A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents

作者：Hu Dan; Barajas Martinez Hector; Medeiros Domingo Argelia; Crotti Lia; Veltmann Christian; Schimpf Rainer; Urrutia Janire; Alday Aintzane; Casis Oscar; Pfeiffer Ryan; Burashnikov Elena; Caceres Gabriel; Tester David J; Wolpert Christian; Borggrefe Martin; Schwartz Peter; Ackerman Michael J; Antzelevitch Charles^*

来源：Heart Rhythm, 2012, 9(5): 760-769.

DOI：10.1016/j.hrthm.2011.12.006

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

BACKGROUND Cardiac sodium channel beta-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. %26lt;br%26gt;OBJECTIVE To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). %26lt;br%26gt;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 patchclamp techniques. %26lt;br%26gt;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 (Na(v)1B) 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 (I-Na) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P%26lt;0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I-to) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P%26lt;0.01). Co-immunoprecipitation indicated structural association between Na-v beta 1B and Na(v)1.5 and K(v)4.3. %26lt;br%26gt;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.

• 出版日期2012-5