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PCCB
propionyl-CoA carboxylase subunit beta
The PCCB gene provides instructions for making the beta subunit of propionyl-CoA carboxylase, an enzyme crucial for processing amino acids and lipids. The PCCB gene encodes a component of the propionyl-CoA carboxylase enzyme, which is vital for the metabolic breakdown of certain amino acids, lipids, and cholesterol.
PCCB is located on the long (q) arm of chromosome 3, at band 3q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The PCCB gene (propionyl-CoA carboxylase subunit beta) is responsible for producing the beta subunit of the propionyl-CoA carboxylase enzyme. This enzyme plays a critical role in metabolic pathways, particularly in the breakdown of specific amino acids and fatty acids.
Disruptions in the PCCB gene can impair the enzyme's function, leading to the accumulation of harmful substances in the body, primarily associated with the condition propionic acidaemia.
What the gene does
The protein encoded by the PCCB gene is a crucial part of the propionyl-CoA carboxylase enzyme. This enzyme is composed of six beta subunits (from PCCB) and six alpha subunits (from the PCCA gene), forming a functional complex. Propionyl-CoA carboxylase is essential for the normal processing of proteins, specifically in the breakdown of amino acids such as isoleucine, methionine, threonine, and valine.
Furthermore, the enzyme participates in the metabolism of certain lipids and cholesterol. It utilises the B vitamin biotin to convert propionyl-CoA into methylmalonyl-CoA, which is then further broken down to produce energy. If this process is disrupted, propionyl-CoA and other toxic compounds can build up.
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Chromosome location
The PCCB gene is situated on chromosome 3 at band 3q22.3. This specific genomic address helps to identify its precise location within the human genome, aiding in genetic research and diagnostic efforts.
Protein structure
The PCCB protein consists of 539 amino acids and features several distinct domains critical for its function. It contains a CoA carboxyltransferase N-terminal domain spanning amino acids 32-290, and a CoA carboxyltransferase C-terminal domain located between amino acids 294-533. The broader carboxyltransferase region extends from amino acids 32-533, encompassing the main catalytic components. Additionally, an acyl-CoA binding region is found between amino acids 325-358, which is involved in substrate interaction.
Key variants
Genetic variations within the PCCB gene can affect the production or function of the propionyl-CoA carboxylase beta subunit. Over 100 different types of variants have been identified, including single nucleotide changes, insertions, and deletions. These variants can lead to a non-functional enzyme or prevent its production entirely, impacting metabolic processes.
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.1199-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1199-2A>G | - | Pathogenic | ★★☆☆ | Propionic acidemia |
c.1217_1218insTA | p.Gly407fs | Pathogenic | ★★☆☆ | Propionic acidemia |
c.1222ATC[1] | p.Ile409del | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1288A>C | p.Ile430Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1351dup | p.Thr451fs | Pathogenic | ★★☆☆ | Propionic acidemia |
c.1398+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.167_179delinsC | p.Asp56_Lys60delinsAla | Pathogenic | ★★☆☆ | Propionic acidemia |
c.369_372del | p.Ser123fs | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.415C>T | p.Gln139Ter | Pathogenic | ★★☆☆ | Propionic acidemia |
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 PCCB gene are primarily associated with propionic acidaemia, an inherited metabolic disorder. This condition typically manifests shortly after birth and can cause severe health problems due to the body's inability to properly break down certain amino acids and fats. It is inherited in an autosomal recessive pattern.
- Propionic acidaemia Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic PCCB 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 PCCB gene is included in several NHS England Genomic Medicine Service national test directories, indicating its clinical relevance in the UK. It is categorised as 'green' for conditions such as paediatric or syndromic cardiomyopathy, early onset or syndromic epilepsy, and likely inborn error of metabolism, as well as several other neurological and metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the PCCB gene?
The PCCB gene provides instructions for making the beta subunit of the propionyl-CoA carboxylase enzyme. This enzyme is essential for the metabolic breakdown of specific amino acids (isoleucine, methionine, threonine, valine) and certain lipids and cholesterol.
What condition is associated with PCCB gene variants?
Pathogenic variants in the PCCB gene are associated with propionic acidaemia. This is an inherited metabolic disorder that results from the body's inability to process certain nutrients, leading to a build-up of harmful substances.
How is propionic acidaemia inherited?
Propionic acidaemia caused by PCCB gene variants is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Gupta D, Bijarnia-Mahay S, Kohli S. Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes. Genetic testing and molecular biomarkers. 2016. PMID: 27227689
- Kraus JP, Spector E, Venezia S. Mutation analysis in 54 propionic acidemia patients. Journal of inherited metabolic disease. 2012. PMID: 22033733
- Desviat LR, Pérez B, Pérez-Cerdá C. Propionic acidemia: mutation update and functional and structural effects of the variant alleles. Molecular genetics and metabolism. 2004. PMID: 15464417
- Pérez-Cerdá C, Clavero S, Pérez B. Functional analysis of PCCB mutations causing propionic acidemia based on expression studies in deficient human skin fibroblasts. Biochimica et biophysica acta. 2003. PMID: 12757933