Paroxysmal extreme pain disorder M1627K mutation in human Nav 1.7 renders DRG neurons hyperexcitable

Sulayman D. Dib-Hajj, Mark Estacion, Brian W. Jarecki, Lynda Tyrrell, Tanya Z. Fischer, Mark Lawden, Theodore Cummins, Stephen G. Waxman

Research output: Contribution to journalArticle

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Abstract

Background: Paroxysmal extreme pain disorder (PEPD) is an autosomal dominant painful neuropathy with many, but not all, cases linked to gain-of-function mutations in SCN9A which encodes voltage-gated sodium channel Nav1.7. Severe pain episodes and skin flushing start in infancy and are induced by perianal probing or bowl movement, and pain progresses to ocular and mandibular areas with age. Carbamazepine has been effective in relieving symptoms, while other drugs including other anti-epileptics are less effective. Results: Sequencing of SCN9A coding exons from an English patient, diagnosed with PEPD, has identified a methionine 1627 to lysine (M1627K) substitution in the linker joining segments S4 and S5 in domain IV. We confirm that M1627K depolarizes the voltage-dependence of fast-inactivation without substantially altering activation or slow-inactivation, and inactivates from the open state with slower kinetics. We show here that M1627K does not alter development of closed-state inactivation, and that M1627K channels recover from fast-inactivation faster than wild type channels, and produce larger currents in response to a slow ramp stimulus. Using current-clamp recordings, we also show that the M1627K mutant channel reduces the threshold for single action potentials in DRG neurons and increases the number of action potentials in response to graded stimuli. Conclusion: M1627K mutation was previously identified in a sporadic case of PEPD from France, and we now report it in an English family. We confirm the initial characterization of mutant M1627K effect on fast-inactivation of Nav1.7 and extend the analysis to other gating properties of the channel. We also show that M1627K mutant channels render DRG neurons hyperexcitable. Our new data provide a link between altered channel biophysics and pain in PEPD patients.

Original languageEnglish
Article number37
JournalMolecular Pain
Volume4
DOIs
StatePublished - Sep 19 2008

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Diagnosis-Related Groups
Neurons
Mutation
Pain
NAV1.7 Voltage-Gated Sodium Channel
Action Potentials
Biophysics
Architectural Accessibility
Carbamazepine
Methionine
Lysine
France
Exons
Skin
Paroxysmal Extreme Pain Disorder
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Molecular Medicine
  • Cellular and Molecular Neuroscience

Cite this

Dib-Hajj, S. D., Estacion, M., Jarecki, B. W., Tyrrell, L., Fischer, T. Z., Lawden, M., ... Waxman, S. G. (2008). Paroxysmal extreme pain disorder M1627K mutation in human Nav 1.7 renders DRG neurons hyperexcitable. Molecular Pain, 4, [37]. https://doi.org/10.1186/1744-8069-4-37

Paroxysmal extreme pain disorder M1627K mutation in human Nav 1.7 renders DRG neurons hyperexcitable. / Dib-Hajj, Sulayman D.; Estacion, Mark; Jarecki, Brian W.; Tyrrell, Lynda; Fischer, Tanya Z.; Lawden, Mark; Cummins, Theodore; Waxman, Stephen G.

In: Molecular Pain, Vol. 4, 37, 19.09.2008.

Research output: Contribution to journalArticle

Dib-Hajj, SD, Estacion, M, Jarecki, BW, Tyrrell, L, Fischer, TZ, Lawden, M, Cummins, T & Waxman, SG 2008, 'Paroxysmal extreme pain disorder M1627K mutation in human Nav 1.7 renders DRG neurons hyperexcitable', Molecular Pain, vol. 4, 37. https://doi.org/10.1186/1744-8069-4-37
Dib-Hajj, Sulayman D. ; Estacion, Mark ; Jarecki, Brian W. ; Tyrrell, Lynda ; Fischer, Tanya Z. ; Lawden, Mark ; Cummins, Theodore ; Waxman, Stephen G. / Paroxysmal extreme pain disorder M1627K mutation in human Nav 1.7 renders DRG neurons hyperexcitable. In: Molecular Pain. 2008 ; Vol. 4.
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AU - Tyrrell, Lynda

AU - Fischer, Tanya Z.

AU - Lawden, Mark

AU - Cummins, Theodore

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