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Relevance to Autism

Reduced GABRA5 mRNA and protein levels were observed in post-mortem brain tissue from ASD cases compared to controls (Fatemi et al., 2010). Deletion of GABRA5 in mice resulted in autism-related behaviors including reduced social interactions, reduced ultrasonic vocalizations, and increased self-grooming (Zurek et al., 2016).

Molecular Function

GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. This gene encodes for a subunit of GABA-A receptors.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
mRNA and protein levels for GABAAalpha4, alpha5, beta1 and GABABR1 receptors are altered in brains from subjects with autism.
ASD
Positive Association
GABAA receptor subunit gene polymorphisms predict symptom-based and developmental deficits in Chinese Han children and adolescents with autistic sp...
ASD subphenotypes (CARS and ABC)
Positive Association
A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.
Positive Association
ASD
Negative Association
No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population.
ASD
Negative Association
An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as ris...
ASD
Negative Association
Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.
ASD
Negative Association
Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder.
Support
De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.
Epilepsy/seizures
DD, autistic features
Support
Integrating de novo and inherited variants in 42
ASD
Recent Recommendation
5GABAA receptor deficiency causes autism-like behaviors.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN827R001 
 missense_variant 
 c.610G>A 
 p.Val204Ile 
 Familial 
 Maternal 
  
 GEN827R002 
 missense_variant 
 c.338G>C 
 p.Gly113Ala 
 Familial 
 Maternal 
  
 GEN827R003 
 missense_variant 
 c.880G>C 
 p.Val294Leu 
 De novo 
  
 Simplex 
 GEN827R004 
 synonymous_variant 
 c.552G>A 
 p.Ala184%3D 
 De novo 
  
  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN827C001 
 intron_variant 
 rs35586628 
 c.497+3436C>T 
  
 99 Han Chinese ASD children and adolescents (79 male, 20 female; age 8.53 0.42 years; 82 with autism, 17 with PDD-NOS) 
 Discovery 
 GEN827C002 
 intron_variant 
 rs35399885 
 c.580+503C>T 
  
 318 Indo-Caucasoid ASD probands (262 male, 54 female; mean age 5.96 +/- 3.31 years) from West Bengal recruited from Manovikas Kendra Rehabilitation and Research Institute of the Handicapped (MRIH), Kolkata, India, and 227 healthy controls (124 male, 103 female; mean age 8.9 +/- 6.8 years) recruited from different regions around Kolkata. 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
15
Duplication
 10
  construct
15
Duplication
 1
 
15
Duplication
 3
 
15
Duplication
 9
 
15
Duplication
 2
 
15
Duplication
 5
 
15
Deletion
 1
 
15
Deletion-Duplication
 114
 
15
Duplication
 10
 
15
Duplication
 81
  construct
15
Duplication
 9
 
15
Duplication
 19
 
15
Duplication
 3
 
15
Deletion-Duplication
 12
 
15
Duplication
 5
 

Model Summary

Deletion of GABRA5 in mice causes autism-like symptoms including reduced social interaction and ultrasonic vocalizations.

References

Type
Title
Author, Year
Primary
5GABAA receptor deficiency causes autism-like behaviors.

M_GABRA5_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: GABRA5 null mice were generated by targeted partial deletion of exons 2 and 4 and inclusion of the neomycin resistance and thymidine kinase genes for insert selection (PMID 12097508); Westernblot analysis showed absence of an 55 kDa GABRA5 in membranes from hippocampi of GABRA5 null mice;.
Allele Type: Targeted
Strain of Origin: C57BL/6J and Sv129Ev
Genetic Background:
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Merck Sharp and Dohme Research Laboratories, UK

M_GABRA5_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Self grooming: perseveration1
Increased
Description: Gabra5 null mice spent more time self-grooming than wt mice
Exp Paradigm: Observation period was 10 min
 Grooming behavior assessments
 3-5 months
Social interaction1
Decreased
Description: Nose-to-nose and nose-to-head contacts were reduced in gabra5 null mice compared to wildtype while other forms of social contact were similar between the genotypes
Exp Paradigm: Behaviors recorded were nose tip-to-nose tip contact, nose-to-head contact, nose-to-anogenital contact, crawl over, crawl under and rearing behaviors, males only
 Novel cage test
 3-5 months
Ultrasonic vocalization: isolation induced1
Decreased
Description: The latency to emit the first usv is greater in gabra5 null mice compared to wts, the total number of calls is lesser in gabra5 null mice compared to wts, the total emitting time in the first minute is lesser in gabra5 null mice compared to wts, the length of individual calls was the same in gabra5 null mice and wts
Exp Paradigm: Both males and females tested, each pup was isolated from the dam for a total of 4 min
 Monitoring ultrasonic vocalizations
 P6-8
Cognitive flexibility1
Decreased
Description: Gabra5 null mice showed a longer latency than wt mice to burrow through bedding, or remove a cardboard plug, to gain access to the goal box
Exp Paradigm: The puzzle box was an illuminated start box and a darkened goal box connected by a doorway and underpass, mice were tested over a 3-day period with 3-trials per day, problem-solving ability and memory was measured by making the task more difficult each day by modifying the entrance to the goal box, 5 min was allowed for the mouse to reach the goal box
 Puzzle box test
 3-5 months
Episodic-like memory1
Decreased
Description: Gabra5 null and wt mice exhibit similar performances on the underpass and burrowing long-term memory tasks
Exp Paradigm: The puzzle box was an illuminated start box and a darkened goal box connected by a doorway and underpass, mice were tested over a 3-day period with 3-trials per day, problem-solving ability and memory was measured by making the task more difficult each day by modifying the entrance to the goal box, 5 min was allowed for the mouse to reach the goal box
 Puzzle box test
 3-5 months
Pup retrieval1
Decreased
Description: The time required for gabra5 null dams to retrieve five pups to the nest following a 3-min separation period was greater than wildtype dams
Exp Paradigm: Time required for the dams to retrieve five pups to the nest following a 3-min separation period was measured
 Pup retrieval assay
 P6-p8
Anxiety1
 No change
 Open field test
 3-5 months
Exploratory activity1
 No change
 Puzzle box test
 3-5 months
General locomotor activity1
 No change
 Open field test
 3-5 months
Social approach1
 No change
 Three-chamber social approach test
 3-5 months
 Not Reported: Circadian sleep/wake cycle, Developmental profile, Immune response, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Seizure, Sensory

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