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Papers of the Week

Papers: 9 Jul 2022 - 15 Jul 2022

Human Studies

2022 Jun 28

Int J Mol Sci



Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy.


Ślęczkowska M, Almomani R, Marchi M, de Greef BTA, Sopacua M, Hoeijmakers JGJ, Lindsey P, Salvi E, Bönhof GJ, Ziegler D, Malik RA, Waxman SG, Lauria G, Faber CG, Smeets H J, Gerrits MM
Int J Mol Sci. 2022 Jun 28; 23(13).
PMID: 35806193.


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 ( = 3), HCN1 ( = 1), KCNK18 ( = 2), TRPA1 ( = 3), TRPM8 ( = 3) and TRPV4 ( = 1) and fourteen painless-DN patients (4.6%-three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 ( = 1), KCNK18 ( = 3), KCNQ3 ( = 1), TRPA1 ( = 2), TRPM8 ( = 1), TRPV1 ( = 3) and TRPV4 ( = 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.