Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Dec 14;444(7121):894-8.
doi: 10.1038/nature05413.

An SCN9A channelopathy causes congenital inability to experience pain

James J Cox  1 , Frank Reimann, Adeline K Nicholas, Gemma Thornton, Emma Roberts, Kelly Springell, Gulshan Karbani, Hussain Jafri, Jovaria Mannan, Yasmin Raashid, Lihadh Al-Gazali, Henan Hamamy, Enza Maria Valente, Shaun Gorman, Richard Williams, Duncan P McHale, John N Wood, Fiona M Gribble, C Geoffrey Woods
Affiliations

An SCN9A channelopathy causes congenital inability to experience pain

James J Cox et al. Nature. .

Abstract

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 alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, 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 Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, 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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to C.G.W. (cw347@cam.ac.uk).

Figures

Fig. 1
Fig. 1. The families used to map the locus for channelopathy-associated insensitivity to pain.
Autozygosity mapping in families 1 and 2 on the left of the diagram enabled the identification of a shared 20 cM homozygous region on chromosome 2q24 (there were no other significant homozygous regions detected). The two-point LOD score was 3.2 at θ = 5 0, for AC064843GT21 and AC092641TG18, but greater for more informative markers, see Supplementary Table 1. Family 3, on the right of the diagram, was used to refine this region to an 11.7-Mb shared homozygous region flanked by the heterozygous markers D2S1353 and AC012594TG25 and defined by the homozygous markers AC064843GT21 and AC092641TG18. Affected individuals are indicated with filled symbols.
Fig. 2
Fig. 2. Sequence chromatograms showing the mutations identified in families 1, 2 and 3.
The arrows indicate the site of the mutations.
Fig. 3
Fig. 3. Schematic representation of Nav1.7, the voltage-gated sodium channel α-subunit encoded by SCN9A, and the locations of the identified human mutations.
SCN9A encodes a plasma membrane protein: in the figure, the plasma membrane is shown in grey; the extracellular region is uppermost; and intracellular region below. Nav1.7 is predicted to fold into four similar domains with each domain comprising six α-helical transmembrane segments (labelled 1–6). Transmembrane segments 5 and 6 are the pore-lining segments and the voltage sensor is located in transmembrane segment 4 of each domain (depicted by a plus symbol). The red arrows indicate the location of the nonsense mutation in each family.
Fig. 4
Fig. 4. Patch-clamping experiments to investigate the voltage-gated sodium channel activity of wild-type and truncated Nav1.7.
a, Constructs used in the patch-clamping experiments (see Supplementary Methods). We cloned wild-type SCN9A and then used site-directed mutagenesis to manufacture three further constructs each containing a family mutation. Each SCN9A construct was sequentially co-transfected with a plasmid containing the auxiliary sodium channel β1 and β2 subunits, and only cells clearly expressing DsRed2 (red fluorescence) and EGFP (green fluorescence) were measured for electrical activity. ECMV, encephalomyocarditis virus; IRES, internal ribosome entry site. b, A typical cell used in the patch-clamping experiments, showing both EGFP fluorescence (left) and DsRed2 fluorescence (middle), with the pipette attached in phase contrast (right). c, Left panel: initial current responses to 50-ms voltage steps of 5-mV increments between −70 and +40 mV from a holding potential of −100 mV, in a whole-cell voltage clamp recording applied at ∼0.5 Hz for a cell co-expressing wild-type (WT) Nav1.7 (top) or Nav1.7 W897X (bottom) with the β-subunits. The inset shows the voltage pulse protocol. Right panel: current–voltage relationship of the peak currents normalized for cell size (pA per pF) obtained using the experimental set-up shown on the left. Black squares, wild type (n = 13); red circles, I767X (n = 7); blue squares, W897X (n = 7); green diamonds, S459X (n = 5); white diamonds, β-subunits only (n = 5). The red line represents a fit of the wild-type data with a Boltzmann equation y = (A2 + (A1 − A2)/(1 + exp((V0.5 − x)/k)))(x − Vrev), where V0.5 = 28.0 mV, k = 4.9 mV, Vrev = 64 mV. d, Left panel: voltage dependence of the steady-state inactivation of wild-type Nav1.7 plus β-subunits was measured by holding the membrane potential for 500 ms at conditioning voltages from −120 to 0 mV (at 5-mV increments) before stepping to a test pulse at −10 mV for 50 ms. The inset shows the voltage pulse protocol, which was applied at 0.5 Hz. Only the current responses to the test pulse are shown. Right panel: the peak currents obtained as on the left were normalized to the maximum peak current, and plotted against the holding potential applied during the conditioning pulse. The red line represents a fit of the data with a Boltzmann equation y = (A1 − A2)/(1 + exp((x − V0.5)/k)) + A2, where V0.5 = −71 mV, k = 5.9 mV, n = 13. Error bars in c and d represent standard errors.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dearborn G. A case of congenital general pure analgesia. J Nerv Ment Dis. 1932;75:612–615.
    1. Dyck PJ, et al. Not ‘indifference to pain’ but varieties of hereditary sensory and autonomic neuropathy. Brain. 1983;106:373–390. - PubMed
    1. Landrieu P, Said G, Allaire C. Dominantly transmitted congenital indifference to pain. Ann Neurol. 1990;27:574–578. - PubMed
    1. Nagasako EM, Oaklander AL, Dworkin RH. Congenital insensitivity to pain: an update. Pain. 2003;101:213–219. - PubMed
    1. Klein CJ, Sinnreich M, Dyck PJ. Indifference rather than insensitivity to pain. Ann Neurol. 2003;53:417–418. author reply Ann. Neurol. 53, 418-419 (2003) - PubMed

Publication types

MeSH terms

Substances

Associated data