An SCN9A channelopathy causes congenital inability to experience pain.
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.
Cox
James J
JJ
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
Reimann
Frank
F
Nicholas
Adeline K
AK
Thornton
Gemma
G
Roberts
Emma
E
Springell
Kelly
K
Karbani
Gulshan
G
Jafri
Hussain
H
Mannan
Jovaria
J
Raashid
Yasmin
Y
Al-Gazali
Lihadh
L
Hamamy
Henan
H
Valente
Enza Maria
EM
Gorman
Shaun
S
Williams
Richard
R
McHale
Duncan P
DP
Wood
John N
JN
Gribble
Fiona M
FM
Woods
C Geoffrey
CG
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*
D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels