A new Nav1.7 sodium channel mutation I234T in a child with severe pain.
Dominant gain-of-function mutations that hyperpolarize activation of the Na(v)1.7 sodium channel have been linked to inherited erythromelalgia (IEM), a disorder characterized by severe pain and redness in the feet and hands in response to mild warmth. Pharmacotherapy remains largely ineffective for IEM patients with cooling and avoidance of triggers being the most reliable methods to relieve pain. We now report a 5 year old patient with pain precipitated by warmth, together with redness in her hands and feet. Her pain episodes were first reported at 12 months, and by the age of 15-16 months were triggered by sitting as well as heat. Pain has been severe, inducing self-mutilation, with limited relief from drug treatment. Our analysis of the patient's genomic DNA identified a novel Na(v)1.7 mutation which replaces isoleucine 234 by threonine (I234T) within domain I/S4-S5 linker. Whole-cell voltage-clamp analysis shows a I234T-induced shift of -18 mV in the voltage-dependence of activation, accelerated time-to-peak, slowed deactivation and enhanced responses to slow ramp depolarizations, together with a -21 mV shift in the voltage-dependence of slow-inactivation. Our data show that I234T induces the largest activation shift for Na(v)1.7 mutations reported thus far. Although enhanced slow-inactivation may attenuate the gain-of-function of the I234T mutation, the shift in activation appears to be dominant, and is consistent with the severe pain symptoms reported in this patient.
Ahn
Hye-Sook
HS
Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.
Dib-Hajj
Sulayman D
SD
Cox
James J
JJ
Tyrrell
Lynda
L
Elmslie
Frances V
FV
Clarke
Antonia A
AA
Drenth
Joost P H
JP
Woods
C Geoffrey
CG
Waxman
Stephen G
SG
D019943:Amino Acid Substitution / Q000235:genetics; D002675:Child, Preschool; D004916:Erythromelalgia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010148:Intractable Pain / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000235:genetics*; D013912:Threonine / Q000235:genetics
D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D007532:Isoleucine; D013912:Threonine