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FOXRED1
FAD dependent oxidoreductase domain containing 1
FOXRED1 is located on the long (q) arm of chromosome 11, at band 11q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
FOXRED1 encodes FAD dependent oxidoreductase domain containing 1, a mitochondrial protein essential for the proper assembly of respiratory chain complex I. Complex I is the largest enzyme complex in the mitochondrial respiratory chain and represents the entry point for electrons derived from cellular metabolism. When FOXRED1 function is impaired, complex I cannot assemble correctly, resulting in severely reduced cellular energy production. Pathogenic variants in FOXRED1 typically cause autosomal recessive mitochondrial disease presenting in infancy or early childhood with neurological impairment, developmental delay, and metabolic crises.
What the gene does
The FOXRED1 protein functions as an assembly factor for mitochondrial complex I, also known as NADH:ubiquinone oxidoreductase. This large multi-subunit enzyme catalyses the transfer of electrons from NADH to ubiquinone whilst pumping protons across the inner mitochondrial membrane, establishing the electrochemical gradient that drives ATP synthesis. FOXRED1 appears to act during the intermediate stages of complex I assembly, facilitating the incorporation of specific subunits into the growing complex. The protein contains a flavin adenine dinucleotide (FAD) binding domain, suggesting it may use redox chemistry to support the folding or stabilisation of complex I components. Loss of FOXRED1 function results in the accumulation of assembly intermediates and a marked reduction in fully assembled, functional complex I. Tissues with high energy demands, particularly the brain and skeletal muscle, are especially vulnerable to complex I deficiency.
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Chromosome location
FOXRED1 is located on chromosome 11 at position 11q24.2, near the telomeric end of the long arm. The gene spans multiple exons encoding a 486-amino-acid protein. This chromosomal region contains several other genes involved in metabolic and cellular regulatory functions.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The FOXRED1 protein comprises 486 amino acids and contains a predicted FAD-binding oxidoreductase domain characteristic of flavoproteins involved in electron transfer reactions. The protein is targeted to mitochondria, where it localises to the mitochondrial matrix and inner membrane, the site of respiratory chain complex assembly. Structural predictions suggest the protein adopts a conformation suitable for binding flavin cofactors and interacting with complex I assembly intermediates.
Key variants
Pathogenic variants in FOXRED1 follow an autosomal recessive inheritance pattern, meaning affected individuals typically inherit one altered copy from each parent. Most disease-causing variants are missense changes that impair protein stability or FAD binding, though nonsense and frameshift variants that eliminate protein function have also been reported. The spectrum of variants includes changes distributed across the coding sequence, with several recurrent variants identified in specific populations.
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.1054C>T | p.Arg352Trp | Pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 19 |
c.1057G>T | p.Glu353Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 19 |
c.1102C>T | p.Gln368Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.530_534del | p.Val177fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.608_609del | p.Glu203fs | Pathogenic | ★★☆☆ | Leigh syndrome |
c.612_615dup | p.Ala206fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 19 |
c.694C>T | p.Gln232Ter | Pathogenic | ★★☆☆ | FOXRED1-related disorder |
c.733+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 19 |
c.86-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 19 |
c.874G>A | p.Gly292Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex I deficiency, nuclear type 19 |
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
FOXRED1-related disorders present as mitochondrial complex I deficiency, typically manifesting in infancy or early childhood. Affected individuals commonly experience severe developmental delay, intellectual disability, hypotonia, and progressive neurological deterioration. Metabolic features may include lactic acidosis, elevated lactate-to-pyruvate ratios, and abnormal organic acid profiles. Neuroimaging often reveals brain abnormalities including white matter changes and basal ganglia involvement. Some individuals develop movement disorders such as dystonia or chorea. The severity and specific features vary between affected individuals, even among those with identical variants. Early diagnosis through genetic testing enables appropriate metabolic monitoring and supportive care.
No disease links recorded for this gene in our reference set.
UK clinical status
FOXRED1 holds green (high evidence) status on multiple NHS Genomic Medicine Service gene panels, reflecting its established role in mitochondrial disease. The gene appears on panels including Mitochondrial disorders, Mitochondrial disorder with complex I deficiency, Likely inborn error of metabolism, Intellectual disability, and Early onset or syndromic epilepsy. It is also included on the DDG2P panel for developmental disorders and panels for Childhood onset dystonia, chorea or related movement disorder, Fetal anomalies, and Undiagnosed metabolic disorders. This broad panel representation indicates that FOXRED1 testing is appropriate for individuals presenting with various combinations of neurological, metabolic, and developmental features suggestive of mitochondrial dysfunction.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the FOXRED1 gene do?
FOXRED1 encodes a protein that helps assemble mitochondrial complex I, the first enzyme in the cellular energy production pathway. This protein ensures that complex I is built correctly so cells can generate ATP efficiently.
How are FOXRED1 variants inherited?
FOXRED1-related conditions follow autosomal recessive inheritance, meaning an individual must inherit an altered copy of the gene from both parents to develop the condition. Parents who each carry one variant are typically unaffected.
What symptoms are associated with FOXRED1 variants?
Individuals with pathogenic FOXRED1 variants typically present with developmental delay, intellectual disability, muscle weakness, and neurological problems such as movement disorders. Metabolic features including lactic acidosis may also occur, reflecting impaired cellular energy production.