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RFX5
regulatory factor X5
The RFX5 gene provides instructions for a protein that plays a critical role in the immune system, primarily by regulating the activity of major histocompatibility complex (MHC) class II genes. RFX5 is essential for the production of MHC class II proteins, which are vital components of the body's immune response to foreign invaders.
RFX5 is located on the long (q) arm of chromosome 1, at band 1q21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The RFX5 gene, also known as regulatory factor X5, encodes a protein that is a key transcription factor within the immune system. This protein helps control the activity of genes responsible for producing major histocompatibility complex (MHC) class II proteins.
MHC class II proteins are found on the surface of certain immune cells and are crucial for presenting fragments of foreign invaders, such as bacteria or viruses, to other immune cells. This process allows the immune system to recognise and mount an appropriate defence against pathogens.
What the gene does
The RFX5 protein is an integral component of the regulatory factor X (RFX) complex. This complex binds to specific DNA regions, regulating the transcription of MHC class II genes, which is the initial step in protein production. RFX5 helps position the complex correctly on the DNA.
By facilitating the binding of the RFX complex and attracting other necessary proteins, RFX5 effectively activates MHC class II gene transcription. This activation leads to the synthesis of MHC class II proteins, which are vital for immune cells to identify and respond to pathogens. The RFX complex also contributes to the transcription of MHC class I genes, though its role here is secondary to other regulatory proteins.
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Chromosome location
The RFX5 gene is situated on chromosome 1 at position 1q21.3. This genomic location specifies where the gene can be found within the human genome.
Protein structure
The RFX5 protein is composed of 616 amino acids and exhibits several distinct functional regions. The N-terminal domain spans amino acids 25-90 and includes a leucine-rich region (amino acids 62-66), which is crucial for forming dimers and interacting with RFXAP. A significant RFX-type winged-helix domain (amino acids 92-168) is responsible for DNA binding. The protein also contains a PxLPxI/L motif (amino acids 173-178), which mediates interaction with RFXANK. Additionally, there are several disordered regions: amino acids 1-29, 252-314, and 391-616, which may confer flexibility or facilitate protein interactions.
Key variants
Genetic variations within the RFX5 gene can affect the protein's ability to regulate immune system genes. These variations may lead to altered protein function, impacting the production of essential immune proteins. Understanding the spectrum of RFX5 variants is important for elucidating their potential clinical consequences.
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.103C>T | p.Arg35Ter | Pathogenic/Likely pathogenic | ★★☆☆ | RFX5-related disorder |
c.1578_1594dup | p.Gln532fs | Pathogenic/Likely pathogenic | ★★☆☆ | MHC class II deficiency |
c.386del | p.Pro129fs | Pathogenic/Likely pathogenic | ★★☆☆ | MHC class II deficiency |
c.56dup | p.Gly20fs | Pathogenic/Likely pathogenic | ★★☆☆ | MHC class II deficiency |
c.715C>T | p.Arg239Ter | Pathogenic | ★★☆☆ | MHC class II deficiency |
c.757+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | MHC class II deficiency |
c.880C>T | p.Arg294Ter | Pathogenic/Likely pathogenic | ★★☆☆ | MHC class II deficiency |
c.1198C>T | p.Arg400Ter | Pathogenic | ★☆☆☆ | MHC class II deficiency 1 |
c.198dup | p.Gln67fs | Pathogenic | ★☆☆☆ | MHC class II deficiency |
c.56del | p.Pro19fs | Pathogenic | ★☆☆☆ | MHC class II deficiency |
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
Mutations in the RFX5 gene are associated with an immune system disorder known as bare lymphocyte syndrome type II (BLS II). This condition is a form of combined immunodeficiency, where affected individuals experience a severe lack of immune protection against foreign invaders. This deficiency can lead to recurring and persistent infections, particularly affecting the respiratory, gastrointestinal, and urinary tracts.
No disease links recorded for this gene in our reference set.
UK clinical status
The RFX5 gene is included in UK NHS national genomic testing strategies. It is listed on PanelApp UK for "COVID-19 research" with a green status, indicating strong evidence for its association. It also appears on the "Primary immunodeficiency or monogenic inflammatory bowel disease" panel, also with a green status (R15), suggesting it is routinely tested for in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the RFX5 gene?
The RFX5 gene primarily provides instructions for making a protein that controls the activity of major histocompatibility complex (MHC) class II genes, which are essential for a healthy immune response to foreign invaders.
What condition is associated with RFX5 gene mutations?
Mutations in the RFX5 gene are associated with bare lymphocyte syndrome type II (BLS II), a severe immune deficiency characterised by a lack of immune protection against pathogens, leading to persistent infections.
How does the RFX5 protein help the immune system?
The RFX5 protein is part of a complex that binds to DNA, activating genes that produce MHC class II proteins. These proteins display fragments of foreign invaders to other immune cells, enabling the body to recognise and fight infections.
References
- Garvie CW, Boss JM. Assembly of the RFX complex on the MHCII promoter: role of RFXAP and RFXB in relieving autoinhibition of RFX5. Biochimica et biophysica acta. 2008. PMID: 18723135
- Burd AL, Ingraham RH, Goldrick SE. Assembly of major histocompatibility complex (MHC) class II transcription factors: association and promoter recognition of RFX proteins. Biochemistry. 2004. PMID: 15461447
- Gobin SJ, Peijnenburg A, van Eggermond M. The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes. Immunity. 1998. PMID: 9806639
- Villard J, Reith W, Barras E. Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency. Human mutation. 1997. PMID: 9401005