Alternative titles; symbols
HGNC Approved Gene Symbol: HDAC4
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38) : 2:239,048,168-239,401,649 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.3 | Neurodevelopmental disorder with central hypotonia and dysmorphic facies | 619797 | Autosomal dominant | 3 |
DNA is wrapped around histone proteins to form nucleosomes and chromatin fiber, a higher-order structure. Chromatin can become alternatively transparent or opaque to transcription factors. Acetylation (see HAT1, 603053) of lysine residues induces conformational changes in core histones by destabilizing nucleosomes and allowing transcription factors access to recognition elements in DNA. Deacetylation (see HDAC1, 601241) of histones, on the other hand, reseals the chromosomal package, leading to a repression of transcription. See Wolffe (1997) and Pazin and Kadonaga (1997) for reviews. There are at least 2 classes of HDACs, class I, consisting of proteins homologous to yeast Rpd3 (e.g., HDAC1, HDAC2 (605164), and HDAC3 (605166)) and class II, consisting of proteins homologous to yeast Hda1. HDAC4 is a class II HDAC.
By searching an EST database for sequences similar to yeast Hda1, followed by screening a cDNA library and PCR, Grozinger et al. (1999) identified cDNAs encoding the class II HDACs HDAC4, HDAC5 (605315), and HDAC6 (300272). Sequence analysis predicted that the 1,085-amino acid HDAC4 protein, which is identical to the KIAA0288 protein, contains a catalytic region beginning at residue 802. Northern blot analysis detected a 9.6-kb HDAC4 transcript apparently restricted to brain, heart, and skeletal muscle. Western blot analysis showed that HDAC4 is expressed as a 119-kD protein that coimmunoprecipitates with RbAp48 (RBBP4; 602923) and HDAC3.
By random sequencing of a size-selected brain cDNA library, Fischle et al. (1999) identified a partial cDNA encoding HDAC4, which they called HDACA. Northern blot analysis detected an 8.4-kb HDAC4 transcript in all tissues tested, with a strong 3.4-kb transcript also present in testis. Immunofluorescence analysis showed a subnuclear localization excluded from nucleoli in interphase cells. SDS-PAGE analysis demonstrated that HDAC4 interacts with multiple proteins.
Functional analysis by Grozinger et al. (1999) confirmed that HDAC4 possesses deacetylation activity against all 4 core histones.
Wang et al. (1999) cloned HDAC4 and demonstrated that its deacetylase activity requires histidine at residues 802 and 803. They determined that HDAC4 does not bind DNA directly, but rather through MEF2C (600662) and MEF2D (600663). Binding of the N terminus of HDAC4 to MEF2C represses MEF2C transcription activity.
Fischle et al. (2002) showed that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor NCOR2 (600848). All experimental conditions leading to the suppression of HDAC4 binding to NCOR2 and to HDAC3 resulted in loss of enzymatic activity associated with HDAC4. These observations indicated that class II HDACs regulate transcription by bridging the enzymatically active NCOR2-HDAC3 complex and select transcription factors.
Youn et al. (2000) reported that HDAC4 and MITR (606543) contain calmodulin-binding domains that overlap with their MEF2 binding domains. Binding of calmodulin to HDAC4 leads to its dissociation from MEF2, relieving MEF2 from the transcriptional repression by HDAC4. Together, HDAC4, MITR, and CABIN1 (604251) constitute a family of calcium-sensitive transcriptional repressors of MEF2.
Um et al. (2006) stated that HDAC4 is sumoylated by RANBP2 (601181). They showed that parkin (602544) controlled the intracellular levels of sumoylated HDAC4 by ubiquitinating RANBP2 and causing its proteasome-dependent degradation.
Using luciferase analysis, Portal et al. (2006) showed that HDAC4 and HDAC5, but not other HDACs, repressed Epstein-Barr virus (EBV) nuclear antigen-2 (EBNA2) activation of EBV promoters, and that this repression could be reversed by EBNA leader protein (EBNALP). HDAC4 could repress EBNA2 and EBNALP coactivation of EBV promoters. Immunoprecipitation and Western blot analyses showed that HDAC4 associated with EBNA2 in the nucleus and with EBNALP in the nucleus and cytoplasm of lymphoblastoid cell lines. EBNALP reduced HDAC4 nuclear localization in B cells. Reporter gene analysis demonstrated that overexpression of HDAC4 or HDAC5 in the presence of overexpressed 14-3-3 (see 605066) protein altered activation of different EBV promoters by EBNA2 and EBNALP. Coimmunoprecipitation and Western blot analyses revealed that 14-3-3, HDAC4, and EBNALP associated in a ternary complex. Portal et al. (2006) concluded that EBNALP coactivates transcription by relocalizing HDAC4 and HDAC5 from EBNA2-activated promoters to the cytoplasm.
Tuddenham et al. (2006) identified the 3-prime UTR of HDAC4 as 1 of 138 putative targets containing the miR140 (MIRN140; 611894) seed sequence (5-prime-GTGGTTT-3-prime). A small interfering RNA that mimicked miR140 (siRNA140) downregulated expression of a reporter gene containing 800 bp of the human HDAC4 3-prime UTR, and transfection of siRNA140 into mouse fibroblasts reduced the level of endogenous Hdac4 protein.
Chen and Cepko (2009) reported that Hdac4 regulates the survival of retinal neurons in the mouse in normal and pathologic conditions. Reduction in Hdac4 expression during normal retinal development led to apoptosis of rod photoreceptors and bipolar interneurons, whereas overexpression reduced naturally occurring cell death of the bipolar cells. Hdac4 overexpression in a mouse model of retinal degeneration prolonged photoreceptor survival. The survival effect was due to the activity of Hdac4 in the cytoplasm and relied at least partly on the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha; 603348). Chen and Cepko (2009) concluded that their data provided evidence that HDAC4 plays an important role in promoting the survival of retinal neurons.
Robert et al. (2011) showed that HDAC inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR, 601215) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CTIP; 604124) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3 (HDAC1; 601241) and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; 602301), have key roles in these processes. Robert et al. (2011) also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; 601231), also causes Sae2 degradation. Robert et al. (2011) proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy.
Using immunofluorescence analysis and coimmunoprecipitation assays, Sasagawa et al. (2012) found that salt-inducible kinase-3 (SIK3; 614776) localized to the cytoplasm and formed a complex with Hdac4, a crucial repressor of chondrocyte hypertrophy, in mouse hypertrophic chondrocytes. The Sik3-Hdac4 interaction anchored Hdac4 in the cytoplasm. In Sik3-deficient mouse chondrocytes, Hdac4 localized to nuclei and repressed Mef2c, a crucial facilitator of chondrocyte hypertrophy, resulting in the blockage of chondrocyte hypertrophy. Sasagawa et al. (2012) concluded that SIK3 plays an essential role in chondrocyte hypertrophy during skeletogenesis through its interaction with HDAC4.
Using FISH analysis, Wang et al. (1999) mapped the HDAC4 gene to chromosome 2q37.2.
In 7 unrelated patients with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified 4 different de novo heterozygous missense mutations (605314.0003-605314.0006) in the HDAC4 gene. The mutations, which were identified by whole-exome sequencing, were predicted to result in reduced HDAC4 affinity for 14-3-3 proteins, leading to reduced sequestration of HDAC4 in the cytoplasm by the 14-3-3 proteins and increased levels of HDAC4 in the nucleus.
Associations Pending Confirmation
For discussion of possible phenotypic consequences of deletion of the HDAC4 gene, see chromosome 2q37 deletion syndrome (600430).
Vega et al. (2004) reported that Hdac4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation in mice by interacting with and inhibiting the activity of Runx2 (600211), a transcription factor necessary for chondrocyte hypertrophy. Hdac4-null mice displayed premature ossification of developing bones due to ectopic and early onset chondrocyte hypertrophy, mimicking the phenotype that results from constitutive Runx2 expression in chondrocytes. Conversely, overexpression of Hdac4 in proliferating chondrocytes in vivo inhibited chondrocyte hypertrophy and differentiation, mimicking a Runx2 loss-of-function phenotype. These results established HDAC4 as a central regulator of chondrocyte hypertrophy and skeletogenesis.
This variant, formerly titled BRACHYDACTYLY-MENTAL RETARDATION SYNDROME, has been reclassified based on the findings of Villavicencio-Lorini et al. (2013) and Wheeler et al. (2014).
In a French Canadian woman with brachydactyly-mental retardation syndrome (BDMR; 600430), Williams et al. (2010) identified a heterozygous de novo 1-bp insertion (2399insC) in exon 19 of the HDAC4 gene, resulting in a frameshift and premature termination. There was no evidence of nonsense-mediated mRNA decay, but the mutation likely resulted in haploinsufficiency. Quantitative RT-PCR analysis showed that lymphocytes from the patient did not alter HDAC4 expression, suggesting that the mutation does not result in nonsense-mediated mRNA decay and produces a nonfunctional protein. The patient had delayed psychomotor development, subvalvular aortic stenosis, dysmorphic facial features, brachydactyly type E (BDE), sleep disturbances, and behavioral problems.
Villavicencio-Lorini et al. (2013) reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (607556) genes. Villavicencio-Lorini et al. (2013) concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE.
Wheeler et al. (2014) provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment of BDE. Wheeler et al. (2014) suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability.
This variant, formerly titled BRACHYDACTYLY-MENTAL RETARDATION SYNDROME, has been reclassified based on the findings of Villavicencio-Lorini et al. (2013) and Wheeler et al. (2014).
In a 16-year-old Caucasian girl with brachydactyly-mental retardation syndrome (BDMR; 600430), Williams et al. (2010) identified a heterozygous de novo 65-bp deletion (490+56_121del65) in intron 5 of the HDAC4 gene, which was predicted to alter the splicing of exons 5 and 6. She had dysmorphic features, brachydactyly type E (BDE), psychomotor retardation, and severe behavioral abnormalities.
Villavicencio-Lorini et al. (2013) reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (607556) genes. Villavicencio-Lorini et al. (2013) concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE.
Wheeler et al. (2014) provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment of BDE. Wheeler et al. (2014) suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability.
In 4 unrelated patients (patients 4-7) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a de novo heterozygous c.743C-T transition (c.743C-T, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-leu (P248L) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. he mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins.
In a patient (patient 3) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a de novo heterozygous c.742C-G transversion (c.742C-G, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-ala (P248A) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding sit and is predicted to result in decreased binding of 14-3-3 proteins.
In a patient (patient 2) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a heterozygous c.740A-G transition (c.740A-G, NM_007037.4) in the HDAC4 gene, resulting in a glu247-to-gly (E247G) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. Coimmunoprecipitation with HDAC4 with the E247G mutation in HEK293 cells demonstrated reduced binding affinity for 14-3-3-beta (601289).
In a patient (patient 1) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a heterozygous 731C-A transversion in the HDAC4 gene resulting in a thr244-to-lys (T244K) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. Coimmunoprecipitation with HDAC4 with the T244K mutation in HEK293 cells demonstrated reduced binding affinity for 14-3-3-beta (601289).
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