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

Abstract

Abstract —Mutations in SCN5A , the gene encoding the cardiac Na + channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT 3 ) 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. LQT 3 and Brugada syndrome are allelic disorders but may also share a common genotype.