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Updated: Jul 17, 2026
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
A sodium channel pore mutation causing Brugada syndrome.
Arnold E Pfahnl1, Prakash C Viswanathan, Raul Weiss
1Division of Cardiology, Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, Georgia 30033, USA.
Heart Rhythm
|January 3, 2007
Summary
A novel SCN5A mutation (T353I) causes Brugada syndrome via a trafficking defect. When trafficking is corrected, the mutation exhibits properties consistent with long QT syndrome, suggesting a dual mechanism for cardiac arrhythmias.
Area of Science:
- Cardiovascular genetics
- Molecular cardiology
- Ion channel biophysics
Background:
- Brugada syndrome and long QT type 3 syndrome are genetic disorders linked to cardiac sodium channel mutations, causing life-threatening arrhythmias.
- A novel threonine-to-isoleucine missense mutation at position 353 (T353I) in the SCN5A gene was identified in a family with Brugada syndrome.
Observation:
- The T353I mutation in the cardiac sodium channel (SCN5A) significantly reduces peak sodium current by 74% upon heterologous expression.
- Mutant T353I channels exhibit impaired trafficking to the sarcolemma, with substantial intracellular sequestration.
Findings:
- Mexiletine treatment partially restored T353I channel trafficking to the sarcolemma.
- Despite improved trafficking, T353I mutant channels displayed a significant late sodium current, a hallmark of long QT syndrome mutations.
Implications:
- The T353I mutation's clinical presentation as Brugada syndrome is likely due to a cardiac Na+ channel trafficking defect.
- The emergence of long QT syndrome biophysical properties upon correction of the trafficking defect suggests a complex interplay between channel function and cellular localization.
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