Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy
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 ch...
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MDPI AG
2022-06-01
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| author | Milena Ślęczkowska Rowida Almomani Margherita Marchi Bianca T. A. de Greef Maurice Sopacua Janneke G. J. Hoeijmakers Patrick Lindsey Erika Salvi Gidon J. Bönhof Dan Ziegler Rayaz A. Malik Stephen G. Waxman Giuseppe Lauria Catharina G. Faber Hubert J. M. Smeets Monique M. Gerrits |
| author_facet | Milena Ślęczkowska Rowida Almomani Margherita Marchi Bianca T. A. de Greef Maurice Sopacua Janneke G. J. Hoeijmakers Patrick Lindsey Erika Salvi Gidon J. Bönhof Dan Ziegler Rayaz A. Malik Stephen G. Waxman Giuseppe Lauria Catharina G. Faber Hubert J. M. Smeets Monique M. Gerrits |
| author_sort | Milena Ślęczkowska |
| collection | DOAJ |
| description | 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 (<i>n</i> = 3), HCN1 (<i>n</i> = 1), KCNK18 (<i>n</i> = 2), TRPA1 (<i>n</i> = 3), TRPM8 (<i>n</i> = 3) and TRPV4 (<i>n</i> = 1) and fourteen painless-DN patients (4.6%—three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (<i>n</i> = 1), KCNK18 (<i>n</i> = 3), KCNQ3 (<i>n</i> = 1), TRPA1 (<i>n</i> = 2), TRPM8 (<i>n</i> = 1), TRPV1 (<i>n</i> = 3) and TRPV4 (<i>n</i> = 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. |
| first_indexed | 2024-03-09T21:49:44Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:49:44Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-503bf0c81ee44ca9984ee208f4169c882023-11-23T20:09:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012313719010.3390/ijms23137190Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic NeuropathyMilena Ślęczkowska0Rowida Almomani1Margherita Marchi2Bianca T. A. de Greef3Maurice Sopacua4Janneke G. J. Hoeijmakers5Patrick Lindsey6Erika Salvi7Gidon J. Bönhof8Dan Ziegler9Rayaz A. Malik10Stephen G. Waxman11Giuseppe Lauria12Catharina G. Faber13Hubert J. M. Smeets14Monique M. Gerrits15Department of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The NetherlandsDepartment of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The NetherlandsNeuroalgology Unit, IRCCS Foundation “Carlo Besta” Neurological Institute, 20133 Milan, ItalyDepartment of Neurology, Maastricht University Medical Centre, 6229 HX Maastricht, The NetherlandsDepartment of Neurology, Maastricht University Medical Centre, 6229 HX Maastricht, The NetherlandsDepartment of Neurology, Maastricht University Medical Centre, 6229 HX Maastricht, The NetherlandsDepartment of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The NetherlandsNeuroalgology Unit, IRCCS Foundation “Carlo Besta” Neurological Institute, 20133 Milan, ItalyInstitute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyInstitute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, GermanyDivision of Cardiovascular Sciences, University of Manchester, Manchester M13 9PL, UKDepartment of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USANeuroalgology Unit, IRCCS Foundation “Carlo Besta” Neurological Institute, 20133 Milan, ItalyDepartment of Neurology, Maastricht University Medical Centre, 6229 HX Maastricht, The NetherlandsDepartment of Toxicogenomics, Maastricht University, 6229 ER Maastricht, The NetherlandsDepartment of Clinical Genetics, Maastricht University Medical Centre, 6229 HX Maastricht, The NetherlandsNeuropathic 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 (<i>n</i> = 3), HCN1 (<i>n</i> = 1), KCNK18 (<i>n</i> = 2), TRPA1 (<i>n</i> = 3), TRPM8 (<i>n</i> = 3) and TRPV4 (<i>n</i> = 1) and fourteen painless-DN patients (4.6%—three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (<i>n</i> = 1), KCNK18 (<i>n</i> = 3), KCNQ3 (<i>n</i> = 1), TRPA1 (<i>n</i> = 2), TRPM8 (<i>n</i> = 1), TRPV1 (<i>n</i> = 3) and TRPV4 (<i>n</i> = 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.https://www.mdpi.com/1422-0067/23/13/7190MIPs-NGSneuropathic painion channelTRP channelsdiabetic neuropathy |
| spellingShingle | Milena Ślęczkowska Rowida Almomani Margherita Marchi Bianca T. A. de Greef Maurice Sopacua Janneke G. J. Hoeijmakers Patrick Lindsey Erika Salvi Gidon J. Bönhof Dan Ziegler Rayaz A. Malik Stephen G. Waxman Giuseppe Lauria Catharina G. Faber Hubert J. M. Smeets Monique M. Gerrits Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy International Journal of Molecular Sciences MIPs-NGS neuropathic pain ion channel TRP channels diabetic neuropathy |
| title | Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy |
| title_full | Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy |
| title_fullStr | Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy |
| title_full_unstemmed | Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy |
| title_short | Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy |
| title_sort | peripheral ion channel gene screening in painful and painless diabetic neuropathy |
| topic | MIPs-NGS neuropathic pain ion channel TRP channels diabetic neuropathy |
| url | https://www.mdpi.com/1422-0067/23/13/7190 |
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