期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 103, 期 6, 页码 1022-1029出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2018.10.023
关键词
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资金
- NIH [NINDS R01 NS069605]
- American Epilepsy Society
- Epilepsy Foundation
- National Health and Medical Research Council of Australia
- National Human Genome Research Institute [UM1HG007301]
- National Cancer Institute [R01CA197139]
- NIH (NINDS) [R01 NS069605]
- NATIONAL CANCER INSTITUTE [R01CA197139] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U01HG007301] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R00NS089858, R01NS069605] Funding Source: NIH RePORTER
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.
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