On this page
PC
pyruvate carboxylase
The PC gene provides instructions for making pyruvate carboxylase, an enzyme crucial for energy production and various metabolic processes within cells. The PC gene is responsible for producing pyruvate carboxylase, an enzyme found in mitochondria.
PC is located on the long (q) arm of chromosome 11, at band 11q13.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 11 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The PC gene encodes the enzyme pyruvate carboxylase, which is integral to several metabolic pathways within the body. This enzyme functions primarily within the mitochondria, the cell's energy-generating organelles. Its activity is fundamental for processes including gluconeogenesis, which is the synthesis of glucose, and the regulation of insulin secretion in the pancreas.
What the gene does
Pyruvate carboxylase, encoded by the PC gene, catalyses the conversion of pyruvate into oxaloacetate. This reaction is a cornerstone for cellular functions in various tissues. In the liver and kidneys, this conversion represents the initial step in gluconeogenesis, a process vital for maintaining blood glucose levels by producing glucose from non-carbohydrate sources. Within the pancreas, pyruvate carboxylase contributes to the regulation of insulin secretion, a hormone critical for managing blood sugar. The enzyme also participates in lipogenesis, the formation of fats, in adipose (fat-storing) tissue. Furthermore, in the nervous system, pyruvate carboxylase is important for replenishing the building blocks of neurotransmitters and for forming myelin, which is the insulating sheath around nerve cells.
Video: Genetics 101
Chromosome location
The PC gene is located on chromosome 11 at position 11q13.2. This specific genomic address helps to pinpoint the gene's precise location within the human genome.
Protein structure
The pyruvate carboxylase protein consists of 1178 amino acids and features several distinct functional domains. These include the Biotin carboxylation domain, spanning amino acids 36-486, the ATP-grasp domain from amino acids 156-353, and the Pyruvate carboxyltransferase domain located between amino acids 563-832. Additionally, a Biotinyl-binding domain is found at the C-terminus, from amino acids 1109-1178.
Key variants
Genetic variations within the PC gene can affect the function of the pyruvate carboxylase enzyme. Over 30 different mutations have been identified, primarily leading to a deficiency in the enzyme's activity. These variants can involve changes to a single amino acid within the protein sequence.
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.1345G>T | p.Glu449Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.1435C>T | p.Gln479Ter | Pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.1639C>T | p.Arg547Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.1663C>T | p.Arg555Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.1712_1728del | p.Arg571fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.1980del | p.Phe660fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.2253del | p.Cys752fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.2473+2_2473+5del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.3089del | p.Leu1030fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase deficiency |
c.3387del | p.Lys1130fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate carboxylase 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 PC gene are associated with Congenital lactic acidosis (pyruvate carboxylase), an autosomal recessive condition. This disorder results from insufficient pyruvate carboxylase activity, leading to an accumulation of lactic acid and other potentially toxic compounds in the bloodstream. Such accumulations can negatively impact various organs and tissues, particularly the nervous system.
Inheritance pattern
Conditions caused by pathogenic PC 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 PC gene is included on several NHS Genomic Medicine Service panels, indicating its clinical relevance in the UK. It is listed as 'green' in DDG2P, Foetal anomalies (R21), Hyperammonaemia, Intellectual disability, Ketotic hypoglycaemia, Likely inborn error of metabolism (R98), Mitochondrial disorders, Possible mitochondrial disorder, nuclear genes (R63), and Undiagnosed metabolic disorders panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the PC gene?
The PC gene provides instructions for making the enzyme pyruvate carboxylase, which is crucial for converting pyruvate to oxaloacetate. This reaction is essential for generating glucose, synthesising fats, and producing neurotransmitters.
What condition is associated with variants in the PC gene?
Variants in the PC gene are associated with Congenital lactic acidosis (pyruvate carboxylase), an autosomal recessive disorder where the body cannot properly metabolise certain compounds, leading to a build-up of lactic acid.
Where in the cell does pyruvate carboxylase function?
Pyruvate carboxylase primarily functions within the mitochondria of cells. These are often referred to as the 'powerhouses' of the cell due to their role in energy production.
References
- Marin-Valencia I, Roe CR, Pascual JM. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Molecular genetics and metabolism. 2010. PMID: 20598931
- Monnot S, Serre V, Chadefaux-Vekemans B. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Human mutation. 2009. PMID: 19306334
- Jitrapakdee S, Vidal-Puig A, Wallace JC. Anaplerotic roles of pyruvate carboxylase in mammalian tissues. Cellular and molecular life sciences : CMLS. 2006. PMID: 16505973
- Pithukpakorn M. Disorders of pyruvate metabolism and the tricarboxylic acid cycle. Molecular genetics and metabolism. 2005. PMID: 16156009
- Carbone MA, MacKay N, Ling M. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. American journal of human genetics. 1998. PMID: 9585612