On this page
BCS1L
BCS1 ubiquinol-cytochrome c reductase complex chaperone
The BCS1L gene provides instructions for a protein essential in mitochondrial energy conversion, specifically for the assembly of Complex III in the oxidative phosphorylation pathway. The BCS1L gene is vital for cellular energy production by encoding a protein that aids in the formation of Complex III within mitochondria.
BCS1L is located on the long (q) arm of chromosome 2, at band 2q35. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 2 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The BCS1L gene, also known as BCS1 ubiquinol-cytochrome c reductase complex chaperone, plays a crucial role in mitochondrial function. Mitochondria are often referred to as the 'powerhouses' of the cell, responsible for converting energy from food into a usable form called adenosine triphosphate (ATP).
The protein produced from the BCS1L gene is particularly important for the proper assembly and function of Complex III, a key component of the oxidative phosphorylation process. Disruptions in BCS1L function are associated with several inherited conditions that primarily affect energy metabolism.
What the gene does
The BCS1L protein is integral to the intricate process of oxidative phosphorylation within mitochondria, which is how cells generate most of their ATP. The BCS1L protein acts as a chaperone, facilitating the assembly of Complex III, also known as ubiquinol-cytochrome c reductase [PMID:16330903]. Its primary role involves incorporating the Rieske iron-sulphur protein, a critical subunit, into Complex III [PMID:11389146].
Complex III is involved in the electron transport chain, where electrons are passed along a series of protein complexes to create a proton gradient that drives ATP synthesis. This process also generates reactive oxygen species as a byproduct, which, while potentially damaging, are thought to have roles in normal cell signalling, especially under low oxygen conditions. Research also suggests a possible, though not fully understood, involvement of the BCS1L protein in iron metabolism within the cell.
Video: Genetics 101
Chromosome location
The BCS1L gene is situated on chromosome 2, specifically at position 2q35. This location indicates it is found on the long (q) arm of chromosome 2, within region 3, band 5. The gene comprises several exons that are transcribed and translated to produce the BCS1L protein.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the BCS1L gene can impact the protein's ability to properly assemble mitochondrial Complex III or perform other critical cellular functions. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, each with the potential to alter protein structure or expression. The clinical consequences of these variants depend on their specific effect on the BCS1L protein's function.
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.1026dup | p.Arg343fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pili torti-deafness syndrome |
c.180T>G | p.Tyr60Ter | Pathogenic/Likely pathogenic | ★★☆☆ | GRACILE syndrome |
c.1A>T | p.Met1Leu | Pathogenic/Likely pathogenic | ★★☆☆ | GRACILE syndrome |
c.340C>T | p.Arg114Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex III deficiency nuclear type 1 |
c.478C>T | p.Gln160Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pili torti-deafness syndrome |
c.588_591dup | p.Ala198fs | Pathogenic/Likely pathogenic | ★★☆☆ | GRACILE syndrome |
c.703G>C | p.Gly235Arg | Pathogenic/Likely pathogenic | ★★☆☆ | GRACILE syndrome |
c.793C>T | p.Arg265Ter | Pathogenic/Likely pathogenic | ★★☆☆ | GRACILE syndrome |
c.916C>T | p.Arg306Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Mitochondrial complex III deficiency nuclear type 1 |
c.950_953del | p.Asp317fs | Pathogenic/Likely pathogenic | ★★☆☆ | GRACILE syndrome |
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 BCS1L gene are associated with a spectrum of inherited disorders, primarily impacting mitochondrial function. These conditions include GRACILE syndrome, a severe, multisystem disorder particularly prevalent in Finland, characterised by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. Additionally, BCS1L variants can cause Björnstad syndrome, which presents with pili torti (twisted hair) and sensorineural hearing loss. Mitochondrial Complex III deficiency, characterised by issues affecting the liver, kidneys, and brain, is also linked to BCS1L variants, as is Leigh syndrome.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic BCS1L 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 BCS1L gene is part of several NHS England National Genomic Test Directory panels, indicating its clinical significance within the UK healthcare system. It is included in panels for Cholestasis, DDG2P, Dystonia, chorea or related movement disorder (childhood onset), Early onset or syndromic epilepsy, Foetal anomalies, Inherited white matter disorders, Intellectual disability, Likely inborn error of metabolism, Mitochondrial disorders, Mitochondrial disorder with complex III deficiency, Mitochondrial liver disease, Monogenic hearing loss, Possible mitochondrial disorder (nuclear genes), Structural basal ganglia disorders, Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification (childhood onset).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the BCS1L gene?
The BCS1L gene provides instructions for a protein that is crucial for assembling Complex III, a vital part of the oxidative phosphorylation pathway in mitochondria. This pathway is responsible for producing most of the cell's energy in the form of ATP.
What happens if the BCS1L gene does not function correctly?
If the BCS1L gene does not function correctly, it can lead to impaired mitochondrial energy production and a range of severe conditions. These include GRACILE syndrome, Björnstad syndrome, and various forms of mitochondrial Complex III deficiency, affecting multiple organ systems.
Is BCS1L-related disease typically inherited?
Yes, conditions associated with the BCS1L gene are typically inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene (one from each parent) to develop the condition.
References
- Bleier L, Dröse S. Superoxide generation by complex III: from mechanistic rationales to functional consequences. Biochimica et biophysica acta. 2013. PMID: 23269318
- Morán M, Marín-Buera L, Gil-Borlado MC. Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency. Human mutation. 2010. PMID: 20518024
- Gil-Borlado MC, González-Hoyuela M, Blázquez A. Pathogenic mutations in the 5' untranslated region of BCS1L mRNA in mitochondrial complex III deficiency. Mitochondrion. 2009. PMID: 19389488
- Hinson JT, Fantin VR, Schönberger J. Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. The New England journal of medicine. 2007. PMID: 17314340
- Fernandez-Vizarra E, Bugiani M, Goffrini P. Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Human molecular genetics. 2007. PMID: 17403714
- Visapää I, Fellman V, Vesa J. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. American journal of human genetics. 2002. PMID: 12215968
- de Lonlay P, Valnot I, Barrientos A. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature genetics. 2001. PMID: 11528392