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

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 (BrS) and sudden infant death syndromes (SIDS). METHODS AND RESULTS Patient 1 was a 44-y/o male with an ajmaline-induced Type-1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-y/o female displaying a coved-type BrS ECG who developed cardiac arrest during fever. Patient 3 was a 4-m/o female SIDS case. All known exons and intron borders of BrS and SIDS susceptibility genes were amplified and sequenced in both directions. A R214Q variant was detected in exon 3A of SCN1Bb (Navβ1B) 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%). Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp and co-immunoprecipitation techniques. 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 (Ito) 70.6% greater compared with KCND3/WT+SCN1Bb/WT(n=10–11, p<0.01). Co-immunoprecipitation indicated structural association between Navβ1B and Nav1.5 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 Brugada or SIDS phenotypes via a combined loss of function of INa and gain of function of Ito.

Cardiac ion channels

“…Recently, mutations in b1 were linked to Brugada syndrome and were shown, in recombinant expression systems, to reduce Na C current and increase Kv4.3 current. 52 …”

NaV1.5 and Regulatory β Subunits in Cardiac Sodium Channelopathies

“…24 Although both b1 and b1B have been shown to modulate I to , their spatial relationship to the K V 4.x/KChiP2 complex is unknown. 55,93,107 Thus, K V 4.x/KChiP2, b1, and b1B are drawn at both the ID and lateral membrane. As shown by coimmunoprecipitation, 22 b2 associates with Nav1.5 in heart and has been detected at both IDs 23 and T tubules 22 separately by different groups using immunofluorescence.…”

Brugada syndrome risk loci seem protective against atrial fibrillation

“…8,9 Accordingly, several rare variants in genes encoding cardiac sodium and potassium channels have been found both in patients with AF and in patients with BrS. This is the case for the variants in SCN5A (c. 647C4T (p.(Ser216Leu)), rs201002736, 10,11 c. 1127G4A (p.(Arg376His)), rs199473101, 10,12 c. 3157G4A (p.(Glu1053Lys)), rs137854617, 10,13 and c. 6010T4C (p.(Phe2004Leu)), rs41311117 14,15 ), SCN1Bb (c. 641G4A (p.(Arg214Gln)), rs66876876 16,17 ), SCN3B (c. 29T4C (p.(Leu10Pro)), rs121918282 18,19 ), MOG1 (c. 181G4T…”