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.

Hu, Dan; Barajas-Martínez, 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 (2012). 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. Heart rhythm, 9(5), pp. 760-769. Elsevier 10.1016/j.hrthm.2011.12.006

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
UniBE Contributor:	Medeiros Domingo, Argelia
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1547-5271
Publisher:	Elsevier
Language:	English
Submitter:	Argelia Medeiros Domingo
Date Deposited:	19 Jun 2014 14:42
Last Modified:	05 Dec 2022 14:28
Publisher DOI:	10.1016/j.hrthm.2011.12.006
PubMed ID:	22155597
URI:	https://boris.unibe.ch/id/eprint/42269