Influence of common SCN1A promoter variants on the severity of SCN1A-related phenotypes.
5' Untranslated Regions
Adolescent
Adult
Alleles
Cell Line, Tumor
Child
Child, Preschool
Epilepsy
/ genetics
Genes, Reporter
Genome-Wide Association Study
Haplotypes
Humans
Male
NAV1.1 Voltage-Gated Sodium Channel
/ genetics
Phenotype
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Severity of Illness Index
Young Adult
SCN1A
Dravet
GEFS+
promoter
variable expression
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
19
11
2018
revised:
22
03
2019
accepted:
22
04
2019
pubmed:
31
5
2019
medline:
12
6
2020
entrez:
31
5
2019
Statut:
ppublish
Résumé
Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants. Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated. All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes. The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes.
Sections du résumé
BACKGROUND
Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants.
METHODS
Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated.
RESULTS
All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes.
CONCLUSION
The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes.
Identifiants
pubmed: 31144463
doi: 10.1002/mgg3.727
pmc: PMC6625088
doi:
Substances chimiques
5' Untranslated Regions
0
NAV1.1 Voltage-Gated Sodium Channel
0
SCN1A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00727Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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