title: Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.
abstract: 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.
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G4W8, Canada. pgoldberg@xenon-pharma.com
authors.forename: Y P
authors.initials: YP
authors.lastname: Goldberg
authors.forename: J
authors.initials: J
authors.lastname: MacFarlane
authors.forename: M L
authors.initials: ML
authors.lastname: MacDonald
authors.forename: J
authors.initials: J
authors.lastname: Thompson
authors.forename: M-P
authors.initials: MP
authors.lastname: Dube
authors.forename: M
authors.initials: M
authors.lastname: Mattice
authors.forename: R
authors.initials: R
authors.lastname: Fraser
authors.forename: C
authors.initials: C
authors.lastname: Young
authors.forename: S
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authors.lastname: Hossain
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authors.lastname: Pape
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authors.initials: B
authors.lastname: Payne
authors.forename: C
authors.initials: C
authors.lastname: Radomski
authors.forename: G
authors.initials: G
authors.lastname: Donaldson
authors.forename: E
authors.initials: E
authors.lastname: Ives
authors.forename: J
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authors.lastname: Cox
authors.forename: H B
authors.initials: HB
authors.lastname: Younghusband
authors.forename: R
authors.initials: R
authors.lastname: Green
authors.forename: A
authors.initials: A
authors.lastname: Duff
authors.forename: E
authors.initials: E
authors.lastname: Boltshauser
authors.forename: G A
authors.initials: GA
authors.lastname: Grinspan
authors.forename: J H
authors.initials: JH
authors.lastname: Dimon
authors.forename: B G
authors.initials: BG
authors.lastname: Sibley
authors.forename: G
authors.initials: G
authors.lastname: Andria
authors.forename: E
authors.initials: E
authors.lastname: Toscano
authors.forename: J
authors.initials: J
authors.lastname: Kerdraon
authors.forename: D
authors.initials: D
authors.lastname: Bowsher
authors.forename: S N
authors.initials: SN
authors.lastname: Pimstone
authors.forename: M E
authors.initials: ME
authors.lastname: Samuels
authors.forename: R
authors.initials: R
authors.lastname: Sherrington
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D016368:Frameshift Mutation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D010375:Pedigree; D017384:Sequence Deletion; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels