A Single Na+ Channel Mutation Causing Both Long-QT and Brugada Syndromes

• Published in: Circulation research Vol. 85; no. 12; p. 1206
• Main Authors: Bezzina, Connie, Veldkamp, Marieke W, van den Berg, Maarten P, Postma, Alex V, Rook, Martin B, Viersma, Jan-Willem, van Langen, Irene M, Tan-Sindhunata, Ghita, Bink-Boelkens, Margreet Th. E, van der Hout, Annemarie H, Mannens, Marcel M. A. M, Wilde, Arthur A. M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 03.12.1999; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adult; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Death, Sudden, Cardiac - etiology; Electrocardiography; Female; Heart; Humans; Long QT Syndrome - etiology; Long QT Syndrome - genetics; Male; Medical sciences; Mutation; Pedigree; Sodium Channels - genetics; Human; Arrhythmia; Brugada syndrome; Family study; Sudden death; Prolonged QT interval; Cardiovascular disease; Ionic channel; Conduction disorder; Excitability disorder; Heart disease; Heart block; Sodium ion; Mutation
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.85.12.1206

Mutations in SCN5A, the gene encoding the cardiac Na channel, have been identified in 2 distinct diseases associated with sudden deathone form of the long-QT syndrome (LQT3) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the “Brugada ECG” occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, n=43; noncarriers, n=36). In affected individuals, PR and QRS durations and QT intervals are prolonged (P <0.0001 for all parameters). ST segment elevation in the right precordial leads is present as well (P <0.0001). Twenty-five family members died suddenly, 16 of them during the night. Expression of wild-type and mutant Na channels in Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV negative shift of the steady-state inactivation curve and an 8.1-mV positive shift of the steady-state activation curve. The functional consequence of both shifts is likely to be a reduced Na current during the upstroke of the action potential. LQT3 and Brugada syndrome are allelic disorders but may also share a common genotype.