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MCCC2
methylcrotonyl-CoA carboxylase subunit 2
The MCCC2 gene provides instructions for a component of the 3-methylcrotonyl-CoA carboxylase enzyme, which is crucial for processing the amino acid leucine within the body. The MCCC2 gene encodes the beta subunit of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme.
MCCC2 is located on the long (q) arm of chromosome 5, at band 5q13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MCCC2 gene, full name methylcrotonyl-CoA carboxylase subunit 2, is essential for normal metabolic function. It directs the production of a specific protein subunit that is part of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme. This enzyme is primarily active within mitochondria, the cellular structures responsible for energy generation.
Mutations in the MCCC2 gene are associated with an autosomal recessive inherited condition known as 3-methylcrotonyl-CoA carboxylase deficiency. This condition impairs the body's ability to properly break down certain proteins, particularly the amino acid leucine.
What the gene does
The protein produced from the MCCC2 gene forms the beta subunit of the 3-methylcrotonyl-CoA carboxylase (MCC) enzyme. Six of these beta subunits combine with six alpha subunits, which are encoded by the MCCC1 gene, to create a fully functional MCC enzyme. This complex enzyme resides within the mitochondria of cells.
The MCC enzyme is critical for the fourth step in the metabolic pathway that breaks down leucine, an essential amino acid derived from dietary proteins. Its specific function is to convert 3-methylcrotonyl-CoA into 3-methylglutaconyl-CoA. Subsequent biochemical reactions further process 3-methylglutaconyl-CoA into molecules that can be used for cellular energy production. A properly functioning MCC enzyme is therefore vital for efficient protein metabolism and energy homeostasis.
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Chromosome location
The MCCC2 gene is situated on the long arm of chromosome 5, specifically at position 5q13.2. This genomic location refers to the precise address of the gene within the human genome. The MCCC2 gene's exact position ensures its correct expression and contributes to its role in cellular metabolism.
Protein structure
The MCCC2 gene encodes a protein that is 563 amino acids in length. This protein features several distinct functional regions and domains. It contains a CoA carboxyltransferase N-terminal domain, spanning amino acids 49-306. A broader Carboxyltransferase region is present from amino acids 49-555, indicating the protein's enzymatic function. Additionally, a CoA carboxyltransferase C-terminal domain is found between amino acids 309-555. The protein also includes an Acyl-CoA binding region, located from amino acids 343-372, which is important for substrate interaction.
Key variants
Variants in the MCCC2 gene refer to changes in its DNA sequence. Many different variants have been identified in individuals with 3-methylcrotonyl-CoA carboxylase deficiency. These genetic alterations can impact the structure and function of the MCCC2 protein, often by changing single amino acids or leading to a premature stop signal. The consequence is typically a significant reduction in the activity of the 3-methylcrotonyl-CoA carboxylase enzyme, impairing 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.100C>T | p.Gln34Ter | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.1184_1192delinsGCATTTGAAGAAA | p.Asn395_Leu398delinsSerIleTer | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.1208A>C | p.Asn403Thr | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.1350T>A | p.Tyr450Ter | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.1486C>T | p.Gln496Ter | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.1580G>A | p.Trp527Ter | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.1676G>A | p.Gly559Asp | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.231_232del | p.Gly79fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.242dup | p.Leu82fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 deficiency |
c.760G>T | p.Glu254Ter | Pathogenic/Likely pathogenic | ★★☆☆ | 3-methylcrotonyl-CoA carboxylase 2 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
Mutations within the MCCC2 gene are known to cause 3-methylcrotonyl-CoA carboxylase deficiency, an inherited metabolic disorder. This condition is characterised by the body's inability to properly break down certain proteins, particularly the amino acid leucine. As an autosomal recessive condition, individuals must inherit two altered copies of the MCCC2 gene (one from each parent) to be affected. Carriers of one altered copy typically do not show symptoms.
Inheritance pattern
Conditions caused by pathogenic MCCC2 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 MCCC2 gene is recognised within several UK NHS Genomic Medicine Service panels. It is included on the DDG2P panel, the Intellectual disability panel, the Likely inborn error of metabolism panel (R98), and the Undiagnosed metabolic disorders panel. Its presence on these panels indicates its clinical relevance for genetic testing and diagnosis within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the MCCC2 gene?
The MCCC2 gene provides instructions for making the beta subunit of the 3-methylcrotonyl-CoA carboxylase enzyme. This enzyme is crucial for breaking down the amino acid leucine, a component of many proteins, within the body's mitochondria.
What condition is associated with the MCCC2 gene?
Mutations in the MCCC2 gene are associated with 3-methylcrotonyl-CoA carboxylase deficiency. This is an inherited metabolic disorder that affects the body's ability to process certain proteins, specifically the amino acid leucine.
How is 3-methylcrotonyl-CoA carboxylase deficiency inherited?
3-methylcrotonyl-CoA carboxylase deficiency is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered MCCC2 gene, one from each parent, to develop the condition. Individuals with only one altered copy are carriers and typically do not show symptoms.
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
- 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