Article

Nature 444, 894-898 (14 December 2006) | doi:10.1038/nature05413; Received 9 August 2006; Accepted 3 November 2006

An SCN9A channelopathy causes congenital inability to experience pain

James J. Cox1,14, Frank Reimann2,14, Adeline K. Nicholas1, Gemma Thornton1, Emma Roberts3, Kelly Springell3, Gulshan Karbani4, Hussain Jafri5, Jovaria Mannan6, Yasmin Raashid7, Lihadh Al-Gazali8, Henan Hamamy9, Enza Maria Valente10, Shaun Gorman11, Richard Williams12, Duncan P. McHale12, John N. Wood13, Fiona M. Gribble2 and C. Geoffrey Woods1

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

Correspondence to: C. Geoffrey Woods1 Correspondence and requests for materials should be addressed to C.G.W. (Email: cw347@cam.ac.uk). The sequence for full-length human SCN9A cloned from fetal brain mRNA is deposited in GenBank under accession number DQ857292

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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, 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 beta1 and beta2 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.

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