Myotonic dystrophy type 1 mimics and exacerbates Brugada phenotype induced by Nav1.5 sodium channel loss-of-function mutation.
BACKGROUND
Myotonic dystrophy type 1 (DM1), a muscular dystrophy due to CTG expansion in the DMPK gene, can cause cardiac conduction disorders and sudden death. These cardiac manifestations are similar to those observed in loss-of-function SCN5A mutations, which are also responsible for Brugada syndrome (BrS).


OBJECTIVE
The purpose of this study was to investigate DM1 effects on clinical expression of a loss-of-function SCN5A mutation causing BrS.


METHODS
We performed complete clinical evaluation, including ajmaline test, in 1 family combining DM1 and BrS. We screened the known BrS susceptibility genes. We characterized an SCN5A mutation using whole-cell patch-clamp experiments associated with cell surface biotinylation.


RESULTS
The proband, a 15-year-old female, was a survivor of out-of-hospital cardiac arrest with ventricular fibrillation. She combined a DMPK CTG expansion from the father's side and an SCN5A mutation (S910L) from the mother's side. S910L is a trafficking defective mutant inducing a dominant negative effect when transfected with wild-type Nav1.5. This loss-of-function SCN5A mutation caused a Brugada phenotype during the mother's ajmaline test. Surprisingly, in the father, a DM1 patient without SCN5A mutation, ajmaline also unmasked a Brugada phenotype. Furthermore, association of both genetic abnormalities in the proband exacerbated the response to ajmaline with a massive conduction defect.


CONCLUSIONS
Our study is the first to describe the deleterious effect of DM1 on clinical expression of a loss-of-function SCN5A mutation and to show a provoked BrS phenotype in a DM1 patient. The modification of the ECG pattern by ajmaline supports the hypothesis of a link between DM1 and Nav1.5 loss of -function.
Département de Cardiologie, CHU de Poitiers, France. Electronic address: thomaspambrun@aol.com.
Thomas
T
Pambrun
Institut de Physiologie et de Biologie Cellulaire, ERL CNRS 7368, Université de Poitiers, France.
Aurélie
A
Mercier
Institut de Physiologie et de Biologie Cellulaire, ERL CNRS 7368, Université de Poitiers, France.
Aurélien
A
Chatelier
Institut de Physiologie et de Biologie Cellulaire, ERL CNRS 7368, Université de Poitiers, France.
Sylvie
S
Patri
Institut du Thorax, CNRS, UMR 6291, Nantes, France; Institut du Thorax, Inserm, UMR 1087, Nantes, France.
Jean-Jacques
JJ
Schott
Institut du Thorax, CNRS, UMR 6291, Nantes, France; Institut du Thorax, Inserm, UMR 1087, Nantes, France.
Solena
S
Le Scouarnec
Centre de Recherche de l'IUSMQ, Quebec, Canada.
Mohamed
M
Chahine
Département de Cardiologie, CHU de Poitiers, France.
Bruno
B
Degand
Institut de Physiologie et de Biologie Cellulaire, ERL CNRS 7368, Université de Poitiers, France.
Patrick
P
Bois
D000293:Adolescent; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020125:Mutation, Missense; D009223:Myotonic Dystrophy / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype
D062554:NAV1.5 Voltage-Gated Sodium Channel
Ajmaline challenge; Brugada syndrome; Cardiac arrhythmia; Myotonic dystrophy cardiomyopathy; Sodium channels