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PHF8
PHD finger protein 8
The PHF8 gene encodes a protein crucial for regulating gene expression through chromatin remodelling, primarily active in brain cells during early development. PHF8 is located on the X chromosome and plays a vital role in modifying how DNA is packaged within cells.
PHF8 is located on the short (p) arm of chromosome X, at band Xp11.22. Arm ratio per GRCh38 - banding schematic.
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Overview
The PHF8 gene, or PHD finger protein 8, provides instructions for creating a protein found predominantly in the nucleus of cells, especially brain cells around the time of birth. This protein is a member of the zinc finger protein family, characterised by specific domains that bind to other molecules. The PHF8 protein is essential for regulating gene activity through a mechanism called chromatin remodelling, which impacts how DNA is packaged and accessed.
What the gene does
The PHF8 protein contributes to regulating gene expression by interacting with chromatin, the complex of DNA and proteins that forms chromosomes. It contains a PHD domain, which allows it to bind to chromatin. This binding initiates changes in chromatin structure, altering the tightness of DNA packaging. Gene activity is influenced by how densely DNA is packed; loosely packed DNA generally allows for gene expression, while tightly packed DNA tends to suppress it.
Within the PHF8 protein, a Jumonji C (JmjC) domain is responsible for removing methyl groups from histone proteins, a process known as demethylation. This demethylation promotes the loosening of chromatin structure, thereby enhancing the expression of specific genes. This function is particularly important in brain development and function.
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Chromosome location
The PHF8 gene is located on the X chromosome at position Xp11.22. As an X-linked gene, its inheritance pattern means that conditions associated with PHF8 variants typically affect males more severely than females.
Protein structure
The PHF8 protein is 1060 amino acids long and contains several distinct functional regions. At amino acids 41-92, it features a PHD-type (Zinc finger) domain. Disordered regions are present at amino acids 100-120, 508-534, 768-840, 852-902, and 915-1046. A Linker (Region) is found between amino acids 101-115. A key JmjC (Domain) involved in demethylation spans amino acids 231-387.
Key variants
Variants within the PHF8 gene can alter the protein's structure and function, impacting its role in chromatin remodelling and gene regulation. These genetic changes may lead to the production of an abnormally short protein or impair its ability to interact correctly with DNA and histones. Such alterations can disrupt normal brain development and function.
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.1516C>T | p.Arg506Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1615C>T | p.Gln539Ter | Pathogenic | ★★☆☆ | not provided |
c.2210C>G | p.Ser737Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2257C>T | p.Arg753Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Syndromic X-linked intellectual disability Siderius type |
GRCh38/hg38 Xp11.22(chrX:54038034-54049437)x0 | - | Pathogenic | ★☆☆☆ | Intellectual disability |
c.1141+5G>C | - | Pathogenic | ★☆☆☆ | Intellectual disability |
c.122dup | p.Ala42fs | Pathogenic | ★☆☆☆ | not provided |
c.1772dup | p.Ile592fs | Pathogenic | ★☆☆☆ | not provided |
c.192dup | p.Arg65fs | Pathogenic | ★☆☆☆ | not provided |
c.1957C>T | p.Arg653Ter | Pathogenic | ★☆☆☆ | not provided |
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
Variants in the PHF8 gene have been associated with X-linked intellectual disability, Siderius type. This condition is primarily characterised by mild to moderate intellectual disability and is observed exclusively in males. Affected individuals may also present with specific physical features, such as cleft lip and palate.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PHF8 variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
PHF8 is included in several UK NHS national genomic testing panels, indicating its recognised clinical significance. It is part of the green-rated panels for Clefting, DDG2P (Developmental Disorders Genotype-to-Phenotype), Foetal anomalies (R21), and Intellectual disability, signifying that there is strong evidence for a gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the PHF8 gene?
The PHF8 gene provides instructions for a protein that regulates gene expression by modifying chromatin structure. This process involves loosening DNA packaging to allow specific genes to be turned on, particularly in brain cells.
How is PHF8 associated with X-linked intellectual disability, Siderius type?
Variants in the PHF8 gene are linked to X-linked intellectual disability, Siderius type, a condition characterised by mild to moderate intellectual disability primarily affecting males, often alongside features like cleft lip and palate.
Why is PHF8 included in UK NHS genomic testing panels?
PHF8 is included in UK NHS genomic testing panels, such as those for intellectual disability and foetal anomalies, because there is strong evidence supporting its association with specific inherited conditions, making it relevant for diagnostic testing.
References
- Loenarz C, Ge W, Coleman ML. PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase. Human molecular genetics. 2010. PMID: 19843542
- Yu L, Wang Y, Huang S. Structural insights into a novel histone demethylase PHF8. Cell research. 2010. PMID: 20101266
- Kleine-Kohlbrecher D, Christensen J, Vandamme J. A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation. Molecular cell. 2010. PMID: 20346720
- Fortschegger K, de Graaf P, Outchkourov NS. PHF8 targets histone methylation and RNA polymerase II to activate transcription. Molecular and cellular biology. 2010. PMID: 20421419
- Qiu J, Shi G, Jia Y. The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. Cell research. 2010. PMID: 20548336