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Mechanisms underlying the EEG biomarker in Dup15q syndrome
- Source :
- Molecular autism, vol 10, iss 1, Molecular Autism, Vol 10, Iss 1, Pp 1-15 (2019), Molecular Autism
- Publication Year :
- 2019
- Publisher :
- eScholarship, University of California, 2019.
-
Abstract
- Background Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype. Methods To test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele). Results Peak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort. Conclusions Our results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome. Electronic supplementary material The online version of this article (10.1186/s13229-019-0280-6) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
Autism
Dup15q syndrome
Electroencephalography
Bioinformatics
lcsh:RC346-429
Cohort Studies
Fathers
GABA
0302 clinical medicine
Receptors
2.1 Biological and endogenous factors
EEG
Aetiology
Child
GABRG3
Pediatric
0303 health sciences
biology
medicine.diagnostic_test
Neurodevelopmental disorders
3. Good health
Psychiatry and Mental health
Phenotype
Mental Health
Autism spectrum disorder
GABRA5
Female
Human
Adult
Midazolam
Intellectual and Developmental Disabilities (IDD)
Clinical Sciences
Dup15q
Chromosomes
03 medical and health sciences
Developmental Neuroscience
Clinical Research
Intellectual Disability
GABRB3
medicine
UBE3A
Genetics
Humans
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
Chromosome Aberrations
Chromosomes, Human, Pair 15
business.industry
GABA-A
Research
Pair 15
Neurosciences
Receptors, GABA-A
medicine.disease
Brain Disorders
biology.protein
business
Genomic imprinting
030217 neurology & neurosurgery
Biomarkers
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Molecular autism, vol 10, iss 1, Molecular Autism, Vol 10, Iss 1, Pp 1-15 (2019), Molecular Autism
- Accession number :
- edsair.doi.dedup.....0142830c0439415f446588c3148678f2