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Aberrant inclusion of a poison exon causes dravet syndrome and related SCN1A-associated genetic epilepsies

Journal Contribution - Journal Article

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.(1-3) This suggests that unknown genetic etiologies exist, potentially in the similar to 98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,(4,5) including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.(6) Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.
Journal: The American journal of human genetics
ISSN: 0002-9297
Volume: 103
Pages: 1022 - 1029
Publication year:2018
Keywords:A1 Journal article
BOF-keylabel:yes
BOF-publication weight:10
CSS-citation score:2
Authors:International
Authors from:Government
Accessibility:Closed