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An SCN9A channelopathy causes congenital inability to experience pain


The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the α-subunit of the voltage-gated sodium channel, Nav1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Nav1.7 by co-expression of wild-type or mutant human Nav1.7 with sodium channel β1 and β2 subunits in HEK293 cells. In cells expressing mutant Nav1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.

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Figure 1: The families used to map the locus for channelopathy-associated insensitivity to pain.
Figure 2: Sequence chromatograms showing the mutations identified in families 1, 2 and 3.
Figure 3: Schematic representation of Na v 1.7, the voltage-gated sodium channel α-subunit encoded by SCN9A , and the locations of the identified human mutations.
Figure 4: Patch-clamping experiments to investigate the voltage-gated sodium channel activity of wild-type and truncated Na v 1.7.


  1. Dearborn, G. A case of congenital general pure analgesia. J. Nerv. Ment. Dis. 75, 612–615 (1932)

    Article  Google Scholar 

  2. Dyck, P. J. et al. Not ‘indifference to pain’ but varieties of hereditary sensory and autonomic neuropathy. Brain 106, 373–390 (1983)

    Article  PubMed  Google Scholar 

  3. Landrieu, P., Said, G. & Allaire, C. Dominantly transmitted congenital indifference to pain. Ann. Neurol. 27, 574–578 (1990)

    Article  CAS  PubMed  Google Scholar 

  4. Nagasako, E. M., Oaklander, A. L. & Dworkin, R. H. Congenital insensitivity to pain: an update. Pain 101, 213–219 (2003)

    Article  PubMed  Google Scholar 

  5. Klein, C. J., Sinnreich, M. & Dyck, P. J. Indifference rather than insensitivity to pain. Ann. Neurol. 53, 417–418 (2003); author reply Ann. Neurol. 53, 418–419 (2003)

    Article  Google Scholar 

  6. Klugbauer, N., Lacinova, L., Flockerzi, V. & Hofmann, F. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 14, 1084–1090 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Toledo-Aral, J. J. et al. Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc. Natl Acad. Sci. USA 94, 1527–1532 (1997)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sangameswaran, L. et al. A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia. J. Biol. Chem. 272, 14805–14809 (1997)

    Article  CAS  PubMed  Google Scholar 

  9. Rush, A. M. et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl Acad. Sci. USA 103, 8245–8250 (2006)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Amir, R. et al. The role of sodium channels in chronic inflammatory and neuropathic pain. J. Pain 7, S1–29 (2006)

    Article  CAS  PubMed  Google Scholar 

  11. Cummins, T. R., Howe, J. R. & Waxman, S. G. Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J. Neurosci. 18, 9607–9619 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Amrani, N., Sachs, M. S. & Jacobson, A. Early nonsense: mRNA decay solves a translational problem. Nature Rev. Mol. Cell Biol. 7, 415–425 (2006)

    Article  CAS  Google Scholar 

  13. Black, J. A. et al. Spinal sensory neurons express multiple sodium channel α-subunit mRNAs. Brain Res. Mol. Brain Res. 43, 117–131 (1996)

    Article  CAS  PubMed  Google Scholar 

  14. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000)

    Article  CAS  PubMed  Google Scholar 

  15. Isom, L. L. Sodium channel β subunits: anything but auxiliary. Neuroscientist 7, 42–54 (2001)

    Article  CAS  PubMed  Google Scholar 

  16. Cummins, T. R., Dib-Hajj, S. D. & Waxman, S. G. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J. Neurosci. 24, 8232–8236 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Catterall, W. A., Goldin, A. L. & Waxman, S. G. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57, 397–409 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. Herzog, R. I., Cummins, T. R., Ghassemi, F., Dib-Hajj, S. D. & Waxman, S. G. Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J. Physiol. (Lond.) 551, 741–750 (2003)

    Article  CAS  Google Scholar 

  19. Renganathan, M., Cummins, T. R. & Waxman, S. G. Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol. 86, 629–640 (2001)

    Article  CAS  PubMed  Google Scholar 

  20. Blair, N. T. & Bean, B. P. Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci. 22, 10277–10290 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Raymond, C. K. et al. Expression of alternatively spliced sodium channel α-subunit genes. Unique splicing patterns are observed in dorsal root ganglia. J. Biol. Chem. 279, 46234–46241 (2004)

    Article  CAS  PubMed  Google Scholar 

  22. Yang, Y. et al. Mutations in SCN9A, encoding a sodium channel α subunit, in patients with primary erythermalgia. J. Med. Genet. 41, 171–174 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dib-Hajj, S. D. et al. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 128, 1847–1854 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. Han, C. et al. Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Ann. Neurol. 59, 553–558 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. Nassar, M. A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl Acad. Sci. USA 101, 12706–12711 (2004)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nassar, M. A., Levato, A., Stirling, L. C. & Wood, J. N. Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8. Mol. Pain 1, 24 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  27. Akopian, A. N., Abson, N. C. & Wood, J. N. Molecular genetic approaches to nociceptor development and function. Trends Neurosci. 19, 240–246 (1996)

    Article  CAS  PubMed  Google Scholar 

  28. Scholz, J. & Woolf, C. J. Can we conquer pain?. Nature Neurosci. 5, (Suppl)1062–1067 (2002)

    Article  CAS  PubMed  Google Scholar 

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We thank the families who participated in this study, A. Boylston for critical advice, and Pfizer, the Wellcome Trust and St John’s College, Cambridge for funding. Author Contributions This study was designed by J.J.C., F.R., E.R., R.W., D.P.M., F.M.G. and C.G.W.; patient identification and phenotype assessment was performed by G.K., H.J., J.M., Y.R., L.A.-G., H.H., E.M.V., S.G. and C.G.W.; DNA extraction, linkage analysis, bioinformatics and sequencing was performed by J.J.C., A.K.N., E.R., K.S. and C.G.W.; cloning was performed by J.J.C.; electrophysiology was performed by F.R. and F.M.G.; and the paper was written by J.J.C., F.R., G.T., J.N.W., F.M.G. and C.G.W.

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Correspondence to C. Geoffrey Woods.

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Competing interests

The sequence for full-length human SCN9A cloned from fetal brain mRNA is deposited in GenBank under accession number DQ857292. Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods discussing cloning methodology used to generate the constructs for this study, Supplementary Figures 1- 2 and Supplementary Tables 1-2. Supplementary Figure 1 shows kinetic properties of whole cell wild-type NaV1.7+NaVβ1+NaVβ2 currents in HEK293 cells. Supplementary Figure 2 shows alignment of the amino acid sequences of the corresponding common splice variants for the human (NP_002968) and mouse Nav1.7 (XP_904764) proteins using the LALIGN program (: = identical amino acid; . = similar amino acid). Supplementary Table 1 shows markers used to search for common haplotype blocks between the three families.Supplementary Table 2 shows primers used to amplify and sequence the coding exons and splice sites of SCN9A (PDF 5083 kb)

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Cox, J., Reimann, F., Nicholas, A. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).

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