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MCCC1
methylcrotonyl-CoA carboxylase subunit 1
The *MCCC1* gene provides instructions for a crucial enzyme subunit involved in the breakdown of amino acids, particularly leucine, within the mitochondria. The *MCCC1* gene encodes the alpha subunit of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme, which plays an essential role in protein metabolism.
MCCC1 is located on the long (q) arm of chromosome 3, at band 3q27.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The *MCCC1* gene, also known as methylcrotonyl-CoA carboxylase subunit 1, is vital for cellular metabolism. It carries the genetic blueprint for a component of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme, which is active in the mitochondria, the cell's energy-producing organelles. This enzyme is primarily involved in breaking down proteins obtained from food.
Dysfunction of the *MCCC1* gene can result in impaired protein processing, specifically affecting the metabolism of the amino acid leucine. Such impairments are characteristic of 3-methylcrotonyl-CoA carboxylase deficiency, an inherited metabolic condition.
What the gene does
The *MCCC1* gene produces the alpha subunit of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme. Six of these alpha subunits combine with six smaller beta subunits, encoded by the *MCCC2* gene, to form a fully functional MCC enzyme complex. The alpha subunit also contains a binding site for biotin, a B vitamin, which is essential for the enzyme's activity.
Located within the mitochondria, the MCC enzyme is critical for the breakdown of proteins. Specifically, it performs the fourth step in the catabolism of leucine, an essential amino acid. This enzymatic reaction converts 3-methylcrotonyl-CoA into 3-methylglutaconyl-CoA, which then undergoes further chemical transformations to produce molecules used for energy generation within the cell. Without a properly functioning MCC enzyme, the body cannot efficiently process leucine, leading to a build-up of potentially harmful substances.
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Chromosome location
The *MCCC1* gene is located on chromosome 3, specifically at position 3q27.1. This precise genomic address helps in mapping and understanding the gene's physical location within the human genome.
Protein structure
The *MCCC1* gene encodes a protein composed of 725 amino acids. This protein contains several functional regions crucial for its role in metabolism. Key domains include the Biotin carboxylation domain, spanning amino acids 48 to 494, which is responsible for the enzymatic carboxylase activity. Additionally, an ATP-grasp domain is found between amino acids 167 and 364, involved in ATP binding. The protein also features a Biotinyl-binding domain from amino acids 643 to 715, which facilitates the attachment of biotin, a necessary cofactor for the enzyme's function.
Key variants
Variants, also referred to as mutations, in the *MCCC1* gene can alter the protein it produces, potentially affecting the function of the 3-methylcrotonyl-CoA carboxylase enzyme. These genetic changes can range from single amino acid substitutions to alterations that lead to the production of shortened or non-functional proteins. The specific impact of a variant often depends on its location and the nature of the genetic change.
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.1126del | p.Thr376fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1378-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1518del | p.Glu506fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1541dup | p.Leu515fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1630del | p.Arg544fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1663_1664dup | p.Lys556fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1679del | p.Asn560fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1731+1del | - | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.1750C>T | p.Gln584Ter | Pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 deficiency |
c.622del | p.Arg208fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 1 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 *MCCC1* gene are the primary genetic cause of 3-methylcrotonyl-CoA carboxylase deficiency. This is an inherited metabolic disorder characterised by the body's inability to properly break down certain proteins, particularly the amino acid leucine. The condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of an altered *MCCC1* gene (one from each parent) to develop the disorder.
Inheritance pattern
Conditions caused by pathogenic MCCC1 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 *MCCC1* gene is included in several UK NHS national genomic testing panels, indicating its recognised clinical significance. It is featured on the DDG2P panel, the Intellectual disability panel, the Likely inborn error of metabolism panel (R98), and the Undiagnosed metabolic disorders panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the MCCC1 gene?
The *MCCC1* gene provides instructions for making the alpha subunit of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme. This enzyme is crucial for breaking down the amino acid leucine within the mitochondria, an important step in protein metabolism.
What condition is associated with variants in the MCCC1 gene?
Variants in the *MCCC1* gene are associated with 3-methylcrotonyl-CoA carboxylase deficiency. This inherited metabolic disorder affects the body's ability to process certain proteins, specifically leading to issues with leucine breakdown.
How is 3-methylcrotonyl-CoA carboxylase deficiency inherited?
3-methylcrotonyl-CoA carboxylase deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the altered *MCCC1* gene, one from each parent, to develop the condition.
References
- Stadler SC, Polanetz R, Maier EM. Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Human mutation. 2006. PMID: 16835865
- Dantas MF, Suormala T, Randolph A. 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. Human mutation. 2005. PMID: 16010683
- Desviat LR, Pérez-Cerdá C, Pérez B. Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. Molecular genetics and metabolism. 2003. PMID: 14680978
- Gallardo ME, Desviat LR, Rodríguez JM. The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism. American journal of human genetics. 2001. PMID: 11170888
- Baumgartner MR, Almashanu S, Suormala T. The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. The Journal of clinical investigation. 2001. PMID: 11181649
- Obata K, Fukuda T, Morishita R. Human biotin-containing subunit of 3-methylcrotonyl-CoA carboxylase gene (MCCA): cDNA sequence, genomic organization, localization to chromosomal band 3q27, and expression. Genomics. 2001. PMID: 11401427
- Holzinger A, Röschinger W, Lagler F. Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency. Human molecular genetics. 2001. PMID: 11406611