PuSH - Publication Server of Helmholtz Zentrum München: A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Nav1.5 and Kv4.3 channel currents.

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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.*

A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na_v1.5 and K_v4.3 channel currents.

Heart Rhythm 9, 760-769 (2012)

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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 (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<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<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. 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.

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