title: An SCN9A channelopathy causes congenital inability to experience pain.
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.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.forename: Adeline K
authors.initials: AK
authors.lastname: Nicholas
authors.forename: Gemma
authors.initials: G
authors.lastname: Thornton
authors.forename: Emma
authors.initials: E
authors.lastname: Roberts
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.forename: Gulshan
authors.initials: G
authors.lastname: Karbani
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Jovaria
authors.initials: J
authors.lastname: Mannan
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Raashid
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Henan
authors.initials: H
authors.lastname: Hamamy
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Shaun
authors.initials: S
authors.lastname: Gorman
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Duncan P
authors.initials: DP
authors.lastname: McHale
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000235:genetics* / Q000503:physiopathology*; D000699:Pain Insensitivity, Congenital / Q000235:genetics* / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels