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Open Access 01-12-2008 | Research

Paroxysmal extreme pain disorder M1627K mutation in human Na_v1.7 renders DRG neurons hyperexcitable

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

Published in: Molecular Pain | Issue 1/2008

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 Na_v1.7. 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 Na_v1.7 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.

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Title: Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable
Authors: Sulayman D Dib-Hajj
Mark Estacion
Brian W Jarecki
Lynda Tyrrell
Tanya Z Fischer
Mark Lawden
Theodore R Cummins
Stephen G Waxman
Publication date: 01-12-2008
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2008
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-4-37

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Paroxysmal extreme pain disorder M1627K mutation in human Na_v1.7 renders DRG neurons hyperexcitable

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

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