A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Nav1.5 and Kv4.3 channel currents

Dan Hu, Hector Barajas-Martínez, Argelia Medeiros-Domingo, Lia Crotti, Christian Veltmann, Rainer Schimpf, Janire Urrutia, Aintzane Alday, Oscar Casis, Ryan Pfeiffer, Elena Burashnikov, Gabriel Caceres, David J. Tester, Christian Wolpert, Martin Borggrefe, Peter Schwartz, Michael John Ackerman, Charles Antzelevitch

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Abstract

BACKGROUND: Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. OBJECTIVE: To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). METHODS: All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. RESULTS: Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Nav1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (INa) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, Ito) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Navβ1B and Na v1.5 and Kv4.3. CONCLUSION: Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.

Original languageEnglish (US)
Pages (from-to)760-769
Number of pages10
JournalHeart Rhythm
Volume9
Issue number5
DOIs
StatePublished - May 2012

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Keywords

  • Arrhythmias
  • Brugada syndrome
  • Potassium
  • SCN1Bb
  • Sodium
  • Sudden infant death syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hu, D., Barajas-Martínez, H., Medeiros-Domingo, A., Crotti, L., Veltmann, C., Schimpf, R., Urrutia, J., Alday, A., Casis, O., Pfeiffer, R., Burashnikov, E., Caceres, G., Tester, D. J., Wolpert, C., Borggrefe, M., Schwartz, P., Ackerman, M. J., & Antzelevitch, C. (2012). A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Nav1.5 and Kv4.3 channel currents. Heart Rhythm, 9(5), 760-769. https://doi.org/10.1016/j.hrthm.2011.12.006