULTS: We found a non–previously described mutation in EGR2 (p.P397H). P397H...

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Autores principales: Blanco-Cantó, Maria Empar, Patel, Nikiben, Velasco-Aviles, Sergio, Casillas-Bajo, Angeles, Salas-Felipe, Juan, García-Escrivá, Alexandre, Díaz-Marín, Carmen, Cabedo, Hugo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164973/
https://www.ncbi.nlm.nih.gov/pubmed/32337334
http://dx.doi.org/10.1212/NXG.0000000000000407
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author Blanco-Cantó, Maria Empar
Patel, Nikiben
Velasco-Aviles, Sergio
Casillas-Bajo, Angeles
Salas-Felipe, Juan
García-Escrivá, Alexandre
Díaz-Marín, Carmen
Cabedo, Hugo
author_facet Blanco-Cantó, Maria Empar
Patel, Nikiben
Velasco-Aviles, Sergio
Casillas-Bajo, Angeles
Salas-Felipe, Juan
García-Escrivá, Alexandre
Díaz-Marín, Carmen
Cabedo, Hugo
author_sort Blanco-Cantó, Maria Empar
collection PubMed
description OBJECTIVE: To identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease. METHODS: We performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy. RESULTS: We found a non–previously described mutation in EGR2 (p.P397H). P397H mutation is located within the loop that connects zinc fingers 2 and 3, a pivotal domain for the activity of this transcription factor. Using promoter activity luciferase assays, we found that this mutation promotes decreased transcriptional activity of EGR2. In this patient, we also found a previously described nonpathogenic polymorphism in lipopolysaccharide-induced TNF-α factor (LITAF) (p.T49M). We show that the p.T49M mutation decreases the steady-state levels of the LITAF protein in Schwann cells. Loss of function of LITAF has been shown to produce deregulation in the NRG1-erbB signaling, a pivotal pathway for EGR2 expression by Schwann cells. Surprisingly, our segregation study demonstrates that p.P397H mutation in EGR2 is not sufficient to produce CMT disease. Most notably, only those patients expressing simultaneously the LITAF T49M polymorphism develop peripheral neuropathy. CONCLUSIONS: Our data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin.
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spelling pubmed-71649732020-04-24 Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism Blanco-Cantó, Maria Empar Patel, Nikiben Velasco-Aviles, Sergio Casillas-Bajo, Angeles Salas-Felipe, Juan García-Escrivá, Alexandre Díaz-Marín, Carmen Cabedo, Hugo Neurol Genet Article OBJECTIVE: To identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease. METHODS: We performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy. RESULTS: We found a non–previously described mutation in EGR2 (p.P397H). P397H mutation is located within the loop that connects zinc fingers 2 and 3, a pivotal domain for the activity of this transcription factor. Using promoter activity luciferase assays, we found that this mutation promotes decreased transcriptional activity of EGR2. In this patient, we also found a previously described nonpathogenic polymorphism in lipopolysaccharide-induced TNF-α factor (LITAF) (p.T49M). We show that the p.T49M mutation decreases the steady-state levels of the LITAF protein in Schwann cells. Loss of function of LITAF has been shown to produce deregulation in the NRG1-erbB signaling, a pivotal pathway for EGR2 expression by Schwann cells. Surprisingly, our segregation study demonstrates that p.P397H mutation in EGR2 is not sufficient to produce CMT disease. Most notably, only those patients expressing simultaneously the LITAF T49M polymorphism develop peripheral neuropathy. CONCLUSIONS: Our data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin. Wolters Kluwer 2020-03-03 /pmc/articles/PMC7164973/ /pubmed/32337334 http://dx.doi.org/10.1212/NXG.0000000000000407 Text en Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Article
Blanco-Cantó, Maria Empar
Patel, Nikiben
Velasco-Aviles, Sergio
Casillas-Bajo, Angeles
Salas-Felipe, Juan
García-Escrivá, Alexandre
Díaz-Marín, Carmen
Cabedo, Hugo
Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism
title Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism
title_full Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism
title_fullStr Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism
title_full_unstemmed Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism
title_short Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism
title_sort novel egr2 variant that associates with charcot-marie-tooth disease when combined with lipopolysaccharide-induced tnf-α factor t49m polymorphism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164973/
https://www.ncbi.nlm.nih.gov/pubmed/32337334
http://dx.doi.org/10.1212/NXG.0000000000000407
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