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

被引：11

作者：

Sleczkowska, Milena ^{[1
,2
]}

Almomani, Rowida ^{[1
,3
,4
]}

Marchi, Margherita ^{[5
]}

de Greef, Bianca T. A. ^{[3
]}

Sopacua, Maurice ^{[3
]}

Hoeijmakers, Janneke G. J. ^{[3
]}

Lindsey, Patrick ^{[1
]}

Salvi, Erika ^{[5
]}

Boenhof, Gidon J. ^{[6
,7
]}

Ziegler, Dan ^{[6
]}

Malik, Rayaz A. ^{[8
,9
]}

Waxman, Stephen G. ^{[10
,11
,12
]}

Lauria, Giuseppe ^{[5
]}

Faber, Catharina G. ^{[3
]}

Smeets, Hubert J. M. ^{[1
,2
]}

Gerrits, Monique M. ^{[13
]}

机构：

[1] Maastricht Univ, Dept Toxicogen, NL-6229 ER Maastricht, Netherlands

[2] Maastricht Univ, Sch Mental Hlth & Neurosci, NL-6229 ER Maastricht, Netherlands

[3] Maastricht Univ, Med Ctr, Dept Neurol, NL-6229 HX Maastricht, Netherlands

[4] Jordan Univ Sci & Technol, Dept Med Lab Sci, Irbid 22110, Jordan

[5] IRCCS Fdn Carlo Besta Neurol Inst, Neuroalgol Unit, I-20133 Milan, Italy

[6] Heinrich Heine Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, D-40225 Dusseldorf, Germany

[7] Heinrich Heine Univ Dusseldorf, Univ Hosp Dusseldorf, Med Fac, Dept Endocrinol & Diabetol, D-40225 Dusseldorf, Germany

[8] Univ Manchester, Div Cardiovasc Sci, Manchester M13 9PL, Lancs, England

[9] Weill Cornell Med Qatar, Dept Med, POB 24144, Doha, Qatar

[10] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA

[11] Yale Univ, Sch Med, Ctr Neurosci & Regenerat Res, New Haven, CT 06510 USA

[12] Vet Affairs Med Ctr, Ctr Neurosci & Regenerat Res, West Haven, CT 06516 USA

[13] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6229 HX Maastricht, Netherlands

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2022年 / 23卷 / 13期

基金：

欧盟地平线“2020”;

关键词：

MIPs-NGS; neuropathic pain; ion channel; TRP channels; diabetic neuropathy; SENSORY NEURONS; ANOCTAMIN; MIGRAINE; PREVALENCE; EXPRESSION; VARIANTS; MUTATION; RECEPTOR; TRPV4; BLOCK;

D O I：

10.3390/ijms23137190

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：16

共 55 条

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