title: Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations.
abstract: SCN9Aencodes the voltage-gated sodium channel Na(v)1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Na(v)1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Na(v)1.7-DeltaR1370-L1374). Both of these mutations map to the pore region of the Na(v)1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Na(v)1.7.
authors.affiliation: Department of Medical Genetics, University of Cambridge, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: Jony
authors.initials: J
authors.lastname: Sheynin
authors.forename: Zamir
authors.initials: Z
authors.lastname: Shorer
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.forename: Adeline K
authors.initials: AK
authors.lastname: Nicholas
authors.forename: Lorena
authors.initials: L
authors.lastname: Zubovic
authors.forename: Marco
authors.initials: M
authors.lastname: Baralle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wraige
authors.forename: Esther
authors.initials: E
authors.lastname: Manor
authors.forename: Jacov
authors.initials: J
authors.lastname: Levy
authors.forename: C Geoffery
authors.initials: CG
authors.lastname: Woods
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D055724:Electrophysiological Phenomena; D005006:Ethnicity / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007557:Israel; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel; D016716:PC12 Cells; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D010375:Pedigree; D051381:Rats; D016364:Reading Frames / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection; D006113:United Kingdom
chemical_list: D050505:Mutant Proteins; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels