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- Title
Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy.
- Authors
Ślęczkowska, Milena; Almomani, Rowida; Marchi, Margherita; de Greef, Bianca T. A.; Sopacua, Maurice; Hoeijmakers, Janneke G. J.; Lindsey, Patrick; Salvi, Erika; Bönhof, Gidon J.; Ziegler, Dan; Malik, Rayaz A.; Waxman, Stephen G.; Lauria, Giuseppe; Faber, Catharina G.; Smeets, Hubert J. M.; Gerrits, Monique M.
- Abstract
Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 (n = 3), HCN1 (n = 1), KCNK18 (n = 2), TRPA1 (n = 3), TRPM8 (n = 3) and TRPV4 (n = 1) and fourteen painless-DN patients (4.6%—three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (n = 1), KCNK18 (n = 3), KCNQ3 (n = 1), TRPA1 (n = 2), TRPM8 (n = 1), TRPV1 (n = 3) and TRPV4 (n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.
- Subjects
TRP channels; CHLORIDE channels; ION channels; CALCIUM-dependent potassium channels; NEUROPATHY; DIABETIC neuropathies; GENETIC variation
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 13, p7190
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23137190