An SCN1B Variant Affects Both Cardiac-Type (NaV1.5) and Brain-Type (NaV1.1) Sodium Currents and Contributes to Complex Concomitant Brain and Cardiac Disorders

Rebecca Martinez-Moreno; Elisabet Selga; Helena Riuró; David Carreras; Mered Parnes; Chandra Srinivasan; Michael F Wangler; Guillermo J Pérez; Fabiana S Scornik; Ramon Brugada

doi:10.3389/fcell.2020.528742

An SCN1B Variant Affects Both Cardiac-Type (Na_V1.5) and Brain-Type (Na_V1.1) Sodium Currents and Contributes to Complex Concomitant Brain and Cardiac Disorders

Front Cell Dev Biol. 2020 Sep 29:8:528742. doi: 10.3389/fcell.2020.528742. eCollection 2020.

Authors

Rebecca Martinez-Moreno^{1

2}, Elisabet Selga^{1

2

3

4}, Helena Riuró², David Carreras², Mered Parnes⁵, Chandra Srinivasan⁶, Michael F Wangler^{7

8}, Guillermo J Pérez^{1

4}, Fabiana S Scornik^{1

4}, Ramon Brugada^{1

2

4

9}

Affiliations

¹ Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Spain.
² Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta, Girona, Spain.
³ Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
⁴ Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) Madrid, Spain.
⁵ Blue Bird Circle Clinic for Pediatric Neurology, Section, of Pediatric Neurology and Developmental Neuroscience, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States.
⁶ Section of Pediatric Cardiac Electrophysiology, Division of Pediatric Cardiology, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX, United States.
⁷ Texas Children's Hospital, Houston, TX, United States.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
⁹ Hospital Josep Trueta, Girona, Spain.

Abstract

Voltage-gated sodium (Na_V) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na_V channel β subunits have been widely studied due to their modulatory role. Mice null for Scn1b, which encodes Na_V β1 and β1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of SCN1B, c.308A>T leading to β1_p.D103V and β1b_p.D103V, was previously found in a patient with a history of proarrhythmic conditions with progressive atrial standstill as well as cognitive and motor deficits accompanying structural brain abnormalities. We investigated whether β1 or β1b subunits carrying this mutation affect Na_V1.5 and/or Na_V1.1 currents using a whole cell patch-clamp technique in tsA201 cells. We observed a decrease in sodium current density in cells co-expressing Na_V1.5 or Na_V1.1 and β1^D103V compared to β1^WT. Interestingly, β1b^D103V did not affect Na_V1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to β1b^WT. The β1b^D103V isoform did not affect Na_V1.5 current properties. Although the SCN1B_c.308A>T mutation may not be the sole cause of the patient's symptoms, we observed a clear loss of function in both cardiac and brain sodium channels. Our results suggest that the mutant β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.

Keywords: NaV1.1; NaV1.5; NaVβ1; NaVβ1b; brain hyperexcitability; cardiac arrhythmia.