Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy

Milena Ślęczkowska; Rowida Almomani; Margherita Marchi; Erika Salvi; Bianca T A de Greef; Maurice Sopacua; Janneke G J Hoeijmakers; Patrick Lindsey; Stephen G Waxman; Giuseppe Lauria; Catharina G Faber; Hubert J M Smeets; Monique M Gerrits

doi:10.3390/ijms232214095

Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy

Milena Ślęczkowska, Rowida Almomani, Margherita Marchi, Erika Salvi, Bianca T A de Greef, Maurice Sopacua, Janneke G J Hoeijmakers, Patrick Lindsey, Stephen G Waxman, Giuseppe Lauria, Catharina G Faber^*, Hubert J M Smeets, Monique M Gerrits

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

Original language	English
Article number	14095
Number of pages	15
Journal	International journal of molecular sciences
Volume	23
Issue number	22
DOIs	https://doi.org/10.3390/ijms232214095
Publication status	Published - 15 Nov 2022

Keywords

Anoctamins
Cohort Studies
Diabetic Neuropathies/genetics
Humans
Ion Channels/genetics
Neuralgia/genetics
Potassium Channels/genetics
Small Fiber Neuropathy/genetics
MIPs-NGS
Ion channel
Peripheral neuropathy
Neuropathic pain
Idiopathic small fiber neuropathy

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Ślęczkowska, M., Almomani, R., Marchi, M., Salvi, E., de Greef, B. T. A., Sopacua, M., Hoeijmakers, J. G. J., Lindsey, P., Waxman, S. G., Lauria, G., Faber, C. G., Smeets, H. J. M., & Gerrits, M. M. (2022). Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy. International journal of molecular sciences, 23(22), Article 14095. https://doi.org/10.3390/ijms232214095

@article{3d554bb13ae84f4c90c5762c029afc8b,

title = "Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy",

abstract = "Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.",

keywords = "Anoctamins, Cohort Studies, Diabetic Neuropathies/genetics, Humans, Ion Channels/genetics, Neuralgia/genetics, Potassium Channels/genetics, Small Fiber Neuropathy/genetics, MIPs-NGS, Ion channel, Peripheral neuropathy, Neuropathic pain, Idiopathic small fiber neuropathy",

author = "Milena {\'S}l{\c e}czkowska and Rowida Almomani and Margherita Marchi and Erika Salvi and {de Greef}, {Bianca T A} and Maurice Sopacua and Hoeijmakers, {Janneke G J} and Patrick Lindsey and Waxman, {Stephen G} and Giuseppe Lauria and Faber, {Catharina G} and Smeets, {Hubert J M} and Gerrits, {Monique M}",

note = "Funding Information: Professor Stephen Waxman received SGW report grants from the European Union{\textquoteright}s Horizon 2020 research and innovation program Marie Sklodowska-Curie grant for PAIN-Net, Molecule-to-Man Pain Network (grant no. 721841) and European Union 7th Framework Programme (grant no. 602273) for the PROPANE study, was supported in part by the Rehabilitation Research and Development Service and Biomedical Laboratory Research Service, Department of Veterans Affairs, has served as a consultant to ChromoCell Corp. and Sangamo Therapeutics, and has served on the Scientific Advisory Board of OliPass Corporation, MedTronics and Navega Therapeutics, outside the submitted work. Funding Information: This work was supported by funding from the Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement No. 721841 and the European Union seventh framework program for the PROPANE study under grant agreement No. 602273. The funding source had no involvement in study design, data collection, analysis and interpretation of data. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = nov,

day = "15",

doi = "10.3390/ijms232214095",

language = "English",

volume = "23",

journal = "International journal of molecular sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "22",

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TY - JOUR

T1 - Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy

AU - Ślęczkowska, Milena

AU - Almomani, Rowida

AU - Marchi, Margherita

AU - Salvi, Erika

AU - de Greef, Bianca T A

AU - Sopacua, Maurice

AU - Hoeijmakers, Janneke G J

AU - Lindsey, Patrick

AU - Waxman, Stephen G

AU - Lauria, Giuseppe

AU - Faber, Catharina G

AU - Smeets, Hubert J M

AU - Gerrits, Monique M

N1 - Funding Information: Professor Stephen Waxman received SGW report grants from the European Union’s Horizon 2020 research and innovation program Marie Sklodowska-Curie grant for PAIN-Net, Molecule-to-Man Pain Network (grant no. 721841) and European Union 7th Framework Programme (grant no. 602273) for the PROPANE study, was supported in part by the Rehabilitation Research and Development Service and Biomedical Laboratory Research Service, Department of Veterans Affairs, has served as a consultant to ChromoCell Corp. and Sangamo Therapeutics, and has served on the Scientific Advisory Board of OliPass Corporation, MedTronics and Navega Therapeutics, outside the submitted work. Funding Information: This work was supported by funding from the Molecule-to-Man Pain Network, a European Commission Multi-Center Collaborative Projects through the European Union’s Horizon 2020 research and innovation program under grant agreement No. 721841 and the European Union seventh framework program for the PROPANE study under grant agreement No. 602273. The funding source had no involvement in study design, data collection, analysis and interpretation of data. Publisher Copyright: © 2022 by the authors.

PY - 2022/11/15

Y1 - 2022/11/15

N2 - Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

AB - Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

KW - Anoctamins

KW - Cohort Studies

KW - Diabetic Neuropathies/genetics

KW - Humans

KW - Ion Channels/genetics

KW - Neuralgia/genetics

KW - Potassium Channels/genetics

KW - Small Fiber Neuropathy/genetics

KW - MIPs-NGS

KW - Ion channel

KW - Peripheral neuropathy

KW - Neuropathic pain

KW - Idiopathic small fiber neuropathy

U2 - 10.3390/ijms232214095

DO - 10.3390/ijms232214095

M3 - Article

C2 - 36430572

SN - 1661-6596

VL - 23

JO - International journal of molecular sciences

JF - International journal of molecular sciences

IS - 22

M1 - 14095

ER -

Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy

Abstract

Keywords

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