title: A single Na(+) channel mutation causing both long-QT and Brugada syndromes.
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.
authors.affiliation: Departments of Clinical Genetics , Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Bezzina
authors.forename: M W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: M P
authors.initials: MP
authors.lastname: van Den Berg
authors.forename: A V
authors.initials: AV
authors.lastname: Postma
authors.forename: M B
authors.initials: MB
authors.lastname: Rook
authors.forename: J W
authors.initials: JW
authors.lastname: Viersma
authors.forename: I M
authors.initials: IM
authors.lastname: van Langen
authors.forename: G
authors.initials: G
authors.lastname: Tan-Sindhunata
authors.forename: M T
authors.initials: MT
authors.lastname: Bink-Boelkens
authors.forename: A H
authors.initials: AH
authors.lastname: van Der Hout
authors.forename: M M
authors.initials: MM
authors.lastname: Mannens
authors.forename: A A
authors.initials: AA
authors.lastname: Wilde
mesh_terms: D000328:Adult; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D015222:Sodium Channels