An SCN9A channelopathy causes congenital inability to experience pain

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

¹Department of Medical Genetics, and ²Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK. ³Section of Ophthalmology and Neuroscience Leeds Institute of Molecular Medicine, ⁴Department of Clinical Genetics, St James's University Hospital, Leeds LS9 7TF, UK. ⁵Gene Tech Lab 146/1, Shadman Jail Road, Lahore, Pakistan. ⁶Department of Paediatrics, Fatima Jinah Medical College, Lahore, Pakistan. ⁷Department of Obstetrics and Gynaecology, King Edward Medical University, Lahore, Pakistan. ⁸Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Anin P O Box 15551, United Arab Emirates. ⁹National Center for Diabetes, Endocrinology and Genetics, Amman P O Box 3165/11942, Jordan. ¹⁰IRCCS CSS, San Giovanni Rotondo and CSS Mendel, Rome I-00168, Italy. ¹¹Department of Paediatrics, St Luke's Hospital, Bradford BD5 0NA, UK. ¹²Pfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, UK. ¹³Molecular Nociception Group, Department of Biology, University College London, London WC1E 6BT, UK.

doi:10.1038/nature05413

*These authors contributed equally to this work.

Received 9 August; accepted 3 November 2006.

Supplementary Information is linked to the online version of the paper at www.nature.com/nature.

Author Information The sequence for full-length human SCN9A cloned from fetal brain mRNA is deposited in GenBank under accession number DQ857292. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to C.G.W. ([email protected]).

Nature 444(7121):p 894-898, December 14, 2006.

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 geneSCN9A,encoding the α-subunit of the voltage-gated sodium channel, Na_v1.7, which is strongly expressed in nociceptive neurons. Sequence analysis ofSCN9Ain affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na_v1.7 by co-expression of wild-type or mutant human Na_v1.7 with sodium channel β₁and β₂subunits in HEK293 cells. In cells expressing mutant Na_v1.7, the currents were no greater than background. Our data suggest thatSCN9Ais 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.