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AFF2
ALF transcription elongation factor 2
The AFF2 gene provides instructions for a protein primarily involved in regulating gene activity and messenger RNA (mRNA) processing, and is associated with Fragile XE syndrome. The AFF2 gene encodes a protein that appears to act as a transcription factor, helping to control other genes.
AFF2 is located on the long (q) arm of chromosome X, at band Xq28. Arm ratio per GRCh38 - banding schematic.
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Overview
The AFF2 gene, also known as FMR2, provides the blueprint for a protein whose precise functions are still being investigated [PMID:10523236]. It is believed to operate within the cell nucleus, where it influences gene expression and the processing of RNA molecules. Research indicates that the AFF2 protein can bind to DNA, suggesting a role as a transcription factor, which helps regulate the activity of other genes [PMID:10523236]. Additionally, it has been observed to interact with messenger RNA (mRNA), implying its involvement in mechanisms like alternative splicing [PMID:10523236].
Variations within the AFF2 gene cause Fragile XE syndrome, a genetic condition primarily characterised by mild intellectual disability and learning difficulties.
What the gene does
The protein produced from the AFF2 gene is located within the nucleus of cells and is thought to contribute to gene regulation. Some evidence suggests it functions as a transcription factor, meaning it can bind to specific DNA regions to help control the activation of other genes, although the identities of these target genes are not yet fully understood. Beyond its potential role in transcription, the AFF2 protein has also been shown to interact with messenger RNA (mRNA). This interaction suggests that it may be involved in the intricate process of alternative splicing, where mRNA templates are cut and rearranged to produce different versions of proteins from a single gene. This capacity for alternative splicing allows for a diverse array of proteins to be generated from a limited number of genes, highlighting the potential importance of AFF2 in cellular function.
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Chromosome location
The AFF2 gene is situated on the long arm of the X chromosome at position Xq28. This region is towards the end of the X chromosome. The gene provides instructions for a protein that is 1311 amino acids long.
Protein structure
The AFF2 protein is 1311 amino acids in length and contains several regions characterised as disordered. These disordered regions include segments spanning amino acids 94-187, 204-229, 377-417, 457-530, 574-726, 818-867, and 881-943. The presence of these intrinsically disordered regions often suggests flexibility and involvement in protein-protein interactions or regulatory roles.
Key variants
Genetic variations within the AFF2 gene can alter the protein's normal function, leading to health implications. These variations can take several forms, including changes in single DNA building blocks or larger structural alterations. A notable type of variant observed in AFF2 involves the expansion of a specific DNA segment, which can disrupt the gene's stability and expression.
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 |
|---|---|---|---|---|
GRCh37/hg19 Xq28(chrX:147516497-147652015)x1 | - | Pathogenic | ★☆☆☆ | not specified |
GRCh37/hg19 Xq28(chrX:147573612-147620560)x1 | - | Pathogenic | ★☆☆☆ | not specified |
GRCh37/hg19 Xq28(chrX:147642893-147870805) | - | Pathogenic | ★☆☆☆ | FRAXE |
c.1193del | p.Pro398fs | Pathogenic | ★☆☆☆ | FRAXE |
c.2016delinsGAG | p.Ala673fs | Pathogenic | ★☆☆☆ | FRAXE |
c.208C>T | p.Arg70Ter | Pathogenic | ★☆☆☆ | FRAXE |
c.2377C>T | p.Arg793Ter | Pathogenic | ★☆☆☆ | FRAXE |
c.2756_2758delinsAA | p.Pro919fs | Pathogenic | ★☆☆☆ | FRAXE |
c.2966dup | p.Ala990fs | Pathogenic | ★☆☆☆ | FRAXE |
c.3229C>T | p.Gln1077Ter | Pathogenic | ★☆☆☆ | Intellectual disability |
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 AFF2 gene are associated with Fragile XE syndrome. This condition is characterised by mild intellectual disability and learning difficulties. Nearly all cases of Fragile XE syndrome are caused by an expansion of the CCG trinucleotide repeat sequence within the AFF2 gene, leading to instability in this region [PMID:10523236].
No disease links recorded for this gene in our reference set.
UK clinical status
The AFF2 gene is included in several UK NHS national genomic testing panels. It is listed on the DDG2P (Deciphering Developmental Disorders) green panel, indicating that there is strong evidence for its association with developmental disorders. Additionally, it features on the Intellectual disability green panel, reflecting its established link to intellectual disability.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the AFF2 gene?
The AFF2 gene produces a protein thought to act as a transcription factor, regulating the activity of other genes. It is also believed to play a role in the processing of messenger RNA (mRNA), specifically in alternative splicing.
What condition is associated with variants in the AFF2 gene?
Variants in the AFF2 gene are primarily associated with Fragile XE syndrome. This condition is characterised by mild intellectual disability and learning difficulties.
What does a 'disordered region' mean in a protein?
A 'disordered region' in a protein refers to a segment of its structure that lacks a fixed three-dimensional shape. These flexible regions are often important for protein interactions and regulatory functions within the cell.
References
- Melko M, Douguet D, Bensaid M. Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability. Human molecular genetics. 2011. PMID: 21330300
- Stettner GM, Shoukier M, Höger C. Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion. American journal of medical genetics. Part A. 2011. PMID: 21739600
- Melko M, Bardoni B. The role of G-quadruplex in RNA metabolism: involvement of FMRP and FMR2P. Biochimie. 2010. PMID: 20570707
- Bensaid M, Melko M, Bechara EG. FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure. Nucleic acids research. 2009. PMID: 19136466
- Hillman MA, Gecz J. Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator. Journal of human genetics. 2001. PMID: 11355014
- Gecz J. The FMR2 gene, FRAXE and non-specific X-linked mental retardation: clinical and molecular aspects. Annals of human genetics. 2000. PMID: 11246464
- Gécz J, Oostra BA, Hockey A. FMR2 expression in families with FRAXE mental retardation. Human molecular genetics. 1997. PMID: 9147647
- Gecz J, Gedeon AK, Sutherland GR. Identification of the gene FMR2, associated with FRAXE mental retardation. Nature genetics. 1996. PMID: 8673085
- Knight SJ, Flannery AV, Hirst MC. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell. 1993. PMID: 8334699