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AFF2
ALF transcription elongation factor 2
The AFF2 gene provides instructions for a protein thought to influence gene activity and RNA processing, with specific variants linked to Fragile XE syndrome. The AFF2 gene encodes a nuclear protein whose precise function is still being investigated.
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 ALF transcription elongation factor 2, encodes a nuclear protein whose precise biological role remains under investigation. Current research indicates this protein may participate in controlling how genetic information is expressed and how RNA molecules are processed. Changes in the AFF2 gene sequence are associated with Fragile XE syndrome, a condition marked by mild intellectual disability and learning challenges.
What the gene does
AFF2 produces a nuclear protein whose exact cellular responsibilities are not yet fully characterised. Research findings suggest this protein may operate as a transcription factor by attaching to particular DNA sequences and influencing how actively certain genes are expressed, though scientists have not yet identified which specific genes are regulated in this manner. Additional evidence indicates the protein can bind to messenger RNA molecules that carry instructions for building other proteins. Through such RNA interactions, the AFF2 protein appears to participate in alternative splicing, whereby RNA transcripts are modified to yield multiple protein variants from a single gene. A distinctive characteristic of AFF2 is a DNA segment consisting of repeated CCG trinucleotide sequences. In the general population, this repeat region typically contains between 6 and approximately 30 copies of the CCG sequence.
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Chromosome location
The AFF2 gene is located on the X chromosome at position Xq28. This specific location refers to the long arm (q) of the X chromosome, within region 2, band 8. The gene codes for a protein that is 1311 amino acids in length.
Protein structure
The AFF2 protein is composed of 1311 amino acids and features multiple intrinsically disordered regions. These flexible segments span residues 94-187, 204-229, 377-417, 457-530, 574-726, 818-867, and 881-943. Such structural disorder typically enables a protein to adopt multiple conformations and engage with diverse molecular partners, suggesting the AFF2 protein may participate in varied cellular interactions.
Key variants
Genetic changes, or variants, in the AFF2 gene can impact its function. These variants can include different types of alterations to the DNA sequence. The most commonly described variants associated with health conditions involve an expansion of a specific trinucleotide repeat 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 |
|---|---|---|---|---|
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.3229C>T | p.Gln1077Ter | Pathogenic | ★☆☆☆ | Intellectual disability |
c.3476+1G>A | - | Pathogenic | ★☆☆☆ | FRAXE |
c.3575del | p.Asn1192fs | Pathogenic | ★☆☆☆ | not provided |
c.3618_3619insA | p.Gly1207fs | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.76A>T | p.Lys26Ter | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.1350_1397+1491del | - | Pathogenic | ★☆☆☆ | FRAXE |
Single allele | - | Pathogenic | ★☆☆☆ | Suleiman-El-Hattab syndrome |
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 changes in the AFF2 gene are responsible for Fragile XE syndrome, a condition characterised by mild intellectual disability and learning difficulties. The genetic basis of this syndrome involves an abnormal expansion of the CCG trinucleotide repeat region within AFF2, where the number of repeated CCG sequences substantially exceeds the typical range observed in unaffected individuals.
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 with a 'green' status on both the DDG2P (Deciphering Developmental Disorders) panel and the Intellectual disability panel, indicating strong evidence for its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the normal function of the AFF2 gene?
The AFF2 gene provides instructions for a protein found in the cell nucleus. It is thought to act as a transcription factor, helping to regulate the activity of other genes, and may also be involved in the alternative splicing of messenger RNA.
What is Fragile XE syndrome?
Fragile XE syndrome is a genetic condition caused by variants in the AFF2 gene. It is characterised by mild intellectual disability and learning difficulties. It typically results from an abnormally large expansion of a CCG trinucleotide repeat within the gene.
How is the AFF2 gene involved in gene regulation?
The AFF2 gene product is believed to influence gene regulation in a few ways. It may bind to DNA to control the expression of other genes (acting as a transcription factor) and may also help process messenger RNA through alternative splicing, which affects the types of proteins produced.
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