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Relevance to Autism

The protein encoded by MECP2 interacts with the NCoR/HDAC3 complex; the Rett syndrome-associated missense variant p.Arg306Cys (MECP2R306C) abolishes this interaction (Lyst et al., 2013; Ebert et al., 2013). Knockdown of HDAC3 in the forebrain excitatory neurons of mice resulted in abnormal locomotor coordination, social deficits, and cognitive deficits (Nott et al., 2016). In the same report, Rett syndrome patient-derived MECP2R306C neural progenitor cells were shown to have deficits in HDAC3 recruitment. A de novo in-frame deletion variant in HDAC3 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).

Molecular Function

The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family; it has histone deacetylase activity and represses transcription when tethered to a promoter.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior.
Support
Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection.
Learning difficulties
Support
Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...
Neurodevelopment disorder
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.
Support
Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN843R001 
 inframe_deletion 
 134+AGA 
 -45 
 De novo 
  
 Simplex 
 GEN843R002 
 missense_variant 
 NM_001355039.2:c.902G>A 
 p.Arg301Gln 
 De novo 
  
  
 GEN843R003 
 missense_variant 
 c.797T>C 
 p.Leu266Ser 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
5
Duplication
 1
 
5
Deletion
 1
 
5
Duplication
 1
 
5
Deletion
 1
 

Model Summary

Neuronal deletion of Hdac3 in mice elicits abnormal locomotor coordination, sociability and cognition.

References

Type
Title
Author, Year
Primary
Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exons 11-14 of Hdac3 using CamkII-cre, in excitatory neurons of the forebrain
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: 129SvEv-derived ES cells
Model Source:
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Clasping reflex1
Increased
 General observations
 12 weeks
Motor coordination and balance1
Decreased
 Accelerating rotarod test
 3 months
Hyperactivity1
Increased
 Open field test
 3 months
Social approach1
Decreased
 Three-chamber social approach test
 3 months
Episodic-like memory1
Decreased
 Object-place recognition test
 3 months
Cued or contextual fear conditioning: memory of cue1
Decreased
 Fear conditioning test
 3 months
Spatial reference memory1
Decreased
 Morris water maze test
 3 months
Cued or contextual fear conditioning: memory of context1
Decreased
 Fear conditioning test
 3 months
Spatial learning1
Decreased
 Morris water maze test
 3 months
Cued or contextual fear conditioning: extinction1
Decreased
 Fear conditioning test
 3 months
Gene expression1
Decreased
 Quantitative pcr (qrt-pcr)
 3 months
Protein expression level evidence1
Increased
 Immunohistochemistry
 3 months
Gene expression1
Increased
 Rna sequencing
 3 months
Targeted expression1
Decreased
 Quantitative pcr (qrt-pcr)
 3 months
Gene expression1
Decreased
 Immunohistochemistry
 3 months
Protein expression level evidence1
Increased
 Western blot
 3 months
Targeted expression1
Decreased
 Immunohistochemistry
 3 months
Gene expression1
Increased
 Quantitative pcr (qrt-pcr)
 3 months
Protein-dna complex assembly1
Decreased
 Chromatin immunoprecipitation sequencing (chip-seq)
 3 months
Protein expression level evidence1
Decreased
 Immunohistochemistry
 3 months
Targeted expression1
Decreased
 Western blot
 3 months
Gene expression1
Decreased
 Rna sequencing
 3 months
Protein modification process1
Increased
 Immunohistochemistry
 3 months
Protein expression level evidence1
Decreased
 Western blot
 3 months
Targeted expression1
Decreased
 Rna sequencing
 3 months
Exploratory activity1
 No change
 Object-place recognition test
 3 months
Exploratory activity1
 No change
 Three-chamber social approach test
 3 months
Protein-dna complex assembly1
 No change
 Chromatin immunoprecipitation sequencing (chip-seq)
 3 months
Targeted expression1
 No change
 Quantitative pcr (qrt-pcr)
 3 months
Targeted expression1
 No change
 Rna sequencing
 3 months
Targeted expression1
 No change
 Western blot
 3 months
Targeted expression1
 No change
 Immunohistochemistry
 3 months
Swimming ability1
 No change
 Morris water maze test
 3 months
Pain or nociception1
 No change
 Foot shock test
 3 months
Social habituation1
 No change
 Reciprocal social interaction test
 3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure

 

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