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FBXL4
F-box and leucine rich repeat protein 4
The FBXL4 gene encodes an F-box protein crucial for mitochondrial function and the maintenance of mitochondrial DNA, with pathogenic variants associated with severe neurological and muscular conditions. FBXL4 is a gene that helps produce a protein involved in maintaining healthy mitochondrial DNA within cells.
FBXL4 is located on the long (q) arm of chromosome 6, at band 6q16.1-q16.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The FBXL4 gene provides instructions for creating a protein known as F-box and leucine rich repeat protein 4. This protein plays a significant role within the mitochondria, which are often described as the 'powerhouses' of the cell due to their central role in energy production. Disruptions in the FBXL4 gene can lead to mitochondrial dysfunction, affecting various body systems, particularly those with high energy demands like the brain and muscles. Understanding FBXL4's function is key to comprehending the pathologies associated with its genetic variations.
What the gene does
The FBXL4 protein belongs to the F-box protein family, characterised by a conserved F-box domain. Inside cells, FBXL4 integrates into a larger protein complex located within the mitochondria. These organelles are essential for numerous cellular activities, including energy generation via cellular respiration, chemical signalling, and the regulation of cell growth, division, and programmed cell death. Mitochondria contain their own distinct genetic material, known as mitochondrial DNA (mtDNA), which is vital for their normal operation and energy production. The protein complex that includes FBXL4 is thought to be involved in sustaining the stability and integrity of this mtDNA. An adequate and healthy supply of mtDNA is fundamental for the proper functioning of cellular energy production processes [PMID:24727192].
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Chromosome location
The FBXL4 gene is situated on the long arm (q) of chromosome 6, specifically within the region designated 6q16.1-q16.2. This precise location helps geneticists identify and study the gene's involvement in various conditions. The human genome contains two copies of chromosome 6, meaning there are two copies of the FBXL4 gene in most individuals.
Protein structure
The FBXL4 protein is composed of 621 amino acids and features several distinct structural domains. A key element is the F-box domain, located between amino acids 277 and 332, which is characteristic of this protein family. Additionally, the protein contains nine leucine-rich repeats (LRRs). These include LRR 1 (amino acids 376-397), LRR 2 (amino acids 402-421), LRR 3 (amino acids 427-448), LRR 4 (amino acids 452-474), LRR 5 (amino acids 480-501), LRR 6 (amino acids 504-524), LRR 7 (amino acids 532-558), LRR 8 (amino acids 559-583), and LRR 9 (amino acids 584-609). These leucine-rich repeats are often involved in protein-protein interactions [PMID:24499092].
Key variants
Genetic variants in the FBXL4 gene refer to alterations in its DNA sequence. These can range from single base pair changes to larger deletions or insertions. Pathogenic variants can disrupt the gene's ability to produce a functional protein, leading to impaired mitochondrial function and associated health conditions. The impact of a specific variant often depends on its location within the gene and the type of change it introduces.
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.1067del | p.Gly356fs | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.1288C>T | p.Arg430Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.141del | p.Asn48fs | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.1648_1649del | p.Asp550fs | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.370C>T | p.Gln124Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.486T>A | p.Tyr162Ter | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.616C>T | p.Arg206Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.627_633del | p.Asn210fs | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
c.827del | p.Asn276fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.859-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 13 |
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 FBXL4 gene are primarily associated with FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome. This condition affects multiple body systems, often presenting with significant brain dysfunction and muscle weakness (encephalomyopathy). Many reported cases have an early childhood onset and are frequently associated with fatality in early childhood. Additionally, variants in FBXL4 have been observed in some individuals diagnosed with Leigh syndrome, another severe neurological disorder [PMID:24727192].
No disease links recorded for this gene in our reference set.
UK clinical status
The FBXL4 gene is well-recognised within the UK's National Health Service (NHS) Genomic Medicine Service. It is included on several NHS England National Genomic Test Directory panels, indicating its established role in diagnosing genetic conditions. These panels include 'Ataxia and cerebellar anomalies - childhood onset', 'Early onset or syndromic epilepsy', 'Foetal anomalies', 'Intellectual disability', 'Likely inborn error of metabolism', 'Mitochondrial disorders', 'Mitochondrial DNA maintenance disorder', 'Paediatric or syndromic cardiomyopathy', 'Possible mitochondrial disorder, nuclear genes', 'Pyruvate dehydrogenase (PDH) deficiency', and 'Undiagnosed metabolic disorders'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the FBXL4 gene?
The FBXL4 gene provides instructions for a protein that is critical for maintaining mitochondrial DNA. This maintenance is essential for normal energy production and overall mitochondrial function within cells.
What happens if there is a pathogenic variant in FBXL4?
Pathogenic variants in the FBXL4 gene can lead to impaired mitochondrial function, specifically affecting the maintenance of mitochondrial DNA. This can result in severe conditions such as FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome, which impacts the brain and muscles.
Is FBXL4 associated with any specific medical conditions?
Yes, pathogenic variants in FBXL4 are primarily associated with FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome, a severe multi-system disorder. Some variants have also been linked to Leigh syndrome.
References
- Dai H, Zhang VW, El-Hattab AW. FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome. Clinical genetics. 2017. PMID: 27743463
- Bonnen PE, Yarham JW, Besse A. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. American journal of human genetics. 2013. PMID: 23993193
- Gai X, Ghezzi D, Johnson MA. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. American journal of human genetics. 2013. PMID: 23993194
- Adam MP, Bick S, Mirzaa GM. FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome. 1993. PMID: 28383868