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An SCN9A channelopathy causes congenital inability to experience pain

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Hama, 2006. "An SCN9A channelopathy causes congenital inability to experience pain," Nature, Nature, vol. 444(7121), pages 894-898, December.
    • Handle: RePEc:nat:nature:v:444:y:2006:i:7121:d:10.1038_nature05413
    DOI: 10.1038/nature05413
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    Cited by:

    1. Noel G. Panagiotides & Fritz Zimprich & Klaus Machold & Oliver Schlager & Markus Müller & Sebastian Ertl & Henriette Löffler-Stastka & Renate Koppensteiner & Patricia P. Wadowski, 2023. "A Case of Autoimmune Small Fiber Neuropathy as Possible Post COVID Sequelae," IJERPH, MDPI, vol. 20(6), pages 1-12, March.
    2. Girolamo Di Maio & Ines Villano & Ciro Rosario Ilardi & Antonietta Messina & Vincenzo Monda & Ashlei Clara Iodice & Chiara Porro & Maria Antonietta Panaro & Sergio Chieffi & Giovanni Messina & Marcell, 2023. "Mechanisms of Transmission and Processing of Pain: A Narrative Review," IJERPH, MDPI, vol. 20(4), pages 1-19, February.
    3. Qiurong Wu & Jian Huang & Xiao Fan & Kan Wang & Xueqin Jin & Gaoxingyu Huang & Jiaao Li & Xiaojing Pan & Nieng Yan, 2023. "Structural mapping of Nav1.7 antagonists," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Tianbo Li & Gang Lu & Eugene Y Chiang & Tania Chernov-Rogan & Jane L Grogan & Jun Chen, 2017. "High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE," PLOS ONE, Public Library of Science, vol. 12(7), pages 1-18, July.
    5. Chiung-Wei Huang & Hsing-Jung Lai & Po-Yuan Huang & Ming-Jen Lee & Chung-Chin Kuo, 2016. "The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia," PLOS Biology, Public Library of Science, vol. 14(9), pages 1-31, September.

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