Congenital insensitivity to pain: Novel SCN9A missense and in-frame deletion mutations

James J. Cox, Jony Sheynin, Zamir Shorer, Frank Reimann, Adeline K. Nicholas, Lorena Zubovic, Marco Baralle, Elizabeth Wraige, Esther Manor, Jacov Levy, C. Geoffery Woods, Ruti Parvari

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

SCN9A encodes the voltage-gated sodium channel Nav1.7, 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 (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370- L1374). Both of these mutations map to the pore region of the Nav1.7 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 Nav1.7.

Original languageEnglish
Pages (from-to)E1670-E1686
JournalHuman Mutation
Volume31
Issue number9
DOIs
StatePublished - 1 Sep 2010

Keywords

  • Channelopathy
  • Congenital insensitivity to pain
  • SCN9A
  • Sodium channel Na1.7

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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