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HDAC8
histone deacetylase 8
The HDAC8 gene provides instructions for making histone deacetylase 8, an enzyme crucial for regulating chromosome structure and organisation during cell division. The HDAC8 gene is responsible for producing histone deacetylase 8, an enzyme that plays a key role in the dynamic processes of chromosome organisation and cell division.
HDAC8 is located on the long (q) arm of chromosome X, at band Xq13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The HDAC8 gene encodes histone deacetylase 8, an enzyme integral to cellular processes involving chromosome structure and organisation. This enzyme is particularly important during cell division, where it helps ensure the proper separation of genetic material. Research indicates that HDAC8 is also involved in maintaining genomic stability, DNA repair mechanisms, and regulating gene activity essential for normal development.
Disruptions in the HDAC8 gene can lead to developmental disorders, including Cornelia de Lange syndrome, which affects various aspects of physical and intellectual development. Understanding the function of HDAC8 is crucial for deciphering the molecular basis of these conditions.
What the gene does
The HDAC8 gene provides instructions for histone deacetylase 8, an enzyme that performs a critical chemical reaction in cells. This enzyme is involved in regulating the structure and organisation of chromosomes, particularly during cell division. Before a cell divides, its chromosomes duplicate, forming two identical structures called sister chromatids. These sister chromatids are temporarily held together by a group of proteins known as the cohesin complex.
Histone deacetylase 8 facilitates the removal of this cohesin complex, allowing the sister chromatids to separate properly so that one copy can move into each new daughter cell. This process is essential for accurate cell division and the recycling of the cohesin complex for subsequent divisions. Beyond its role in chromatid separation, histone deacetylase 8 is also thought to contribute to maintaining the stability of a cell's genetic information, repairing damaged DNA, and controlling the expression of specific genes vital for normal development.
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Chromosome location
The HDAC8 gene is located on the long arm of the X chromosome at position 13.1, a region designated Xq13.1. This genomic location means that males, who have only one X chromosome, typically express any variants present on their single X chromosome. The gene provides the blueprint for a protein consisting of 377 amino acids.
Protein structure
The HDAC8 protein is composed of 377 amino acids. A prominent feature of its structure is the Histone deacetylase region, spanning amino acids 14-324. This region is critical for the enzyme's catalytic activity, allowing it to modify histones and other proteins by removing acetyl groups, which is fundamental to its role in chromatin remodelling and gene expression regulation.
Key variants
Genetic variations, or variants, in the HDAC8 gene can alter the normal function of the histone deacetylase 8 enzyme. These variants often involve changes to single protein building blocks (amino acids) or result in the addition or deletion of sections of the protein. Such changes can impair the enzyme's ability to regulate chromosome structure and cell division effectively. The clinical impact of these variants can vary widely, depending on their specific nature and location within the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.110G>A | p.Arg37Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.134_137del | p.Ile45fs | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.165-2A>G | - | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.356C>G | p.Thr119Arg | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.356C>T | p.Thr119Met | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.467A>G | p.Asn156Ser | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.490C>T | p.Arg164Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
c.496C>T | p.Arg166Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.562G>A | p.Ala188Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability |
c.738-1G>A | - | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 5 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the HDAC8 gene are associated with several developmental conditions. One notable condition is Cornelia de Lange syndrome, a developmental disorder characterised by a range of physical and intellectual challenges. Researchers estimate that HDAC8 variants account for approximately 5 percent of all cases of Cornelia de Lange syndrome. Additionally, a specific variant in HDAC8 has been identified in a large Dutch family with a form of X-linked intellectual disability, presenting in affected males with severe intellectual disability, short stature, obesity, breast enlargement (gynaecomastia), and reduced production of sex hormones.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic HDAC8 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The HDAC8 gene is included in several NHS Genomic Medicine Service national testing panels, indicating its recognised clinical significance within the UK. It is categorised as 'green' on PanelApp for conditions such as Clefting, Developmental Disorders Gene 2 Panel (DDG2P), Foetal anomalies (R21), Intellectual disability, Intrauterine Growth Restriction (IUGR) and IGF abnormalities, Limb disorders, Radial dysplasia, Severe microcephaly (R88), and Skeletal dysplasia (R104). This signifies that there is sufficient evidence for genes in these panels to be considered clinically actionable.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the HDAC8 gene?
The HDAC8 gene provides instructions for making histone deacetylase 8, an enzyme primarily involved in regulating chromosome structure and organisation, especially during cell division where it helps separate genetic material.
Which conditions are associated with HDAC8 gene variants?
Variants in the HDAC8 gene are associated with developmental disorders such as Cornelia de Lange syndrome and a form of X-linked intellectual disability, which can involve a range of physical and developmental challenges.
How does HDAC8 contribute to cell division?
HDAC8 plays a crucial role in cell division by helping to remove the cohesin complex, which allows sister chromatids to separate. This process ensures that each new cell receives an accurate set of chromosomes.
References
- Mordaunt DA, McLauchlan A. HDAC8-deficiency causes an X-linked dominant disorder with a wide range of severity. Clinical genetics. 2015. PMID: 25800122
- Kaiser FJ, Ansari M, Braunholz D. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Human molecular genetics. 2014. PMID: 24403048
- Decroos C, Bowman CM, Moser JA. Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders. ACS chemical biology. 2014. PMID: 25075551
- Deardorff MA, Bando M, Nakato R. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature. 2012. PMID: 22885700
- Harakalova M, van den Boogaard MJ, Sinke R. X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face. Journal of medical genetics. 2012. PMID: 22889856