A single Na(+) channel mutation causing both long-QT and Brugada syndromes.
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.
Bezzina
C
C
Departments of Clinical Genetics , Academic Medical Center, Amsterdam, The Netherlands.
Veldkamp
M W
MW
van Den Berg
M P
MP
Postma
A V
AV
Rook
M B
MB
Viersma
J W
JW
van Langen
I M
IM
Tan-Sindhunata
G
G
Bink-Boelkens
M T
MT
van Der Hout
A H
AH
Mannens
M M
MM
Wilde
A A
AA
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*
D015222:Sodium Channels