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Relevance to Autism

A paternally-inherited deletion disrupting seven exons of the DAGLA gene was identified in a male ASD proband and an affected male sibling; however, this deletion was also observed in an unaffected male sibling but was not observed in controls (Prasad et al., 2012).

Molecular Function

This gene encodes a diacylglycerol lipase. The encoded enzyme is involved in the biosynthesis of the endocannabinoid 2-arachidonoyl-glycerol.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia.
ASD, SCZ
Support
Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior.
Support
Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN508R001 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN508R002 
 missense_variant 
 c.263C>T 
 p.Thr88Met 
 Unknown 
  
  
 GEN508R003 
 missense_variant 
 c.589C>T 
 p.Arg197Trp 
 Unknown 
  
  
 GEN508R004 
 missense_variant 
 c.757G>T 
 p.Ala253Ser 
 Unknown 
  
  
 GEN508R005 
 missense_variant 
 c.940G>A 
 p.Ala314Thr 
 Unknown 
  
  
 GEN508R006 
 missense_variant 
 c.992C>T 
 p.Ala331Val 
 Unknown 
  
  
 GEN508R007 
 missense_variant 
 c.1105G>A 
 p.Val369Ile 
 Unknown 
  
  
 GEN508R008 
 missense_variant 
 c.1375C>T 
 p.Arg459Cys 
 Unknown 
  
  
 GEN508R009 
 missense_variant 
 c.1742G>A 
 p.Arg581Gln 
 Unknown 
  
  
 GEN508R010 
 missense_variant 
 c.2243C>T 
 p.Ala748Val 
 Unknown 
  
  
 GEN508R011 
 missense_variant 
 c.2294G>A 
 p.Arg765Gln 
 Unknown 
  
  
 GEN508R012 
 missense_variant 
 c.2300C>T 
 p.Ala767Val 
 Unknown 
  
  
 GEN508R013 
 missense_variant 
 c.2377G>A 
 p.Asp793Asn 
 Unknown 
  
  
 GEN508R014 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R015 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R016 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R017 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R018 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R019 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R020 
 missense_variant 
 c.2430C>A 
 p.His810Gln 
 Unknown 
  
  
 GEN508R021 
 missense_variant 
 c.2444G>A 
 p.Arg815His 
 Unknown 
  
  
 GEN508R022 
 missense_variant 
 c.2444G>A 
 p.Arg815His 
 Unknown 
  
  
 GEN508R023 
 missense_variant 
 c.2444G>A 
 p.Arg815His 
 Unknown 
  
  
 GEN508R024 
 missense_variant 
 c.2444G>A 
 p.Arg815His 
 Unknown 
  
  
 GEN508R025 
 missense_variant 
 c.2444G>A 
 p.Arg815His 
 Unknown 
  
  
 GEN508R026 
 missense_variant 
 c.2525C>T 
 p.Ala842Val 
 Unknown 
  
  
 GEN508R027 
 missense_variant 
 c.2573C>T 
 p.Ala858Val 
 Unknown 
  
  
 GEN508R028 
 missense_variant 
 c.2573C>T 
 p.Ala858Val 
 Unknown 
  
  
 GEN508R029 
 missense_variant 
 c.2621C>T 
 p.Ala874Val 
 Unknown 
  
  
 GEN508R030 
 missense_variant 
 c.2653G>C 
 p.Gly885Arg 
 Unknown 
  
  
 GEN508R031 
 missense_variant 
 c.2675G>T 
 p.Arg892Leu 
 Unknown 
  
  
 GEN508R032 
 missense_variant 
 c.2909C>A 
 p.Pro970His 
 Unknown 
  
  
 GEN508R033 
 missense_variant 
 c.2962C>G 
 p.Leu988Val 
 Unknown 
  
  
 GEN508R034 
 missense_variant 
 c.2962C>G 
 p.Leu988Val 
 Unknown 
  
  
 GEN508R035 
 missense_variant;missense_variant 
 c.[2962C>G];[2962C>G] 
 p.[Leu988Val];[Leu988Val] 
 Unknown 
  
  
 GEN508R036 
 missense_variant 
 c.3049G>C 
 p.Asp1017His 
 Unknown 
  
  
 GEN508R037 
 stop_lost 
 c.3127T>C 
 p.Ter1043GlnextTer29 
 Unknown 
  
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion-Duplication
 6
 

Model Summary

Viral mediated targeted deletion of diacylglycerol lipase , DGL from dopamine D1 receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) constituting the direct pathway shows decreased social interaction, increased grooming, decreased exploration of a novel environment and increased glutamatergic transmission. DGLa CKOs of the indirect pathway shows unaltered social interaction, grooming and exploration of a novel environment. Subregional DGL deletion from the dorsal striatum decreased social interaction. Subregional DGLalpha deletion from the ventral striatum increased repetitive grooming (Shonesy BC, Biol Psychiatry. 2017).

References

Type
Title
Author, Year
Primary
Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior.

M_DAGLA_1_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 9 of the DGLa gene using Drd1a-cre (D1-cre), in medial spiny neurons (MSNs) and other neurons.
Allele Type: Conditional loss-of-function
Strain of Origin:
Genetic Background: C57Bl/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source: Drd1a-Cre mice were generated by the Gene Expression Nervous System Atlas Project (New York, NY).

M_DAGLA_2_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 9 of the DAGLA gene using Adora2a-Cre (A2a-Cre), in medium spiny neurons (MSNs) of striatal indirect pathway (striatopallidal) expressing adenosine-2a receptor, that are also known to express dopamine receptor 2 (Drd2) . The line was further crossed with Drd1a-tdTomato mice for electrophysiology experiments
Allele Type: Conditional loss-of-function
Strain of Origin:
Genetic Background: C57Bl/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source: Adora2a-Cre mice were generated by the Gene Expression Nervous System Atlas Project (New York, NY).

M_DAGLA_3_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 9 of the DAGLA gene by bilateral injection of AAV-cre into the dorsal striatum
Allele Type: Conditional loss-of-function
Strain of Origin:
Genetic Background: C57Bl/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source: 29458998

M_DAGLA_4_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 9 of the DAGLA gene by bilateral injection of AAV-cre into the nucleus accumbens of the ventral straitum
Allele Type: Conditional loss-of-function
Strain of Origin:
Genetic Background: C57Bl/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source: 29458998

M_DAGLA_1_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: Ambulatory activity1
Decreased
Description: Mutants show reduction in total distance travelled on the open field in comparison with controls.
 Open field test
 2-3 months
Spontaneous post synaptic event frequency: excitatory currents1
Increased
Description: Mutants show increased sEPSC frequency compared to controls.
 Whole-cell voltage clamp
 2-3 months
Miniature post synaptic currents: excitatory1
Decreased
Description: Mutants show decreased percentage maximum depolarizaton-induced suppresion of excitation (DSE) compared to controls.
Exp Paradigm: Depolarization-induced suppression of excitation (DSE). Depolarization-induced suppression of excitation (DSE) was recorded from Drd1a-tdTomato fluorescent striatal dMSNs from DGLaD1-Cre1/Drd1a-tdTomato1 mice.
 Whole-cell voltage clamp
 2-3 months
Self grooming: perseveration1
Increased
Description: Mutants show increase in repetitive self grooming in comparison with controls.
 Grooming behavior assessments
 2-3 months
Social approach1
Decreased
Description: Mutants show no preference for the social stimulus in comparison with controls.
 Three-chamber social approach test
 2-3 months
Rearing behavior1
Decreased
Description: Mutants show reduced rearing in comparison with controls.
 Open field test
 2-3 months
Metabolite levels: Neurometabolites1
Decreased
Description: Mutants show decreased striatal levels of 2-arachidonoylglycerol (2-AG) compared to controls.
Exp Paradigm: The effect of DGLa deletion from Drd1a-Cre (D1-Cre)‚??expressing striatal MSNs (dMSNs) on striatal levels of 2-arachidonoylglycerol (2-AG). Endocannabinoids (eCBs) and related lipids were detected from mouse striatal punches using multiple reaction monitoring with a mass spectrometer in tandem with ultrahigh performance liquid chromatography.
 Liquid chromatography-mass spectrometry (LC-MS)
 2-3 months
Anxiety1
 No change
 Open field test
 2-3 months
Anxiety1
 No change
 Light-dark exploration test: Light-dark exploration test
 2-3 months
Reward reinforced choice behavior1
 No change
 Operant conditioning paradigm: fixed or progressive reinforcement training
 2-3 months
Metabolite levels: Neurometabolites1
 No change
 Liquid chromatography-mass spectrometry (LC-MS)
 2-3 months
Metabolite levels: Neurometabolites1
 No change
 Liquid chromatography-mass spectrometry (LC-MS)
 2-3 months
Protein expression level evidence1
 No change
 
 2-3 months
General locomotor activity: Ambulatory activity1
 No change
 Three-chamber social approach test
 2-3 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 2-3 months
Motor coordination and balance1
 No change
 Balance beam test
 2-3 months
Spontaneous post synaptic event amplitude: excitatory currents1
 No change
 Whole-cell voltage clamp
 2-3 months
Spontaneous post synaptic event amplitude: inhibitory currents1
 No change
 Whole-cell voltage clamp
 2-3 months
Spontaneous post synaptic event frequency: inhibitory currents1
 No change
 Whole-cell voltage clamp
 2-3 months
Synaptic neuroreceptor ratio (NMDAR/AMPAR) dependent transmission1
 No change
 Whole-cell voltage clamp
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Maternal behavior, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory

M_DAGLA_2_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synaptic plasticity: DSE 1
Decreased
Description: Mutants show decreased percentage maximum depolarizaton-induced suppresion of excitation (DSE) compared to controls.
Exp Paradigm: DSE recorded from Drd1a-tdTomato2 striatal iMSNs from DGLa^A2A-Cre1, Drd1a-tdTomato1 mice and their DGLaflx/flx/Drd1a-tdTomato1 littermates.
 Whole-cell voltage clamp
 2-3 months
Anxiety1
 No change
 Open field test
 2-3 months
Exploratory activity1
 No change
 Light-dark exploration test: Light-dark exploration test
 2-3 months
Reward reinforced choice behavior1
 No change
 Operant conditioning paradigm: fixed or progressive reinforcement training
 2-3 months
Metabolite levels: Neurometabolites1
 No change
 Liquid chromatography-mass spectrometry (LC-MS)
 2-3 months
Metabolite levels: Neurometabolites1
 No change
 Liquid chromatography-mass spectrometry (LC-MS)
 2-3 months
Metabolite levels: Neurometabolites1
 No change
 Liquid chromatography-mass spectrometry (LC-MS)
 2-3 months
General locomotor activity: Ambulatory activity1
 No change
 Three-chamber social approach test
 2-3 months
General locomotor activity: Ambulatory activity1
 No change
 Open field test
 2-3 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 2-3 months
Motor coordination and balance1
 No change
 Balance beam test
 2-3 months
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 2-3 months
Rearing behavior1
 No change
 Open field test
 2-3 months
Social approach1
 No change
 Three-chamber social approach test
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Maternal behavior, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory

M_DAGLA_3_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Social approach1
Decreased
Description: Mutant mice show no preference for the social stimulus in comparison with controls.
 Three-chamber social approach test
 2-3 months
Targeted expression1
Decreased
Description: Mutants show decreased DGLa immunoreactivity in the dorsal striatum compared to controls.
 Immunofluorescence staining
 2-3 months
Anxiety1
 No change
 Open field test
 2-3 months
General locomotor activity: Ambulatory activity1
 No change
 Three-chamber social approach test
 2-3 months
General locomotor activity: Ambulatory activity1
 No change
 Open field test
 2-3 months
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 2-3 months
Rearing behavior1
 No change
 Open field test
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory

M_DAGLA_4_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Self grooming: perseveration1
Increased
Description: Mutants spent more time grooming compared to controls.
 Grooming behavior assessments
 2-3 months
Targeted expression1
Decreased
Description: Mutants show decreased DGLa immunoreactivity in the NAc compared to controls.
 Immunofluorescence staining
 2-3 months
General locomotor activity: Ambulatory activity1
 No change
 Three-chamber social approach test
 2-3 months
Social approach1
 No change
 Three-chamber social approach test
 2-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory

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