Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/19988
Title: Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies.
Authors: Carvill, Gemma L;Engel, Krysta L;Ramamurthy, Aishwarya;Cochran, J Nicholas;Roovers, Jolien;Stamberger, Hannah;Lim, Nicholas;Schneider, Amy L;Hollingsworth, Georgie;Holder, Dylan H;Regan, Brigid M;Lawlor, James;Lagae, Lieven;Ceulemans, Berten;Bebin, E Martina;Nguyen, John;Barsh, Gregory S;Weckhuysen, Sarah;Meisler, Miriam;Berkovic, Samuel F;De Jonghe, Peter;Scheffer, Ingrid E;Myers, Richard M;Cooper, Gregory M;Mefford, Heather C
Affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp 2610, Belgium; Department of Neurology, University Hospital Antwerp, Antwerp 2610, Belgium
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Department of Biochemistry and Molecular Genetics, Anschutz School of Medicine, University of Colorado Denver, Denver, CO 80204, USA
Department of Neurology, University Hospital Antwerp, Antwerp 2610, Belgium
University of Melbourne, Royal Children's Hospital, Murdoch Children's Research Institute, Florey Institute, Melbourne, VIC 3084, Australia
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60610, USA
University of Alabama at Birmingham, Birmingham, AL 35294, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Department of Development and Regeneration - Section Pediatric Neurology, University Hospitals KU Leuven, Leuven 3000, Belgium
Department of Pediatric Neurology, University and University Hospital Antwerp, Antwerp 2610, Belgium
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Issue Date: 6-Dec-2018
Citation: American journal of human genetics 2018; 103(6): 1022-1029
Abstract: 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 ∼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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/19988
DOI: 10.1016/j.ajhg.2018.10.023
ORCID: 0000-0002-2311-2174
0000-0003-4580-841X
PubMed URL: 30526861
Type: Journal Article
Subjects: Dravet syndrome
SCN1A
alternative splicing
epilepsy
genome sequencing
noncoding
poison exon
variant interpretation
Appears in Collections:Journal articles

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