HGNC Approved Gene Symbol: HDAC8
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:72,329,516-72,572,843 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Cornelia de Lange syndrome 5 | 300882 | X-linked dominant | 3 |
Reversible acetylation of N-terminal histone tails is a key determinant of gene expression, with hyperacetylation resulting in transcriptional activation, and deacetylation correlating with transcriptional silencing. The level of histone acetylation is determined by the opposing activities of histone acetyltransferases (see HAT1, 603053) and deacetylases (see HDAC1, 601241). HDACs are divided into 2 classes: class I, which contains HDACs similar to HDAC1, and class II, which contains HDACs whose C termini share homology with yeast Hda1 (e.g., HDAC4, 605314). HDAC8 is a class I HDAC (Van den Wyngaert et al., 2000).
By searching an EST database for sequences similar to HDAC1, HDAC2, and HDAC3, followed by 5-prime and 3-prime RACE, Hu et al. (2000) and Van den Wyngaert et al. (2000) obtained cDNAs encoding HDAC8. Sequence analysis predicted that the 377-amino acid HDAC8 protein contains the 9 conserved HDAC blocks that are presumably important for catalytic function (Hu et al., 2000). Van den Wyngaert et al. (2000) noted that the approximately 30 amino acids at the N and C termini of HDAC8 are quite distinct from those of other HDACs. HDAC8 shares 54% sequence similarity with HDAC1 and HDAC2 and 39% similarity with HDAC3, making it a class I HDAC. Northern blot analysis detected HDAC8 transcripts of approximately 2.0 and 2.4 kb in all normal tissues tested, with strongest expression in brain, unlike other class I HDACs, and in cancer cell lines. Immunofluorescence analysis indicated a nuclear localization with possible exclusion from the nucleolus. By Western blot analysis, Hu et al. (2000) confirmed the nuclear localization and showed that HDAC8 is expressed as a 49-kD protein.
Buggy et al. (2000) also cloned and characterized HDAC8.
Hu et al. (2000) demonstrated that HDAC8 expresses deacetylation activity in nuclear extracts as well as with histones H3 and H4; this activity could be inhibited by Zn(2+), Cu(+), Fe(2+), trichostatin, and other inhibitors.
Mutation analysis by Buggy et al. (2000) showed that 2 adjacent histidine residues in the predicted active site, his142 and his143, are required for HDAC activity on H4 peptide substrates and core histones.
Vannini et al. (2004) found that knockdown of HDAC8 by RNA interference inhibited the growth of human lung, colon, and cervical cancer cell lines.
Deardorff et al. (2012) used RNAi-based screening of all known human histone deacetylases and sirtuins to identify HDAC8 as the vertebrate SMC3 (606062) deacetylase. Loss of HDAC8 activity using either HDAC8 RNAi or an HDAC8-specific inhibitor did not alter cell cycle progression, but clearly increased acetylated SMC3 in both soluble and chromatin fractions throughout the cell cycle. Deardorff et al. (2012) then showed that reduction in HDAC8 led to decreased occupancy of cohesin localization sites.
Vannini et al. (2004) determined the crystal structure of HDAC8 complexed with an HDAC inhibitor to 2.5-angstrom resolution. HDAC8 forms a single compact alpha/beta domain composed of a central 8-stranded parallel beta sheet and 11 alpha helices. The twisted beta sheet is flanked by 5 helices on one side and 3 helices on the other. The active site has a narrow pocket to accommodate the acetylated lysine during the catalytic reaction, and at the bottom of this tunnel a pentacoordinated active site Zn(2+) ion is found. Below the active site there is a tube-like cavity filled with several water molecules that may shuttle the reaction product acetate. HDAC8 also has 2 K+ ion-binding sites, one of which interacts with key catalytic residues and is directly connected to the zinc-binding site. The K+ ions are required for the structural stability of HDAC8.
By genomic sequence analysis, Van den Wyngaert et al. (2000) determined that the HDAC8 gene contains 11 exons and spans 243 kb.
Using FISH, Van den Wyngaert et al. (2000) mapped the HDAC8 gene to Xq13, in the proximity of the XIST gene (314670). XIST is involved in the initiation of X chromosome inactivation, which correlates with histone deacetylation and DNA hypermethylation of the inactive X. The localization is also near Xq13 breakpoints associated with preleukemia.
By radiation hybrid analysis, Buggy et al. (2000) mapped the HDAC8 gene to chromosome Xq21.2-q21.3.
In affected members of a large family with a syndromic mental retardation disorder resembling Cornelia de Lange syndrome (CDLS5; 300882), Harakalova et al. (2012) identified a splice site mutation in the HDAC8 gene (300269.0001).
Deardorff et al. (2012) screened 154 individuals with Cornelia de Lange syndrome negative for mutations in other implicated genes and identified 4 de novo missense mutations and 1 de novo nonsense mutation in HDAC8 (see, e.g., 300269.0002-300269.0005). In addition, 1 familial mutation (300269.0006) was identified in a boy, his mildly affected sister, and his unaffected mother; the mutant allele was inactivated in the mother's blood. This mutation occurred de novo in an unrelated girl. None of the mutations were found in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.
By whole-exome sequencing in a patient with Cornelia de Lange syndrome, Jezela-Stanek et al. (2019) identified a hemizygous missense mutation in the HDAC8 gene (c.938G-A, R313Q, NM_018486.2). The mutation was inherited from his unaffected mosaic mother. X-inactivation studies on the mother showed her to have random inactivation.
In affected members of a large family with a syndromic disorder resembling Cornelia de Lange syndrome (CDLS5; 300882), Harakalova et al. (2012) identified a G-to-A transition in the donor splice site of exon 2 of the HDAC8 gene (164+5G-A). Analysis of mRNA in lymphocytes derived from a male patient showed that the mutation resulted in a transcript lacking exon 2 and caused premature protein truncation (Ala38AspfsTer3) at the beginning of the histone deacetylase catalytic domain. However, a very small amount of normal HDAC8 transcript was also identified. The mutation, which was found by exome sequencing of the X chromosome, was not found in 96 Dutch male controls or in about 5,000 control exomes. Affected males had intellectual disability, gynecomastia, hypogonadism, and distinctive facial features. Female carriers showed milder features, including learning disabilities and facial dysmorphism; all female carriers showed skewed X inactivation, with the mutated allele inactivated.
In a 6-year-old female with features consistent with Cornelia de Lange syndrome (CDLS5; 300882), Deardorff et al. (2012) identified a heterozygous de novo C-to-T transition at nucleotide 490 of the HDAC8 gene resulting in an arg-to-ter codon substitution at codon 164 (R164X). The patient had growth delays, absent speech, and characteristic facial features as well as asymmetric skull, limb length discrepancy, and dysplastic kidneys. This mutation was not seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.
In a female patient with growth and facial features consistent with severe Cornelia de Lange (CDLS5; 300882), Deardorff et al. (2012) identified a de novo heterozygous mutation in the HDAC8 gene, an A-to-G transition at nucleotide 539 resulting in a his-to-arg substitution at codon 180 (H180R). At 3 years of age the patient had moderate to severe cognitive impairment without limb abnormalities. She subsequently died in her teens. This mutation was not seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.
In a 1-year-old female with severe growth and cognitive delays and facial features of classic Cornelia de Lange syndrome (CDLS5; 300882), Deardorff et al. (2012) identified a de novo C-to-T transition at nucleotide 932 in the HDAC8 gene, resulting in a thr-to-met substitution at codon 311 (T311M). The infant also had large fontanels, pulmonary stenosis, and unilateral hearing loss. She had no limb anomalies. This mutation was not seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.
In a 5-year-boy boy with severe cognitive and growth delays and facial features consistent with Cornelia de Lange syndrome (CDLS5; 300882), Deardorff et al. (2012) identified a hemizygous de novo G-to-A transition at nucleotide 958 of the HDAC8 gene, resulting in a gly-to-arg substitution at codon 320 (G320R). Additionally the boy had large fontanels, atrial septum aneurysm, bilateral hearing loss, and a happy personality. This mutation was not seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.
In a 7-year-old heterozygous female with severe cognitive and growth delays and facial features suggestive of Cornelia de Lange syndrome (CDLS5; 300882), Deardorff et al. (2012) identified an A-to-G transition at nucleotide 1001 of the HDAC8 gene, resulting in a his-to-arg substitution at codon 334 (H334R). The patient also had delayed fontanel closure, limb length difference but no deficiencies, and a happy and introverted demeanor. This mutation was heterozygous and de novo in this female, but was identified in a second family. The proband was a 13-year-old hemizygous male with severe cognitive and growth delay and facial features consistent with Cornelia de Lange syndrome. He had an 8-year-old heterozygous affected sister with mild cognitive and growth delays and mildly affected facial features. The unaffected mother was heterozygous with completely skewed X inactivation. This mutation was not seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.
Buggy, J. J., Sideris, M. L., Mak, P., Lorimer, D. D., McIntosh, B., Clark, J. M. Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem. J. 350: 199-205, 2000. [PubMed: 10926844]
Deardorff, M. A., Bando, M., Nakato, R., Watrin, E., Itoh, T., Minamino, M., Saitoh, K., Komata, M., Katou, Y., Clark, D., Cole, K. E., De Baere, E., and 30 others. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489: 313-317, 2012. [PubMed: 22885700] [Full Text: https://doi.org/10.1038/nature11316]
Harakalova, M., van den Boogaard, M.-J., Sinke, R., van Lieshout, S., van Tuil, M. C., Duran, K., Renkens, I., Terhal, P. A., de Kovel, C., Nijman, I. J., van Haelst, M., Knoers, N. V. A. M., van Haaften, G., Kloosterman, W., Hennekam, R. C. M., Cuppen, E., Ploos van Amstel, H. K. X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face. J. Med. Genet. 49: 539-543, 2012. [PubMed: 22889856] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100921]
Hu, E., Chen, Z., Fredrickson, T., Zhu, Y., Kirkpatrick, R., Zhang, G.-F., Johanson, K., Sung, C.-M., Liu, R., Winkler, J. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J. Biol. Chem. 275: 15254-15264, 2000. [PubMed: 10748112] [Full Text: https://doi.org/10.1074/jbc.M908988199]
Jezela-Stanek, A., Murcia, P. V., Jurkiewicz, D., Iwanicka-Pronicka, K., Jedrzejowska, M., Krajewska-Walasek, M., Ploski, R. Novel variant in HDAC8 gene resulting in the severe Cornelia de Lange phenotype. Clin. Dysmorph. 28: 126-130, 2019. [PubMed: 30921088] [Full Text: https://doi.org/10.1097/MCD.0000000000000277]
Van den Wyngaert, I., de Vries, W., Kremer, A., Neefs, J.-M., Verhasselt, P., Luyten, W. H. M. L., Kass, S. U. Cloning and characterization of human histone deacetylase 8. FEBS Lett. 478: 77-83, 2000. [PubMed: 10922473] [Full Text: https://doi.org/10.1016/s0014-5793(00)01813-5]
Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., Steinkuhler, C., Di Marco, S. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Nat. Acad. Sci. 101: 15064-15069, 2004. [PubMed: 15477595] [Full Text: https://doi.org/10.1073/pnas.0404603101]