Referenced in: none

Automatically associated channels: Kv7.1 , Nav1.5

Title: A single Na(+) channel mutation causing both long-QT and Brugada syndromes.

Authors: C Bezzina, M W Veldkamp, M P van den Berg, A V Postma, M B Rook, J W Viersma, I M Van Langen, G Tan-Sindhunata, M T Bink-Boelkens, A H van Der Hout, M M Mannens, A A Wilde

Journal, date & volume: Circ. Res., 1999 Dec 3-17 , 85, 1206-13

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/10590249

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.