An SCN9A channelopathy causes congenital inability to experience pain

James J. Cox, Frank Reimann, Adeline K. Nicholas, Gemma Thornton, Emma Roberts, Kelly Springell, Gulshan Karbani, Hussain Jafri, Jovaria Mannan, Yasmin Raashid, Lihadh Al-Gazali, Henan Hamamy, Enza Maria Valente, Shaun Gorman, Richard Williams, Duncan P. McHale, John N. Wood, Fiona M. Gribble and C. Geoffrey Woods ()
Additional contact information
James J. Cox: Department of Medical Genetics
Frank Reimann: Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke’s Hospital
Adeline K. Nicholas: Department of Medical Genetics
Gemma Thornton: Department of Medical Genetics
Emma Roberts: Section of Ophthalmology and Neuroscience Leeds Institute of Molecular Medicine
Kelly Springell: Section of Ophthalmology and Neuroscience Leeds Institute of Molecular Medicine
Gulshan Karbani: St James’s University Hospital
Hussain Jafri: Gene Tech Lab 146/1
Jovaria Mannan: Fatima Jinah Medical College
Yasmin Raashid: King Edward Medical University
Lihadh Al-Gazali: United Arab Emirates University
Henan Hamamy: National Center for Diabetes, Endocrinology and Genetics
Enza Maria Valente: IRCCS CSS, San Giovanni Rotondo and CSS Mendel
Shaun Gorman: St Luke’s Hospital
Richard Williams: Pfizer Global Research and Development, Sandwich Laboratories
Duncan P. McHale: Pfizer Global Research and Development, Sandwich Laboratories
John N. Wood: University College London
Fiona M. Gribble: Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke’s Hospital
C. Geoffrey Woods: Department of Medical Genetics

Nature, 2006, vol. 444, issue 7121, 894-898

Abstract: 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 α-subunit of the voltage-gated sodium channel, Nav1.7, 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 Nav1.7 by co-expression of wild-type or mutant human Nav1.7 with sodium channel β1 and β2 subunits in HEK293 cells. In cells expressing mutant Nav1.7, 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.

Date: 2006
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DOI: 10.1038/nature05413

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