title: Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.
abstract: The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.
authors.affiliation: University of Cambridge, Wellcome Trust/MRC Institute for Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Emery
authors.affiliation: University College London, Molecular Nociception Group, London, WC1E 6BT, United Kingdom, and.
authors.forename: Abdella M
authors.initials: AM
authors.lastname: Habib
authors.affiliation: University College London, Molecular Nociception Group, London, WC1E 6BT, United Kingdom, and.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 0XY, United Kingdom.
authors.forename: Adeline K
authors.initials: AK
authors.lastname: Nicholas
authors.affiliation: University of Cambridge, Wellcome Trust/MRC Institute for Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 0XY, United Kingdom fr222@cam.ac.uk cw347@cam.ac.uk.
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.affiliation: University of Cambridge, Wellcome Trust/MRC Institute for Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom, fr222@cam.ac.uk cw347@cam.ac.uk.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
mesh_terms: D002648:Child; D004916:Erythromelalgia / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D020125:Mutation, Missense; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D000699:Pain Insensitivity, Congenital / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012007:Rectum / Q000002:abnormalities* / Q000378:metabolism
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human
keywords: Nav1.7; SCN9A; congenital insensitivity to pain; inherited erythromelalgia; pain; paroxysmal extreme pain disorder