An SCN9A channelopathy causes congenital inability to experience pain. Nature

Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
Nature (Impact Factor: 41.46). 01/2007; 444(7121):894-8. DOI: 10.1038/nature05413
Source: PubMed


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.

80 Reads
  • Source
    • "as an analgesic target. Gain-of-function mutations in the SNC9A gene encoding hNaV1.7 cause painful inherited neuropathies (Yang et al., 2004; Fertleman et al., 2006; Estacion et al., 2008; Cheng et al., 2011; Theile et al., 2011), whereas loss-offunction mutations result in congenital indifference to all forms of pain (Cox et al., 2006). Moreover, single nucleotide polymorphisms in SCN9A are associated with differences in pain sensitivity (Reimann et al., 2010; Duan et al., 2013; Reeder et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose-limiting side effects. Humans with loss-of-function mutations in the voltage-gated sodium channel NaV 1.7 (hNaV 1.7) are indifferent to pain, making hNaV 1.7 a promising target for analgesic development. Since spider venoms are replete with NaV channel modulators, we examined their potential as a source of hNaV 1.7 inhibitors. We developed a high-throughput fluorescent-based assay to screen spider venoms against hNaV 1.7 and isolate 'hit' peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S3b-S4 paddle motif from each voltage sensor domain of hNaV 1.7 was transplanted into the homotetrameric KV 2.1 channel. We screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV 1.7. By deconvoluting 'hit' venoms, we discovered seven novel members of the NaSpTx family 1. One of these peptides, Hd1a (peptide μ-TRTX-Hd1a from venom of the spider Haplopelma doriae), inhibited hNaV 1.7 with a high level of selectivity over all other subtypes, except hNaV 1.1. We showed that Hd1a is a gating modifier that inhibits hNaV 1.7 by interacting with the S3b-S4 paddle motif in channel domain II. The structure of Hd1a, determined using heteronuclear NMR, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability. Our data indicate that spider venoms are a rich natural source of hNaV 1.7 inhibitors that might be useful leads for the development of novel analgesics. © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 03/2015; 172(10). DOI:10.1111/bph.13081 · 4.84 Impact Factor
  • Source
    • "For example, mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) and nerve growth factor-í µí»½ (NGFB) result in CIP with an anhidrosis phenotype [2] [3]. In contrast, homozygous loss of function mutations in sodium channel voltage-gated type IX, alpha subunit (SCN9A) gene has been reported to result in the CIP with an anosmia phenotype [4]. Although this condition is rare, genotype phenotype studies of such patients are important. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital insensitivity to pain (CIP) is a rare autosomal recessive genetic disease caused by mutations in the SCN9A gene. We report a patient with the clinical features consistent with CIP in whom we detected a novel homozygous G2755T mutation in exon 15 of this gene. Routine electrophysiological studies are typically normal in patients with CIP. In our patient, these studies were abnormal and could represent the consequences of secondary complications of cervical and lumbosacral spine disease and associated severe Charcot's joints.
    09/2014; 2014:141953. DOI:10.1155/2014/141953
  • Source
    • "An important aspect for the survival of all organisms is the sensation of potential harmful (noxious) threats, which often are experienced as pain (nociception). Accordingly, it has been known for a long time that, even humans with congenital insensitivity to pain often die as children because they fail to notice injuries and illnesses, which underlies the importance of proper nociception (see for review: Indo, 2001; Cox et al., 2006; Costigan et al., 2009). Nociceptive neurons, like all primary afferent neurons, innervate organs and the periphery. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. Recently, two chemokines have been suggested as potential factors that mediate the communication between injured neurons and microglia namely CCL2 and CCL21. This assumption is based on the following findings. Both chemokines are not found in healthy neurons, but are expressed in response to neuronal injury. In injured dorsal root ganglion cells CCL2 and CCL21 are expressed in vesicles in the soma and transported through the axons of the dorsal root into the dorsal horn of the spinal cord. Finally, microglia in vitro are known to respond to CCL2 and CCL21. Whereas the microglial chemokine receptor involved in CCL21-induced neuropathic pain is not yet defined the situation concerning the receptors for CCL2 in microglia in vivo is even less clear. Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.
    Frontiers in Cellular Neuroscience 08/2014; 8:210. DOI:10.3389/fncel.2014.00210 · 4.29 Impact Factor
Show more

Similar Publications