Back to Search
Start Over
Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors
- Source :
- Brain Communications
- Publication Year :
- 2021
- Publisher :
- Oxford University Press, 2021.
-
Abstract
- Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic–clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p. L215P; c.640C>T, p. R214C; c.859G>A; V287I; c.641G>A, p. R214H) and GABRG2 (c.269C>G, p. T90R; c.1025C>T, p. P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p. F331S; c.542A>T, p. Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p. T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.<br />Next-generation sequencing on 870 patients with Dravet syndrome identified nine variants in GABRA1, GABRB2 and GABRG2 genes, which encode the most common α1β2γ2 GABAA receptor in the CNS. Hernandez et al. report that mutations in multiple genes (GABRA1, GABRB2 and GABRG2) have a common target (α1β2γ2) to cause Dravet syndrome.<br />Graphical Abstract Graphical Abstract
- Subjects :
- 0301 basic medicine
Protein subunit
GABRG2
Pathogenesis
03 medical and health sciences
Cellular and Molecular Neuroscience
GABRB2
0302 clinical medicine
Dravet syndrome
PIP2
medicine
Receptor
Gene
Dravet syndrome-associated mutations
Biological Psychiatry
Genetics
biology
GABAA receptor
AcademicSubjects/SCI01870
medicine.disease
Phenotype
Psychiatry and Mental health
GABRA1
030104 developmental biology
Neurology
biology.protein
Original Article
AcademicSubjects/MED00310
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 26321297
- Volume :
- 3
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Brain Communications
- Accession number :
- edsair.doi.dedup.....614106e9d1894354f9b9360b7b09e87a