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...

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Bibliographic Details
Published in:	Nature Vol. 444; no. 7121; pp. 894 - 898
Main Authors:	Reimann, Frank, McHale, Duncan P, Valente, Enza Maria, Jafri, Hussain, Al-Gazali, Lihadh, Gribble, Fiona M, Thornton, Gemma, Gorman, Shaun, Williams, Richard, Wood, John N, Nicholas, Adeline K, Roberts, Emma, Mannan, Jovaria, Springell, Kelly, Woods, C. Geoffrey, Cox, James J, Raashid, Yasmin, Karbani, Gulshan, Hamamy, Henan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing 14-12-2006 Nature Publishing Group
Subjects:	Base Sequence Biological and medical sciences Cell Line Chromosomes, Human, Pair 2 - genetics Congenital diseases Female Gene expression General aspects Humans Male Medical sciences Molecular Sequence Data Mutants Mutation Mutation - genetics NAV1.7 Voltage-Gated Sodium Channel Neurons Neurosciences Pain Pain - genetics Pain - physiopathology Pain Insensitivity, Congenital - genetics Pain Insensitivity, Congenital - physiopathology Patch-Clamp Techniques Pedigree Phenotype Physical Chromosome Mapping Quantitative genetics Sodium Sodium Channels - chemistry Sodium Channels - genetics Sodium Channels - metabolism Case study Human Analgesia Genetics Mutation Family study
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0028-0836 1476-4687 1476-4679
DOI:	10.1038/nature05413