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Relevance to Autism

Expression profiling of the superior temporal gyrus of six autistic subjects and matched controls revealed differential expression of the GADD45B gene (Garbett et al., 2008). Knockdown of GADD45B in mice and rats resulted in altered long-term contextual fear conditioning and altered juvenile social behaviors, respectively (Leach et al., 2012; Kigar et al., 2015). A de novo missense variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

This gene is a member of a group of genes that respond to environmental stresses by mediating activation of the p38/JNK pathway via binding and activation of MTK1/MEKK4 kinase, which is an upstream activator of both p38 and JNK MAPKs. The function of these genes or their protein products is involved in the regulation of growth and apoptosis.

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References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Immune transcriptome alterations in the temporal cortex of subjects with autism.
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory.
Recent Recommendation
Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN742R001 
 missense_variant 
 c.293T>C 
 p.Leu98Pro 
 De novo 
 NA 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion-Duplication
 32
 
19
Deletion-Duplication
 9
 

Model Summary

Gadd45b may be a novel therapeutic target for the cognitive deficits associated with many neurodevelopmental, neurological, and psychiatric disorders.

References

Type
Title
Author, Year
Primary
Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala.

R_GADD45B_1_KD

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Bilateral infusion of 1 L (100 M) Gadd45b siRNA in amygdala of P0 rat.
Allele Type: Targeted (Knock Down)
Strain of Origin: Not Specified
Genetic Background: Sprague Dawley
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Charles River

R_GADD45B_1_KD

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Social approach1
Decreased
Description: Decreased time in social chamber, no change in non-social chamber or middle chamber. No change in number of exits or entries into social chamber.
Exp Paradigm: Three-chamber social approach test
 Three-chamber social approach test
 3.5-4 weeks
Juvenile play1
Increased
Description: Increased social play in home cage
Exp Paradigm: Reciprocal social interaction test
 Reciprocal social interaction test
 3.5-4 weeks
Gene expression1
Decreased
Description: Decreased expression of Bdnf, Adra2a at P33
Exp Paradigm: Quantitative PCR (qRT-PCR)
 Quantitative pcr (qrt-pcr)
 P33
Dna methylation1
Increased
Description: At P2 and P33 there is an increase in distal Adra2a promoter methylation (CRE), but not proximal (Egr1-RE)
Exp Paradigm: Methylation-sensitive restriction enzyme assay
 Methylation-sensitive restriction enzyme assay
 P2, P33
Targeted expression1
Decreased
Description: Gadd45b 20% reduced in amygdala (P2). No reduction in hypothalamus (no spreading). No reduction in Gadd45a or Gadd45g in amygdala (specific).
Exp Paradigm: Western blot
 Western blot
 P2
Gene expression1
Decreased
Description: Decreased expression of Reelin, Mecp2, Il-6, Il-1 at P2
Exp Paradigm: Quantitative PCR (qRT-PCR)
 Quantitative pcr (qrt-pcr)
 P2
Anxiety1
 No change
 Elevated plus maze test
 
Anxiety1
 No change
 Light-dark exploration test
 
Anxiety1
 No change
 Open field test
 
Dna methylation1
 No change
 Methylation-sensitive restriction enzyme assay
 P2, P33
Gene expression1
 No change
 Quantitative pcr (qrt-pcr)
 P2, P33
Targeted expression1
 No change
 Western blot
 P33
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
C2ORF29 CCR4-NOT transcription complex, subunit 11 55571 Q9UKZ1 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT1 CCR4-NOT transcription complex, subunit 1 23019 A5YKK6 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT10 CCR4-NOT transcription complex, subunit 10 25904 Q9H9A5 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT2 CCR4-NOT transcription complex, subunit 2 4848 B2RDX7 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT3 CCR4-NOT transcription complex, subunit 3 4849 O75175 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT6 CCR4-NOT transcription complex, subunit 6 57472 Q9ULM6 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT6L CCR4-NOT transcription complex, subunit 6-like 246175 Q96LI5 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT7 CCR4-NOT transcription complex, subunit 7 29883 Q9UIV1 IP; LC-MS/MS
Huttlin EL , et al. 2015
CNOT8 CCR4-NOT transcription complex, subunit 8 9337 Q9UFF9 IP; LC-MS/MS
Huttlin EL , et al. 2015
HBA2 Hemoglobin subunit alpha 3039 P69905 IP; LC-MS/MS
Huttlin EL , et al. 2015
IL1F6 Interleukin-36 alpha 27179 Q9UHA7 IP; LC-MS/MS
Huttlin EL , et al. 2015
MAP3K4 mitogen-activated protein kinase kinase kinase 4 4216 Q9P1M2 IP; LC-MS/MS
Huttlin EL , et al. 2015
POLR3C polymerase (RNA) III (DNA directed) polypeptide C (62kD) 10623 Q9BUI4 IP; LC-MS/MS
Huttlin EL , et al. 2015
RAVER1 ribonucleoprotein, PTB-binding 1 125950 E9PAU2 IP; LC-MS/MS
Huttlin EL , et al. 2015
RQCD1 RCD1 required for cell differentiation1 homolog (S. pombe) 9125 B7Z1E5 IP; LC-MS/MS
Huttlin EL , et al. 2015
TNKS1BP1 tankyrase 1 binding protein 1, 182kDa 85456 Q9C0C2 IP; LC-MS/MS
Huttlin EL , et al. 2015
Sox2 SRY-box containing gene 2 20674 P48432 ChIP-Seq
Amador-Arjona A , et al. 2015

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