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A de novo gain-of-function mutation in SCN11A causes loss of pain perception

Abstract

The sensation of pain protects the body from serious injury1,2,3. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system4,5. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

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Figure 1: An SCN11A mutation results in the inability to experience pain in humans.
Figure 2: Scn11a+/L799P mice recapitulate aspects of the human phenotype.
Figure 3: Electrophysiological properties of mouse DRG neurons.
Figure 4: Mutant Nav1.9 channels display gain-of-function properties.
Figure 5: Gain of function with the p.Leu811Pro alteration in human Nav1.9.

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Acknowledgements

We are grateful to the families participating in the study. Excellent technical assistance was provided by K. Schorr, A. Roßner, P. Schroth and the team from the Jena University Hospital animal facility. Scn11a−/− mice were generously provided by J.N. Wood (Wolfson Institute for Biomedical Research, University College London). ND7/23 cells were generously provided by C. Nau (University Hospital Erlangen). We thank D.G.G. McMillan for critical reading of the manuscript. This work was supported by grants from the DFG (Deutsche Forschungsgemeinschaft) to I.K. (KU 1587/2-1) and C.A.H. (HU 800/5-1, RTG 1715, HU 800/6-1 and HU 800/7-1). Funding to J.B., P.D.J. and V.T. was provided by the University of Antwerp, Fund for Scientific Research (FWO-Flanders), Association Belge contre les Maladies neuro-Musculaires (ABMM) and Medical Foundation Queen Elisabeth (GSKE). Funding to R.B. was provided by the DFG (BL567/3-1). Funding to J.W. was provided by the DFG (WE 1406/13-1) and IZKF (Interdisziplinäres Zentrum für Klinische Forschung) Aachen (N5-3).

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I.K., C.A.H., E.L. and S.H.H. designed this study. G.C.K., J.B., V.T., P.D.J. and T.S. assessed the phenotypes of the affected individuals. M.B. and J.W. performed neuropathological analysis. J.A., H.T. and P.N. performed exome sequencing. Additional experiments were performed by I.K. (genetics, generation of knock-in mice and molecular biology), E.L., R.O.G. and L.L. (electrophysiology), S.G. (molecular biology and histology), J.C.H., A.W. and R.B. (molecular biology) and T.H. (tail-flick assay and histology). M.E. and H.-G.S. performed behavioral analysis and evaluation. I.K., L.L., E.L., S.H.H. and C.A.H. analyzed the data and wrote the manuscript with input from the coauthors.

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Correspondence to Ingo Kurth.

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Leipold, E., Liebmann, L., Korenke, G. et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet 45, 1399–1404 (2013). https://doi.org/10.1038/ng.2767

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