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ETFA
electron transfer flavoprotein subunit alpha
The ETFA gene provides instructions for synthesising the alpha subunit of the electron transfer flavoprotein (ETF) enzyme, which is vital for cellular energy production through the breakdown of fats and proteins within mitochondria. The ETFA gene is fundamental for metabolic processes, particularly in the mitochondria, the cell's energy factories.
ETFA is located on the long (q) arm of chromosome 15, at band 15q24.2-q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ETFA gene, or electron transfer flavoprotein subunit alpha, is responsible for producing a key component of the electron transfer flavoprotein (ETF) enzyme. This enzyme plays a critical role in cellular metabolism, specifically in the mitochondria where energy is generated. It helps process fats and proteins, converting them into usable energy for the body's various functions.
What the gene does
The ETFA gene encodes the alpha subunit, which is an integral component of the electron transfer flavoprotein (ETF) enzyme. Located in the mitochondria, where cells generate their energy, this enzyme facilitates metabolic reactions that convert dietary fats and proteins into forms the body can use. When genetic changes affect the alpha subunit, the enzyme's capacity to support these essential energy-producing pathways may be reduced.
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Chromosome location
The ETFA gene is situated on chromosome 15, specifically at the band position 15q24.2-q24.3. This chromosomal location indicates where the gene resides within the human genome, providing its precise address for genetic studies and diagnostic purposes.
Protein structure
The ETFA gene produces a protein subunit that is 333 amino acids long. This protein contains distinct structural elements critical for its function. It comprises Domain I, spanning amino acids 20-204, and Domain II, located from amino acids 205-333. These domains are integral to the protein's overall structure and its ability to interact with other molecules in the metabolic pathways.
Key variants
Genetic changes in the ETFA gene may affect how the alpha subunit of electron transfer flavoprotein is made or how well it works. Some variants prevent the enzyme from being synthesised at all, whilst others result in a structurally altered protein that cannot fulfil its normal metabolic duties. Such alterations can interfere with the body's capacity to process fats and proteins for energy.
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.177del | p.Lys59fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Glutaric acidemia type 2A |
c.203_204del | p.Leu67_Cys68insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric acidemia type 2A |
c.284dup | p.Leu95fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.298_325del | p.Gln100fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.321_322del | p.Ile108fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.3G>A | p.Met1Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal anomalies with a likely genetic cause |
c.44C>A | p.Ser15Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric acidemia type 2A |
c.693dup | p.Lys232Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.826_833dup | p.Gly279fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric acidemia type 2A |
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 ETFA gene are primarily associated with Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as Glutaric Acidaemia Type II (GA-II). This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected. When the electron transfer flavoprotein enzyme cannot function normally due to ETFA variants, the mitochondrial pathways that metabolise fats and proteins may be disrupted.
- Multiple acyl-CoA dehydrogenase deficiency (MADD / GA-II) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ETFA variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the ETFA gene is included on several NHS Genomic Medicine Service panels, indicating its clinical significance. It is part of panels for conditions such as Acute rhabdomyolysis, Foetal anomalies (R21), Hyperammonaemia, Intellectual disability, Likely inborn error of metabolism (R98), Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders. It is also covered under the DDG2P framework.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the ETFA gene?
The ETFA gene provides instructions for a key part of the electron transfer flavoprotein enzyme. This enzyme is crucial for breaking down fats and proteins in the mitochondria to produce cellular energy.
What condition is associated with variants in the ETFA gene?
Variants in the ETFA gene are primarily linked to Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as Glutaric Acidaemia Type II (GA-II). This is an inherited metabolic disorder affecting the body's ability to process certain nutrients.
How is Multiple acyl-CoA dehydrogenase deficiency (MADD) inherited?
MADD is inherited in an autosomal recessive pattern. This means an individual must inherit a pathogenic variant from each parent to develop the condition. Parents who each carry one pathogenic variant are typically unaffected.
References
- Schiff M, Froissart R, Olsen RK. Electron transfer flavoprotein deficiency: functional and molecular aspects. Molecular genetics and metabolism. 2006. PMID: 16510302
- Olsen RK, Andresen BS, Christensen E. DNA-based prenatal diagnosis for severe and variant forms of multiple acyl-CoA dehydrogenation deficiency. Prenatal diagnosis. 2005. PMID: 15662686
- Olsen RK, Andresen BS, Christensen E. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Human mutation. 2003. PMID: 12815589
- Purevjav E, Kimura M, Takusa Y. Molecular study of electron transfer flavoprotein alpha-subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II. European journal of clinical investigation. 2002. PMID: 12486872
- Bross P, Pedersen P, Winter V. A polymorphic variant in the human electron transfer flavoprotein alpha-chain (alpha-T171) displays decreased thermal stability and is overrepresented in very-long-chain acyl-CoA dehydrogenase-deficient patients with mild childhood presentation. Molecular genetics and metabolism. 1999. PMID: 10356313
- Salazar D, Zhang L, deGala GD. Expression and characterization of two pathogenic mutations in human electron transfer flavoprotein. The Journal of biological chemistry. 1997. PMID: 9334218
- White RA, Dowler LL, Angeloni SV. Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human. Genomics. 1996. PMID: 8617498