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Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed f...

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Autores principales: Blesneac, Iulia, Themistocleous, Andreas C., Fratter, Carl, Conrad, Linus J., Ramirez, Juan D., Cox, James J., Tesfaye, Solomon, Shillo, Pallai R., Rice, Andrew S.C., Tucker, Stephen J., Bennett, David L.H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828379/
https://www.ncbi.nlm.nih.gov/pubmed/29176367
http://dx.doi.org/10.1097/j.pain.0000000000001116
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author Blesneac, Iulia
Themistocleous, Andreas C.
Fratter, Carl
Conrad, Linus J.
Ramirez, Juan D.
Cox, James J.
Tesfaye, Solomon
Shillo, Pallai R.
Rice, Andrew S.C.
Tucker, Stephen J.
Bennett, David L.H.
author_facet Blesneac, Iulia
Themistocleous, Andreas C.
Fratter, Carl
Conrad, Linus J.
Ramirez, Juan D.
Cox, James J.
Tesfaye, Solomon
Shillo, Pallai R.
Rice, Andrew S.C.
Tucker, Stephen J.
Bennett, David L.H.
author_sort Blesneac, Iulia
collection PubMed
description Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel Na(V)1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare Na(V)1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of Na(V)1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare Na(V)1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively.
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spelling pubmed-58283792018-03-06 Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy Blesneac, Iulia Themistocleous, Andreas C. Fratter, Carl Conrad, Linus J. Ramirez, Juan D. Cox, James J. Tesfaye, Solomon Shillo, Pallai R. Rice, Andrew S.C. Tucker, Stephen J. Bennett, David L.H. Pain Research Paper Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel Na(V)1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare Na(V)1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of Na(V)1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare Na(V)1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively. Wolters Kluwer 2018-03 2017-11-12 /pmc/articles/PMC5828379/ /pubmed/29176367 http://dx.doi.org/10.1097/j.pain.0000000000001116 Text en Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Blesneac, Iulia
Themistocleous, Andreas C.
Fratter, Carl
Conrad, Linus J.
Ramirez, Juan D.
Cox, James J.
Tesfaye, Solomon
Shillo, Pallai R.
Rice, Andrew S.C.
Tucker, Stephen J.
Bennett, David L.H.
Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy
title Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy
title_full Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy
title_fullStr Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy
title_full_unstemmed Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy
title_short Rare Na(V)1.7 variants associated with painful diabetic peripheral neuropathy
title_sort rare na(v)1.7 variants associated with painful diabetic peripheral neuropathy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828379/
https://www.ncbi.nlm.nih.gov/pubmed/29176367
http://dx.doi.org/10.1097/j.pain.0000000000001116
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