A potentially deleterious de novo missense variant in the GABBR1 gene was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020. FENRIR prioritization of a brain-specific enhancer network in Chen et al., 2021 concluded that a de novo ASD-associated intronic variant in the GABBR1 gene (originally identified in Zhou et al., 2019) resided within an ASD-associated enhancer for which GABBR1 was the most likely target gene; experimental validation of the allele-specific regulatory effects of the enhancer for this gene by dual-luciferase assays demonstrated that the proband-specific allele resulted in significantly reduced luciferase activity compared to the sibling-specific allele (p<0.0001). A cross-trait meta-analysis of genome-wide association study on schizophrenia, bipolar disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and depression samples in Wu et al., 2020 implicated GABBR1 in schizophrenia, depression, and ASD [odds ratio (OR)=464.8, Fishers P=0.002]. Previous studies had reported reduced levels of GABBR1 in post-mortem brain samples from ASD probands (Fatemi et al., 2009; Fatemi et al., 2010), as well as in subjects with schizophrenia, bipolar disorder and major depression (Fatemi et al., 2011), when compared with controls. Cediel et al., 2022 identified four individuals through GeneMatcher with de novo non-synonymous variants in the GABBR1 gene presenting with developmental delay and variable additional phenotypes, including autism spectrum disorder in one individual; functional analyses of GABBR1 variants in this study demonstrated effects on surface expression and/or GABA efficacy in transfected HEK293 cells.
Molecular Function
This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Previous studies have pointed to a link between decreased Gabbr1 expression and the presentation of ASD in both patients and animal models. The Gabbr1 knockdown model shows deficits in behavior, with decreased social approach and social memory as tested in the three chamber social approach test. Additionally, the model shows increased repetitive digging, self grooming, and anxiety. The model also exhibits altered neural physiology, displaying a significant increase in action potential discharge frequency.
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
The recombinant adeno-associated virus (rAAV) vectors expressing GABAB1R shRNA (4.57 � 1012 vg/ml) were supplied by Shanghai Biotechnology Co. Under anesthesia with pentobarbital sodium (80 mg/kg), mice were placed in a stereotaxic apparatus. Then, a volume of 2 μL rAAV- GABAB1R shRNA was infused bilaterally into the PFC (anterior-posterior 1.9 mm, medial-lateral ± 0.36 mm, and dorsal- ventral 2.0 mm) at a speed of 0.2 μL/min. To prevent backflow of viral particles, the needle was left at injection site for a 10 more min after each injection.
Allele Type: Knockdown
Strain of Origin: C57BL/6J
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source: Zhengzhou University
Description: Gabbr1 exhibited a significant increase in the action potential discharge frequency in response to depolarizing steps from 320 to 340 pA compared to controls. However, the spike frequency was comparable during depolarizing steps from 200 to 280 pA and 360â??380 pA in slices between two groups.
Exp Paradigm: prefrontal cortex
Description: Gabbr1 mutant mice exhibited no difference in exploration and sniffing time with a wildtype stranger mouse (as opposed to an empty cage) compared to controls, which exhibited increased exploration and sniffing time with the stranger mouse.
Exp Paradigm: stranger mouse (s1) in chamber 1, empty cage (object) in chamber 2
Description: Gabbr1 mutant mice exhibited no difference in the amount of time spent exploring and sniffing a novel mouse (s2) as opposed to a familiar mouse (s1) compared to controls, suggesting a deficit in social memory.
Exp Paradigm: familiar mouse in chamber 1 (s1), stranger mouse (s2) in chamber 2
Description: Gabbr1 mutant mice spent significantly less time exploring a novel object compared to a familiar one, while controls spent significantly more time exploring the novel object. This relationship was further demonstrated by a significantly decreased discrimination ratio in mutant mice.
