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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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.
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 www.nature.com/reprints. The authors declare no competing financial interests.
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). https://doi.org/10.1038/nature05413
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