A single Na+ channel mutation causing both long-QT and Brugada syndromes

Mutations in SCN5A, the gene encoding the cardiac Na+ channel, have been id entified in 2 distinct diseases associated with sudden death: one form of t he long-QT syndrome (LQT(3)) and the Brugada syndrome. We have screened SCN 5A in a large 8-generation kindred characterized by a high incidence of noc turnal sudden death, and QT-interval prolongation and the "Brugada ECG" occ urring in the same subjects. An insertion of 3 nucleotides (TCA) at positio n 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 ident ified in all electrocardiographically affected family members. ECGs were ob tained from 79 adults with a defined genetic status (carriers, n=43; noncar riers, n=36), In affected individuals, PR and QRS durations and QT interval s 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 me mbers died suddenly, 16 of them during the night. Expression of wild-type a nd mutant Na+ channels in Xenopus oocytes revealed that the 1795insD mutati on gives rise to a 7.3-mV negative shift of the steady-state inactivation c urve 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+ curren t during the upstroke of the action potential. LQT(3) and Brugada syndrome are allelic disorders but may also share a common genotype.