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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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).

Author information

Affiliations

  1. Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Jena, Germany.

    • Enrico Leipold
    • , R Oliver Goral
    •  & Stefan H Heinemann
  2. Institute of Human Genetics, Jena University Hospital, Jena, Germany.

    • Lutz Liebmann
    • , Theresa Heinrich
    • , Sebastian Gießelmann
    • , J Christopher Hennings
    • , Christian A Hübner
    •  & Ingo Kurth
  3. Department of Neuropediatrics, Pediatric Center, Oldenburg Hospital, Oldenburg, Germany.

    • G Christoph Korenke
  4. Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

    • Jonathan Baets
    • , Vincent Timmerman
    •  & Peter De Jonghe
  5. Neurogenetics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium.

    • Jonathan Baets
    •  & Peter De Jonghe
  6. Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.

    • Jonathan Baets
    •  & Peter De Jonghe
  7. Institute of Physiology, Division of Neurophysiology, Jena University Hospital, Jena, Germany.

    • Matthias Ebbinghaus
    •  & Hans-Georg Schaible
  8. Department of Neuropediatrics, Karolinska University Hospital, Stockholm, Sweden.

    • Tommy Stödberg
  9. Institute for Neuropathology, Hospital Bremen-Mitte, Bremen, Germany.

    • Markus Bergmann
  10. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.

    • Janine Altmüller
    • , Holger Thiele
    •  & Peter Nürnberg
  11. Institute for Clinical Neurobiology, University of Würzburg, Würzburg, Germany.

    • Andrea Wetzel
    •  & Robert Blum
  12. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  13. ATLAS Biolabs, Berlin, Germany.

    • Peter Nürnberg
  14. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  15. Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium.

    • Vincent Timmerman
  16. Institute of Neuropathology, RWTH Aachen University Hospital and Jülich Aachen Research Alliance (JARA) Brain Translational Medicine, Aachen, Germany.

    • Joachim Weis

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ingo Kurth.

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DOI

https://doi.org/10.1038/ng.2767

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