Malignant perinatal variant of long-QT syndrome caused by a profoundly dysfunctional cardiac sodium channel.
BACKGROUND
Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity.


RESULTS
Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by approximately 10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block ( approximately 5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant.


CONCLUSIONS
Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting.
Wang
Dao W
DW
Department of Medicine, Vanderbilt University, Nashville, TN 37232-0275, USA.
Crotti
Lia
L
Shimizu
Wataru
W
Pedrazzini
Matteo
M
Cantu
Francesco
F
De Filippo
Paolo
P
Kishiki
Kanako
K
Miyazaki
Aya
A
Ikeda
Tomoaki
T
Schwartz
Peter J
PJ
George
Alfred L
AL
D000200:Action Potentials; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D008133:Long QT Syndrome / Q000188:drug therapy / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008801:Mexiletine / Q000627:therapeutic use; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D011433:Propranolol / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000378:metabolism; D012720:Severity of Illness Index; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000627:therapeutic use; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine; D012964:Sodium; D011433:Propranolol