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ETFB
electron transfer flavoprotein subunit beta
The ETFB gene provides instructions for making a critical component of the electron transfer flavoprotein, an enzyme essential for cellular energy production. The ETFB gene is responsible for producing the beta subunit of electron transfer flavoprotein (ETF).
ETFB is located on the long (q) arm of chromosome 19, at band 19q13.41. Arm ratio per GRCh38 - banding schematic.
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Overview
The ETFB gene, or electron transfer flavoprotein subunit beta, encodes a crucial part of the electron transfer flavoprotein (ETF) enzyme. This enzyme is located within the mitochondria, the organelles often referred to as the 'powerhouses' of the cell, where it is instrumental in cellular energy metabolism.
ETF is particularly important for the catabolism (breakdown) of fatty acids and certain amino acids. Dysfunction of the ETFB gene can lead to impaired energy production and the accumulation of metabolic intermediates, contributing to conditions like Multiple acyl-CoA dehydrogenase deficiency (MADD).
What the gene does
The ETFB gene provides instructions for synthesising the beta subunit of the electron transfer flavoprotein (ETF) enzyme. Within the mitochondria, the ETF enzyme is vital for metabolism. It plays a role in the breakdown of both fats and proteins, which is necessary for the cell to produce energy [PMID:17926189]. This process is fundamental for maintaining energy production within the body.
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Chromosome location
The ETFB gene is situated on chromosome 19, specifically at position 19q13.41. This genomic address indicates its precise location on the long arm (q arm) of chromosome 19. The gene provides the genetic blueprint for a protein composed of 255 amino acids.
Protein structure
The ETFB protein is 255 amino acids long and contributes to the overall structure and function of the electron transfer flavoprotein. A key region within the ETFB protein is the recognition loop, located at amino acids 183-205.
Key variants
Genetic variations within the ETFB gene can alter its normal function. These changes, known as variants, can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. Depending on their nature and location, variants in ETFB can lead to a non-functional or improperly functioning beta subunit of the electron transfer flavoprotein, impacting metabolic pathways.
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.124T>C | p.Cys42Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.178G>T | p.Glu60Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.253C>T | p.Arg85Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ETFB-related disorder |
c.406C>T | p.Gln136Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.491G>A | p.Arg164Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.61C>T | p.Arg21Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.61del | p.Arg21fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
Single allele | - | Pathogenic | ★★☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.368del | p.Gly123fs | Pathogenic | ★☆☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
c.81del | p.Gly28fs | Pathogenic | ★☆☆☆ | Multiple acyl-CoA dehydrogenase deficiency |
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 ETFB gene are associated with inherited metabolic disorders, most notably Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as Glutaric aciduria type II [PMID:17926189]. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two affected copies of the gene (one from each parent) to develop the disorder. MADD is characterised by the body's inability to properly break down fats and proteins, leading to a build-up of harmful substances [PMID:10780424]. Some variants may prevent the enzyme's production entirely, while others can result in a defective enzyme that cannot fulfil its role in metabolic pathways.
- Multiple acyl-CoA dehydrogenase deficiency (MADD / GA-II) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ETFB 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 ETFB gene is included in several NHS England Genomic Medicine Service national test panels, indicating its recognised clinical significance within the UK. It is assessed for conditions such as Acute rhabdomyolysis, Foetal anomalies, Hyperammonaemia, Intellectual disability, Likely inborn error of metabolism, Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders. This inclusion reflects its importance in diagnosing and understanding a range of inherited conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the ETFB gene?
The ETFB gene provides instructions for creating the beta subunit of the electron transfer flavoprotein (ETF). This enzyme is crucial for breaking down fats and proteins into energy within the mitochondria, the cell's energy-producing centres.
What condition is associated with variants in the ETFB gene?
Pathogenic variants in the ETFB gene are associated with Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as Glutaric aciduria type II. This is an autosomal recessive metabolic disorder affecting the body's ability to process fats and proteins.
How is Multiple acyl-CoA dehydrogenase deficiency (MADD) inherited?
MADD is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered ETFB gene, one from each parent, to develop the condition. Individuals with only one altered copy are typically carriers and do not show symptoms.
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
- Curcoy A, Olsen RK, Ribes A. Late-onset form of beta-electron transfer flavoprotein deficiency. Molecular genetics and metabolism. 2003. PMID: 12706375
- 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
- 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
- Whitfield J, Hurst D, Bennett MJ. Fetal polycystic kidney disease associated with glutaric aciduria type II: an inborn error of energy metabolism. American journal of perinatology. 1996. PMID: 8688100