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PCCA
propionyl-CoA carboxylase subunit alpha
The PCCA gene provides instructions for the alpha subunit of propionyl-CoA carboxylase, an enzyme critical for processing specific amino acids and fatty acids within the body. PCCA is a gene that codes for a key component of the propionyl-CoA carboxylase enzyme.
PCCA is located on the long (q) arm of chromosome 13, at band 13q32.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The PCCA gene, formally known as propionyl-CoA carboxylase subunit alpha, contains the genetic blueprint for one of the two main subunits of the propionyl-CoA carboxylase enzyme. This enzyme is essential for normal metabolic processes, specifically involved in the breakdown of amino acids and fatty acids.
Changes within the PCCA gene can impair the enzyme's function, leading to the accumulation of harmful substances in the body. Such genetic variations are typically inherited in an autosomal recessive manner.
What the gene does
The PCCA gene directs the synthesis of the alpha subunit of propionyl-CoA carboxylase. Six alpha subunits combine with six beta subunits (produced from the PCCB gene) to form the complete, functional enzyme. This enzyme performs a crucial step in the catabolism (breakdown) of several amino acids, including isoleucine, methionine, threonine, and valine, as well as certain lipids and cholesterol.
Initially, various chemical reactions convert these substances into a molecule called propionyl-CoA. Propionyl-CoA carboxylase then, utilising the B vitamin biotin as a cofactor, converts propionyl-CoA into methylmalonyl-CoA. Subsequent enzymatic reactions further break down methylmalonyl-CoA into molecules that the body can use for energy production.
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Chromosome location
The PCCA gene is situated on chromosome 13, specifically at position 13q32.3. This means it is located on the long arm (q) of chromosome 13, within band 32.3.
Protein structure
The PCCA protein consists of 728 amino acids and features several distinct functional regions. It contains a Biotin carboxylation domain spanning amino acids 62-509, which is crucial for attaching carbon dioxide to propionyl-CoA. An ATP-grasp domain is located between amino acids 181-378, indicating its role in ATP binding and hydrolysis to drive the carboxylation reaction. Additionally, a Biotinyl-binding domain is present from amino acids 653-728, responsible for binding the biotin cofactor essential for enzyme activity.
Key variants
Genetic variations within the PCCA gene can lead to altered or non-functional protein products, impacting the activity of the propionyl-CoA carboxylase enzyme. Over 120 different types of mutations have been identified in individuals with associated conditions. These variations range from single nucleotide changes to larger insertions or deletions of genetic material, all of which can disrupt the gene's ability to produce a functional alpha subunit.
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.1168del | p.Arg390fs | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1178dup | p.Trp394fs | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1349C>G | p.Ser450Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1364_1365del | p.Tyr455fs | Pathogenic | ★★☆☆ | Propionic acidemia |
c.1495del | p.Ile499fs | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.16del | p.Val6fs | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.188_189del | p.Thr62_Phe63insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.1987dup | p.Arg663fs | Pathogenic/Likely pathogenic | ★★☆☆ | Propionic acidemia |
c.2119-1G>C | - | Pathogenic | ★★☆☆ | Propionic acidemia |
c.27_36del | p.Pro10fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
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
Variations in the PCCA gene are primarily associated with Propionic acidaemia. This inherited metabolic disorder results from deficient activity of the propionyl-CoA carboxylase enzyme, leading to a build-up of propionic acid and other toxic compounds in the blood. Symptoms often appear shortly after birth and can be severe, affecting various organ systems.
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Inheritance pattern
Conditions caused by pathogenic PCCA 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 PCCA gene is actively reviewed by several NHS Genomic Medicine Service national panels in the UK. It is classified as 'green' on panels such as DDG2P, Dystonia, chorea or related movement disorder (childhood onset) (R57), Early onset or syndromic epilepsy, Hyperammonaemia, Intellectual disability, Ketotic hypoglycaemia, Likely inborn error of metabolism (R98), Paediatric or syndromic cardiomyopathy (R135), Structural basal ganglia disorders, and Undiagnosed metabolic disorders, indicating strong evidence for its involvement in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the PCCA gene in the body?
The PCCA gene provides instructions for making the alpha subunit of the propionyl-CoA carboxylase enzyme. This enzyme is vital for breaking down specific amino acids (isoleucine, methionine, threonine, valine) and certain types of fats and cholesterol into molecules the body can use for energy.
What happens if there is a mutation in the PCCA gene?
Mutations in the PCCA gene can lead to a deficiency in the propionyl-CoA carboxylase enzyme. This deficiency causes a build-up of propionic acid and other harmful compounds, resulting in a metabolic disorder known as Propionic acidaemia.
How is Propionic acidaemia inherited?
Propionic acidaemia is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the PCCA gene, one from each parent, to develop the condition. People who inherit only one altered copy are carriers and typically do not show symptoms.
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 B, Desviat LR, Rodríguez-Pombo P. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Molecular genetics and metabolism. 2003. PMID: 12559849