title: Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.
abstract: We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype-phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Cregg
authors.forename: Bisola
authors.initials: B
authors.lastname: Laguda
authors.forename: Robert
authors.initials: R
authors.lastname: Werdehausen
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: John E
authors.initials: JE
authors.lastname: Linley
authors.forename: Juan D
authors.initials: JD
authors.lastname: Ramirez
authors.forename: Istvan
authors.initials: I
authors.lastname: Bodi
authors.forename: Michael
authors.initials: M
authors.lastname: Markiewicz
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Howell
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: Karen
authors.initials: K
authors.lastname: Agnew
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lunn
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Maria
authors.initials: M
authors.lastname: Kinali
mesh_terms: D000200:Action Potentials; D017668:Age of Onset; D000595:Amino Acid Sequence; D000700:Analgesics / Q000627:therapeutic use; D002675:Child, Preschool; D004916:Erythromelalgia / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012678:Sensation Disorders / Q000235:genetics / Q000503:physiopathology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012964:Sodium / Q000378:metabolism; D014162:Transfection
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C486866:SCN9A protein, human; D012964:Sodium