Inability to Experience Pain: Pathophysiology of the SCN11A disorder
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
In 2013, we linked for the first time mutations in the voltage-gated sodium channel NaV1.9 to human congenital insensitivity to pain. The finding was also interesting in that Nav1.9 has always been considered a target for pain therapy. For a profound understanding of the disease and for research into the appropriateness of the molecule as drug target, we aimed to better understand this channelopathy within the funding period. We were able to show that most likely mutations in only very specific regions of the ion-channel lead to the phenotype of painlessness. These are amino-acids at the last transmembrane segment (S6) of one of the four domains (D1-D4) of the channel. Here a mutation causes a pronounced "gain-of-function" effect and pain conduction to the CNS is impaired. Milder "gain-of-function" mutations lead to channel hyperexcitability and an opposite phenotype, i.e. severe episodic pain. Detailed phenotyping of knockin-mice with a corresponding painless mutation (Scn11a - L799P) suggests that the respective mouse model does reflect some, but not all aspects of the human disease. Importantly, the mouse model revealed that hyperactivity of NaV1.9 already has an influence on the development of pain-processing pathways, suggesting that this may already partially explain the phenotype of painlessness. In this respect, it remains uncertain whether drugs modulating NaV1.9 function are suited for pain therapy. In a further subproject, we simultaneously knocked out the two TTX-resistant sodium-channels NaV1.8 (Scn10a) and NaV1.9 (Scn11a) in mice using CRISPR/Cas technologies. This strategy was chosen since both channels are genetically linked and by crossing individual knockout strains no double-KO can be generated. Both channels are significantly involved in pain perception and an effect of disrupting both channels at the same time was investigated. Initial results showed that there are only subtle differences in pain perception in Scn10a/Scn11a double-KO mice, and further phenotypic characterization still needs to show whether there are differences for certain pain qualities. The nociceptors of the double-KO model could successfully be used for the electrophysiological characterization of novel NaV1.9 mutants, since the investigation of these mutations in the absence of NaV1.8 expression is more comprehensive. In summary, the investigations have yielded further insights into the role of voltage-gated sodium channels and pain.
Publications
- 2015. Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant. Nat Commun 6,10049
Leipold, E., Hanson-Kahn, A., Frick, M., Gong, P., Bernstein, J.A., Voigt, M., Katona, I., Oliver Goral, R., Altmuller, J., Nurnberg, P., Weis, J., Hubner, C.A., Heinemann, S.H., Kurth, I.
(See online at https://doi.org/10.1038/ncomms10049) - 2015. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur J Hum Genet 23(5), 561-563
Woods, C.G., Babiker, M.O., Horrocks, I., Tolmie, J., Kurth, I.
(See online at https://doi.org/10.1038/ejhg.2014.166) - 2017. Pain insensitivity: distal S6-segment mutations in NaV1.9 emerge as critical hotspot. Neurogenetics 18(3), 179-181
King, M.K., Leipold, E., Goehringer, J.M., Kurth, I., Challman, T.D.
(See online at https://doi.org/10.1007/s10048-017-0513-9) - 2018. Hereditary Neuropathies. Dtsch Arztebl Int 115(6), 91-97
Eggermann, K., Gess, B., Hausler, M., Weis, J., Hahn, A., Kurth, I.
(See online at https://doi.org/10.3238/arztebl.2018.0091) - 2019. [Neuropathic pain syndromes and channelopathies]. Internist (Berl) 60(1), 90-97
Dohrn, M.F., Lampert, A., Uceyler, N., Kurth, I.
- 2019. A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain. Front Neurosci 13, 918
Huang, J., Estacion, M., Zhao, P., Dib-Hajj, F.B., Schulman, B., Abicht, A., Kurth, I., Brockmann, K., Waxman, S.G., Dib-Hajj, S.D.
(See online at https://doi.org/10.3389/fnins.2019.00918) - (2018) Human genetics of pain. In: The Oxford Handbook of the Neurobiology of Pain. Oxford University Press. S. 101-127
Cox JJ., Kurth I., Woods CG
