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FBXO7
F-box protein 7
The FBXO7 gene provides instructions for making the F-box protein 7, which is involved in protein degradation pathways and has roles in immunity and neurodegenerative disease. FBXO7 is a gene that codes for F-box protein 7, a component of ubiquitin ligase complexes responsible for tagging proteins for destruction.
FBXO7 is located on the long (q) arm of chromosome 22, at band 22q12.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FBXO7 gene, or F-box protein 7, is integral to the cellular process of protein degradation. It forms part of the SCF (SKP1-CUL1-F-box) ubiquitin ligase complex, which targets specific proteins for ubiquitination and subsequent breakdown. This mechanism is vital for regulating a multitude of cellular processes, including cell cycle progression, immune responses, and nervous system function. Dysregulation of FBXO7 is linked to several neurodegenerative disorders, particularly those affecting movement.
What the gene does
The F-box protein 7, encoded by the FBXO7 gene, acts as a substrate-targeting component within the SCF ubiquitin ligase complex. This complex orchestrates the tagging of specific proteins with ubiquitin chains, marking them for degradation by the proteasome. This degradation pathway is critical for maintaining cellular proteostasis, ensuring that damaged or unneeded proteins are efficiently removed. FBXO7's involvement in this process is particularly important for neuronal health and function, with implications for regulating processes like mitochondrial maintenance and immune cell differentiation.
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Chromosome location
The FBXO7 gene is located on the long arm of chromosome 22 at position 12.3, often written as 22q12.3. This specific chromosomal address helps geneticists and researchers pinpoint the gene's exact position within the human genome.
Protein structure
The FBXO7 protein is composed of 522 amino acids and contains several distinct regions crucial for its function. The N-terminal end features a Ubiquitin-like region (amino acids 1-88) and a Disordered region (amino acids 85-144). Within these, a segment from amino acids 92-129 is Important for interaction with PINK1, and another from amino acids 129-169 is Important for interaction with CDK6. Further along, a large region spanning amino acids 180-324 is Important for dimerization and interaction with PSMF1. A key structural element is the F-box Domain (amino acids 329-375), which is characteristic of this protein family. The C-terminal part includes another region Important for interaction with CDK6 (amino acids 381-522), featuring an RFDP motif (amino acids 481-484) and a final Disordered region (amino acids 483-522).
Key variants
Genetic variations within the FBXO7 gene can impact the function of the F-box protein 7, potentially disrupting its role in protein degradation. These changes can range from small alterations in DNA sequence to larger structural rearrangements. The specific effect of a variant depends on its location and the type of change it introduces into the protein structure, which can lead to a spectrum of clinical manifestations.
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.1033C>T | p.Arg345Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.1141C>T | p.Arg381Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.1206_1207dup | p.Arg403fs | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.1268_1272dup | p.Tyr425fs | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.133C>T | p.Arg45Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.1451del | p.Pro484fs | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.709C>T | p.Gln237Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.726_727del | p.Cys243fs | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.917_918del | p.Arg306fs | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal syndrome |
c.961C>T | p.Arg321Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Parkinsonian-pyramidal 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 variants in the FBXO7 gene are associated with various neurological conditions, primarily affecting movement. These include forms of dystonia, Parkinson's disease, and other neurodegenerative disorders. The diverse inheritance patterns observed for FBXO7-related conditions highlight the complex genetic landscape underlying these neurological presentations.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the FBXO7 gene is included on several NHS Genomic Medicine Service national test panels. These panels cover conditions such as adult onset dystonia, chorea or related movement disorder, adult onset hereditary spastic paraplegia, adult onset neurodegenerative disorder (R58), childhood onset dystonia, chorea or related movement disorder (R57), early onset dystonia, and Parkinson Disease and Complex Parkinsonism. Its inclusion on these panels indicates its recognised clinical significance in diagnosing these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the FBXO7 gene product?
The FBXO7 gene encodes F-box protein 7, which primarily functions as a component of the SCF ubiquitin ligase complex. This complex marks specific proteins with ubiquitin, targeting them for degradation and ensuring proper protein turnover within cells.
Which types of medical conditions are associated with FBXO7 gene variants?
Variants in the FBXO7 gene are linked to several neurological conditions, particularly those characterised by movement disorders. These include various forms of dystonia, Parkinson's disease, and other neurodegenerative disorders that impact motor function.
Is FBXO7 testing available through the NHS?
Yes, testing for the FBXO7 gene is available through the NHS Genomic Medicine Service. It is included on several national test panels for conditions such as adult-onset and childhood-onset dystonia, hereditary spastic paraplegia, adult-onset neurodegenerative disorders, and Parkinson's disease.