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ETFA
electron transfer flavoprotein subunit alpha
The ETFA gene provides instructions for the alpha subunit of electron transfer flavoprotein, an enzyme critical for breaking down fats and proteins to produce energy within cellular mitochondria. The ETFA gene is fundamental for cellular energy production, encoding a component of an enzyme involved in metabolism.
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 vital for metabolic processes within the human body. It provides the genetic blueprint for one part of the electron transfer flavoprotein enzyme. This enzyme plays a crucial role in the mitochondria, often referred to as the 'powerhouses' of the cell, where it helps convert fats and proteins into usable energy.
What the gene does
The electron transfer flavoprotein (ETF) enzyme, partly encoded by the ETFA gene, is essential for mitochondrial energy production. Specifically, the ETFA gene codes for the alpha subunit of this enzyme. ETF acts as an electron acceptor from several acyl-CoA dehydrogenases, transferring these electrons further down the electron transport chain. This process is integral to the beta-oxidation of fatty acids and the catabolism of certain amino acids, ensuring the cell can efficiently extract energy from these nutrient sources. When the ETF enzyme is deficient or non-functional due to variants in ETFA, the body's ability to break down these molecules is impaired, leading to an accumulation of metabolic intermediates.
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Chromosome location
The ETFA gene is located on chromosome 15, specifically within the 15q24.2-q24.3 region. This chromosomal band position helps geneticists and clinicians pinpoint its precise location within the human genome.
Protein structure
The protein encoded by the ETFA gene is 333 amino acids long and forms the alpha subunit of the electron transfer flavoprotein. This subunit contains two distinct regions: Domain I, spanning amino acids 20-204, and Domain II, encompassing amino acids 205-333. These domains are crucial for the protein's overall structure and its ability to interact with other components of the electron transfer flavoprotein complex and facilitate electron transfer.
Key variants
Variants within the ETFA gene can affect the production or function of the electron transfer flavoprotein alpha subunit. These genetic changes can lead to a range of impacts, from completely preventing the enzyme's formation to producing a defective enzyme that cannot perform its metabolic role effectively.
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 an inherited metabolic disorder known as Multiple acyl-CoA dehydrogenase deficiency (MADD), also referred to as Glutaric acidaemia type II (GA-II). This condition is inherited in an autosomal recessive pattern. It arises when the dysfunctional electron transfer flavoprotein impairs the body's ability to break down fats and proteins, leading to an accumulation of partially broken-down compounds.
- 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
The ETFA gene is recognised within the UK's NHS Genomic Medicine Service pathways. It is included on several green-rated PanelApp panels, indicating strong evidence for its association with conditions such as Acute rhabdomyolysis, Foetal anomalies, Hyperammonaemia, Intellectual disability, and as a cause of Likely inborn errors of metabolism and Rhabdomyolysis and metabolic muscle disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ETFA gene?
The ETFA gene provides instructions for the alpha subunit of electron transfer flavoprotein, an enzyme crucial for breaking down fats and proteins into energy within the mitochondria of cells.
What condition is associated with variants in the ETFA gene?
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), an inherited metabolic disorder.
How is Multiple acyl-CoA dehydrogenase deficiency inherited?
Multiple acyl-CoA dehydrogenase deficiency (MADD) is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic ETFA variant (one from each parent) to develop the condition.
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