Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What's behind the scenes?
3′UTR
Brugada syndrome
Genotype-phenotype correlation
SCN5A
microRNAs
Journal
Biomedical journal
ISSN: 2320-2890
Titre abrégé: Biomed J
Pays: United States
ID NLM: 101599820
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
09
04
2018
revised:
20
02
2019
accepted:
11
03
2019
entrez:
20
10
2019
pubmed:
20
10
2019
medline:
15
4
2020
Statut:
ppublish
Résumé
Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3). Mutations in SCN5A gene coding for the α-subunit of the NaV1.5 cardiac sodium channel are identified in 15-30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of the protein-coding portions and flanking intronic regions of SCN5A. This excludes the 5'UTR and 3'UTR from the routine genetic testing. We here screened the coding sequence, the flanking intronic regions as well as the 5' and 3'UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with BrS. A new SCN5A-Q1000K mutation was identified along with two common polymorphisms (H558R and D1819). Multiple genetic variants were identified on the SCN5A 3'UTR, one of which is predicted to create additional microRNA binding site for miR-1270. Additionally, we identified the hsa-miR-219a-rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes. The absence of genotype-phenotype concordance within all the identified genetic variants in this family gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors, rather than a single variant. Most SCN5A variants were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities.
Sections du résumé
BACKGROUND
Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3). Mutations in SCN5A gene coding for the α-subunit of the NaV1.5 cardiac sodium channel are identified in 15-30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of the protein-coding portions and flanking intronic regions of SCN5A. This excludes the 5'UTR and 3'UTR from the routine genetic testing.
METHODS
We here screened the coding sequence, the flanking intronic regions as well as the 5' and 3'UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with BrS.
RESULTS
A new SCN5A-Q1000K mutation was identified along with two common polymorphisms (H558R and D1819). Multiple genetic variants were identified on the SCN5A 3'UTR, one of which is predicted to create additional microRNA binding site for miR-1270. Additionally, we identified the hsa-miR-219a-rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes.
CONCLUSIONS
The absence of genotype-phenotype concordance within all the identified genetic variants in this family gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors, rather than a single variant. Most SCN5A variants were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities.
Identifiants
pubmed: 31627867
pii: S2319-4170(18)30167-7
doi: 10.1016/j.bj.2019.03.003
pmc: PMC6818142
pii:
doi:
Substances chimiques
MicroRNAs
0
NAV1.5 Voltage-Gated Sodium Channel
0
Potassium Channels, Voltage-Gated
0
SCN5A protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
252-260Informations de copyright
Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.
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