Blesneac, I., Themistocleous, A.C., Fratter, C. et al. (8 more authors) (2018) Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy. Pain, 159 (3). pp. 469-480. ISSN 0304-3959
Abstract
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 NaV1.7 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 NaV1.7 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 NaV1.7, 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 NaV1.7 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 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 ((http://creativecommons.org/licenses/by/4.0)), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited |
Keywords: | Diabetic peripheral neuropathy; Neuropathic pain; Voltage-gated sodium channel NaV1.7; Genetics |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 17 May 2021 13:24 |
Last Modified: | 17 May 2021 13:24 |
Status: | Published |
Publisher: | Ovid Technologies (Wolters Kluwer Health) |
Refereed: | Yes |
Identification Number: | 10.1097/j.pain.0000000000001116 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174190 |
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Filename: Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.pdf
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