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Unformatted text preview: ARTICLES An SCN9A channelopathy causes congenital inability to experience pain James J. Cox 1 *, Frank Reimann 2 *, Adeline K. Nicholas 1 , Gemma Thornton 1 , Emma Roberts 3 , Kelly Springell 3 , Gulshan Karbani 4 , Hussain Jafri 5 , Jovaria Mannan 6 , Yasmin Raashid 7 , Lihadh Al-Gazali 8 , Henan Hamamy 9 , EnzaMariaValente 10 ,ShaunGorman 11 ,RichardWilliams 12 ,DuncanP.McHale 12 ,JohnN.Wood 13 ,FionaM.Gribble 2 & C. Geoffrey Woods 1 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 a-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 b 1 and b 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. Pain is an essential sense that has evolved in all complex organisms to minimize tissue and cellular damage, and hence prolong survival. The onset of pain results in the adoption of behaviours that both remove the organism from a dangerous environment and allow for tissue repair; for example, resting a broken limb so that new bone can form. Pain also protects us from our environment, by teaching us what situations and behaviours are likely to lead to injury. Pain path- ways operate at numerous levels in the nervous system and are under both voluntary and involuntary control. Blockade of this system with analgesics has been a major pharmacological achievement. Whereas individuals with a congenital absence of the sense of vision or of hearing are relatively common, a congenital absence of the sense of pain is very rare. The first case of a patient with a con- genital inability to perceive pain was said to have been reported in the early twentieth century 1 . Only a handful of such patients have since been described and are usually categorized as having congenital indifference to pain (OMIM 243000, also known as autosomal recessive congenital analgesia) or as being misdiagnoses of congen- ital insensitivity to pain (OMIM 608654, also known as hereditary sensory and autonomic neuropathy type 5 (HSAN5)) 24 . Historically these two conditions have been largely distinguished by the absence or presence, respectively, of an associated neuropathy 2 . The existence of congenital indifference to pain has, however, been questioned and...
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