A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia.
Heart Rhythm
; 17(2): 296-304, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-31437535
ABSTRACT
BACKGROUND:
Triadin is a protein expressed in cardiac and skeletal muscle that has an essential role in the structure and functional regulation of calcium release units and excitation-contraction coupling. Mutations in the triadin gene (TRDN) have been described in different forms of human arrhythmia syndromes with early onset and severe arrhythmogenic phenotype, including triadin knockout syndrome.OBJECTIVE:
The purpose of this study was to characterize the pathogenetic mechanism underlying a case of severe pediatric malignant arrhythmia associated with a defect in the TRDN gene.METHODS:
We used a trio whole exome sequencing approach to identify the genetic defect in a 2-year-old boy who had been resuscitated from sudden cardiac arrest and had frequent episodes of ventricular fibrillation and a family history positive for sudden death. We then performed in vitro functional analysis to investigate possible pathogenic mechanisms underlying this severe phenotype.RESULTS:
We identified a novel homozygous missense variant (p.L56P) in the TRDN gene in the proband that was inherited from the heterozygous unaffected parents. Expression of a green fluorescent protein (GFP)-tagged mutant human cardiac triadin isoform (TRISK32-L56P-GFP) in heterologous systems revealed that the mutation alters protein dynamics. Furthermore, when co-expressed with the type 2 ryanodine receptor, caffeine-induced calcium release from TRISK32-L56P-GFP was relatively lower compared to that observed with the wild-type construct.CONCLUSION:
The results of this study allowed us to hypothesize a pathogenic mechanism underlying this rare arrhythmogenic recessive form, suggesting that the mutant protein potentially can trigger arrhythmias by altering calcium homeostasis.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Proteínas de Transporte
/
Taquicardia Ventricular
/
Proteínas Musculares
/
Mutação
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Child, preschool
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article