Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.


Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

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@article{Goldberg2007LossoffunctionMI, title={Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.}, author={Yigal Paul Goldberg and Julie Macfarlane and Marcia L E Macdonald and Jay Thompson and M-P P Dub{\'e} and Maryanne Mattice and Regina Fraser and Chris Young and Shahrier Hossain and Thomas Pape and BJ Payne and Christopher C Radomski and Gary Donaldson and Edward J Ives and Janet E Cox and H. B. Younghusband and Rachel Kramer Green and AOIFE DUFF and Eugen Boltshauser and G A Grinspan and Joseph H. Dimon and B G Sibley and Generoso Andria and Ennio Toscano and Jacques Kerdraon and David Bowsher and Simon Neil Pimstone and Mark E. Samuels and Robin P. Sherrington and Michael R. Hayden}, journal={Clinical genetics}, year={2007}, volume={71 4}, pages={311-9} }