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Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations in the HDAC4 gene have been identified with brachydactyly mental retardation syndrome (Williams et al., 2010). Genetic association has been found between the HDAC4 gene and schizophrenia in a Korean population cohort (Kim et al., 2010).

Molecular Function

Regulation of transcription

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral probl...
Brachydactyly mental retardation syndrome
ID
Positive Association
Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...
ASD
Positive Association
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
ASD, ADHD, BPD, MDD, SCZ
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Dysmorphic features
Support
Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals.
Brachydactyly mental retardation syndrome
ASD or autistic features
Support
Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes.
Brachydactyly mental retardation syndrome
ASD or autistic features
Support
DD, ID
Learning disability
Support
Integrating de novo and inherited variants in 42
ASD
Highly Cited
The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation.
Highly Cited
Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.
Highly Cited
Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation.
Recent Recommendation
Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.
Recent Recommendation
Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary g...
Brachydactyly mental retardation syndrome
ASD or autistic features
Recent Recommendation
Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome.
Recent Recommendation
Association of histone deacetylase genes with schizophrenia in Korean population.
SCZ
Recent Recommendation
A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation.
Recent Recommendation
HDAC4 regulates neuronal survival in normal and diseased retinas.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN117R001 
 copy_number_loss 
  
  
  
  
  
 GEN117R0010 
 missense_variant 
 c.2363G>A 
 p.Gly788Glu 
 De novo 
  
  
 GEN117R0011 
 frameshift_variant 
 c.1410_1411del 
 p.Gln471ValfsTer65 
 De novo 
  
  
 GEN117R0012 
 missense_variant 
 c.646C>T 
 p.Pro216Ser 
 De novo 
  
  
 GEN117R0013 
 splice_site_variant 
 c.611+1G>C 
  
 De novo 
  
  
 GEN117R0014 
 synonymous_variant 
 c.555G>A 
 p.Ala185%3D 
 De novo 
  
  
 GEN117R0015 
 synonymous_variant 
 c.108G>A 
 p.Thr36%3D 
 De novo 
  
 Simplex 
 GEN117R002 
 copy_number_loss 
  
  
  
  
  
 GEN117R003 
 copy_number_loss 
  
  
  
  
  
 GEN117R004 
 copy_number_loss 
  
  
  
  
  
 GEN117R005 
 copy_number_loss 
  
  
  
  
  
 GEN117R006 
 frameshift_variant 
 insC 
  
 De novo 
  
  
 GEN117R007 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN117R008 
 missense_variant 
 c.1510C>T 
 p.Arg504Cys 
 Familial 
 Paternal 
 Simplex 
 GEN117R009 
 splice_site_variant 
 c.3074-3_3074-2insG 
  
 Familial 
 Maternal 
  
 GEN117R010 
 missense_variant 
 c.2204G>A 
 p.Arg735Gln 
 Familial 
 Paternal 
 Multiplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN117C001 
 synonymous_variant 
 rs1063639 
 c.2565C>T;c.2580C>T;c.2637C>T;c.2499C>T 
 p.(=) 
 278 patients with schizophrenia and 234 normal controls from a Korean population. 
 Discovery 
 GEN117C002 
 intron_variant 
 rs3791556 
 c.95-1199C>T;c.80-1199C>T;c.167-1199C>T;c.14-1199C>T 
 A/G 
 Psychiatrics Genomic Consortium (PGC): 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls 
 Discovery 
 GEN117C003 
 2KB_upstream_variant 
 rs2931203 
 c.-2465T>A;c.-1440T>A;c.-1864T>A;c.-2150T>A 
  
 7387 ASD cases and 8567 controls from Autism Center of Excellence Network (ACE), Autism Genetic Resource Exchange (AGRE), Autism Genome Project (AGP), Finnish Case-Control ASD Collection, NIMH Repository and Montreal/Boston (MonBos) Collection, Population-Based Autism Genetics and Environment Study (PAGES), Simons Simplex Collection (SSC), and Weiss Laboratory Autism Collection 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
2
Duplication
 1
 
2
Duplication
 1
 
2
Duplication
 1
 
2
Deletion-Duplication
 2
 
2
Deletion
 10
 
2
Deletion
 9
 
2
Deletion-Duplication
 59
 

Model Summary

HDAC4 as a central regulator of chondrocyte hypertrophy and skeletogenesis and suggest general roles for class II HDACs in the control of cellular hypertrophy.

References

Type
Title
Author, Year
Primary
Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.

M_HDAC4_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Homologous recombination mediated insertion of lacZ cassette into exon 6 resulting in deletion of MEF2 binding domain of Hdac4 gene.
Allele Type: Targeted (Knock-out)
Strain of Origin: Not Specified
Genetic Background: 123Sv/EV-C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_HDAC4_2_TG_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Transgenic mice in which the signal-resistant Hdac4 mutant, in which serines 246,467, and 632 were changed to alanines, under control of alpha1(II) collagen promoter.
Allele Type: Targeted(Transgene)
Strain of Origin: Not Specified
Genetic Background: C57BL/6/129
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_HDAC4_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Skeletal development1
Abnormal
Description: Abnormal skeletal morphology demonstrated by premature mineralization of cartilage in skeletal elemtns ossifying through endochondral osffication
Exp Paradigm: Mineralized bone/cartilage and non mineralized cartilage staining with alziarin red and alcian blue respectively
 Histology
 P8
Mortality/lethality1
Increased
Description: Increased lethality with no mice surviving to weaning
Exp Paradigm: General observations
 General observations
 Unreported
General characteristics1
Abnormal
Description: Abnormal "dome-shaped" heads and misshaped spines
Exp Paradigm: General observations
 General observations
 P8
Vertebrae morphology1
Abnormal
Description: Abnormal vertebrae with fused ossification centers of arch and body with no remaining cartilage
Exp Paradigm: Mineralized bone/cartilage and non mineralized cartilage staining with alziarin red and alcian blue respectively
 Histology
 P8
Developmental trajectory1
Abnormal
Description: Abnormal developmental trajectory indicated by premature mineralization of wrist and vertebrae
Exp Paradigm: Mineralized bone/cartilage and non mineralized cartilage staining with alziarin red and alcian blue respectively
 Histology
 E18
Marker expression1
Increased
Description: Increased expression of hypertrophic chondrocytes and bone markers - indian hedgehog (ihh), runx2, alpha(1)x collagen
Exp Paradigm: Chondrocyte markers
 In situ hybridization (ish)
 E18.5, e16.5
Developmental trajectory1
 No change
 Histology
 P8
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_HDAC4_2_TG_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Skeletal development1
Abnormal
Description: Abnormal skeletal morphology with lack of mineralized bone
Exp Paradigm: Mineralized bone staining as detected by alziarin red
 Histology
 E18.5
Skeletal development1
Abnormal
Description: Abnormal morphology with complete lack of hypertrophic chondrocytes and osteoblasts with an absence of bone trabeculae
Exp Paradigm: Histological analysis and in situ hybridization
 Histology
 E18.5
Developmental trajectory1
Abnormal
Description: Abnormal developmental trajectory with severe fore-shortening of the limbs
Exp Paradigm: Staining analysis of skeletal preparation with alizarin red and alcian blue
 Histology
 E18.5
Marker expression1
Decreased
Description: Decreased expression of alpha1(x) collagen and alpha1(i) collage in the cartilaginous skeletal elements - markers for hypertrophic chondrocytes and trabeculate bone respectively
Exp Paradigm: Chondrocyte markers
 In situ hybridization (ish)
 E16.5, e18.5
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior





Download HDAC4's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
AIB1 nuclear receptor coactivator 3 8202 Q9Y6Q9 IP/WB; ChIP
Garee JP , et al. 2014
ANCO1 Ankyrin repeat domain-containing protein 11 29123 Q6UB99 IP/WB; ChIP
Garee JP , et al. 2014
ANKRA2 ankyrin repeat, family A (RFXANK-like), 2 57763 Q9H9E1 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
ANKRD11 ankyrin repeat domain 11 29123 Q6UB99 GST; IP/WB
Zhang A , et al. 2004
AR androgen receptor 367 P10275 IP; Ni-NTA pull-down assay; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Yang Y , et al. 2011
CCDC136 coiled-coil domain containing 136 64753 Q96JN2 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
CDR2 cerebellar degeneration-related protein 2, 62kDa 1039 Q01850 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 1499 Q9WU82 IP/WB
Vietor I , et al. 2005
EFEMP2 EGF containing fibulin-like extracellular matrix protein 2 30008 O95967 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
GOLGA2 golgin A2 2801 Q08379 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
HOXB13 homeobox B13 10481 Q4KR72 ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Ren G , et al. 2008
HTR3C 5-hydroxytryptamine receptor 3C 170572 Q8WXA8 GST; In vivo acetylation assay; in vitro kinase assay; AMPK kinase assay; IP/WB
Lin YY , et al. 2012
KDM5B lysine (K)-specific demethylase 5B 10765 Q9UGL1 Luciferase reporter assay; IP/WB
Barrett A , et al. 2007
KRT31 keratin 31 3881 Q15323 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
KRT38 keratin 38, type I 8687 O76015 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
KRT40 keratin 40, type I 125115 Q6A162 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
LDOC1 Protein LDOC1 23641 O95751 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
MEF2C myocyte enhancer factor 2C 4208 Q06413 IP; Luciferase reporter assay
Wang AH , et al. 1999
miR-1 microRNA 1-1 406904 N/A Luciferase reporter assay
Yu H , et al. 2014
miR-133 microRNA 133a-1 406922 N/A Luciferase reporter assay
Yu H , et al. 2014
MTA1 metastasis associated 1 9112 Q13330 EMSA; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Reddy SD , et al. 2012
MTUS2 microtubule associated tumor suppressor candidate 2 23281 J3KQA9 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
NCOR2 nuclear receptor corepressor 2 9612 Q9Y618 Fluorescence anisotropy
Hudson GM , et al. 2015
PNMA1 paraneoplastic Ma antigen 1 9240 Q8ND90 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
PTEN phosphatase and tensin homolog 5728 F6KD01 ChIP
Reddy SD , et al. 2012
RINT1 RAD50 interactor 1 60561 Q6NUQ1 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box) 6934 Q9NQB0 GST; In vivo acetylation assay; in vitro kinase assay; AMPK kinase assay; IP/WB
Lin YY , et al. 2012
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013
YWHAG tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, gamma polypeptide 7532 P61981 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
YY1 YY1 transcription factor 7528 P25490 IP; in vitro kinase assay
Ren G , et al. 2008
ARR19 CKLF-like MARVEL transmembrane domain containing 2A 73381 Q9DAR1 GST
Jeong BC , et al. 2003
Arx aristaless related homeobox 11878 O35085 ChIP-qPCR
Quill ML , et al. 2011
ATF4 Cyclic AMP-dependent transcription factor ATF-4 11911 Q06507 ELISA
Makinistoglu MP and Karsenty G 2015
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011
Lkb1 serine/threonine kinase 11 20869 Q9WTK7 IP/WB; in vitro kinase assay
Gormand A , et al. 2014
Stat6 signal transducer and activator of transcription 6 20852 P52633 IP/WB
Yang Q , et al. 2014
TDP-43 TAR DNA-binding protein 43 23435 Q13148 IP/WB; CLIP; MS
King IN , et al. 2014
Acta1 actin, alpha 1, skeletal muscle 29437 P68136 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Angptl4 angiopoietin-like 4 362850 Q6TMA8 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Atp2a2 ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 29693 P11507 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Cacna1c calcium channel, voltage-dependent, L type, alpha 1C subunit 24239 A0SLC4 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Cav3 caveolin 3 29161 P51638 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Csrp3 cysteine and glycine-rich protein 3 (cardiac LIM protein) 117505 P50463 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Fosl1 fos-like antigen 1 25445 P10158 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Nppb natriuretic peptide B 25105 P13205 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Nup155 nucleoporin 155 117021 P37199 Y2H
Kehat I , et al. 2011
Pln phospholamban 64672 P61016 DamID; qRT-PCR; ChIP
Kehat I , et al. 2011
Slc8a1 solute carrier family 8 (sodium/calcium exchanger), member 1 29715 Q01728 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Tnfrsf12a tumor necrosis factor receptor superfamily, member 12a 302965 Q80XX9 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
Tpm1 tropomyosin 1, alpha 24851 Q63607 DamID; qRT-PCR; ChIP; Bimolecular fluorescence complementation assay; IP/WB; Y2H
Kehat I , et al. 2011
EHMT1 G9a 30971 Q95RU8 ChIP-Seq
Kramer JM , et al. 2011
KDM5 Lysine-specific demethylase lid 33837 Q9VMJ7 GST; IP/WB; ChIP
Liu X , et al. 2014

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