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MMACHC
metabolism of cobalamin associated C
The *MMACHC* gene provides instructions for a protein crucial in processing vitamin B12 (cobalamin), enabling its conversion into vital cofactors for metabolic enzymes. The *MMACHC* gene is fundamental for vitamin B12 metabolism, directing the production of a protein that converts cobalamin into active forms.
MMACHC is located on the short (p) arm of chromosome 1, at band 1p34.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The *MMACHC* gene, also known as *cblC*, encodes a protein vital for vitamin B12 processing within the body. This protein facilitates the conversion of dietary vitamin B12 into specific forms required as cofactors for key metabolic enzymes.
Proper *MMACHC* function is critical for various biochemical pathways, including those involved in breaking down certain fats and proteins, and for the production of methionine. Impaired function of the *MMACHC* protein is associated with specific inherited metabolic conditions.
What the gene does
The *MMACHC* gene directs the synthesis of a protein involved in the intricate process of vitamin B12 (cobalamin) metabolism. This protein's primary role is to prepare vitamin B12 for conversion into two essential cofactors: adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl).
AdoCbl is a cofactor for methylmalonyl CoA mutase, an enzyme that plays a key part in breaking down specific amino acids, fatty acids, and cholesterol. MeCbl acts as a cofactor for methionine synthase, an enzyme responsible for converting homocysteine into methionine, an amino acid vital for protein synthesis and other important biological compounds.
The *MMACHC* protein interacts with other proteins, such as MMADHC, to transport processed vitamin B12 to cellular compartments where these cofactors are needed, specifically the mitochondria for AdoCbl and the cytoplasm for MeCbl. This coordinated action ensures the subsequent conversion into their active forms, supporting crucial metabolic functions.
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Chromosome location
The *MMACHC* gene is located on the short arm of chromosome 1, at position 1p34.1. This genomic location specifies where the gene resides within the human genome.
Protein structure
The MMACHC protein consists of 282 amino acids. Its structural organisation includes a C-terminal Disordered region spanning amino acids 234-282. This region is characterised by a lack of stable secondary or tertiary structure under physiological conditions, suggesting flexibility that may be important for protein interactions or function.
Key variants
Variants within the *MMACHC* gene can disrupt its normal function, leading to impaired vitamin B12 metabolism. These genetic changes can affect the protein's ability to process cobalamin, thereby impacting the production of essential cofactors. The severity and manifestation of conditions associated with *MMACHC* variants can vary depending on the specific genetic alteration.
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.151_152del | p.Leu51fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.228_231del | p.Asp77fs | Pathogenic | ★★☆☆ | Cobalamin C disease |
c.271_272insC | p.Arg91fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.281_290del | p.Leu94fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.430-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.435_436del | p.Ser146fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.452A>G | p.His151Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.484G>T | p.Gly162Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.542_545dup | p.Cys182Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
c.81+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cobalamin C disease |
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 *MMACHC* gene are primarily associated with methylmalonic acidaemia with homocystinuria, cblC type. This is the most prevalent form of a disorder characterised by developmental delay, neurological issues, eye defects, and abnormalities in blood composition. The underlying cause is an inability to properly metabolise vitamin B12, leading to the accumulation of toxic metabolites.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MMACHC 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 *MMACHC* gene is included in several NHS Genomic Medicine Service national test panels, indicating its clinical relevance in the UK. These panels cover a range of conditions, including "Ataxia and cerebellar anomalies - childhood onset", "Atypical haemolytic uraemic syndrome", "Early onset or syndromic epilepsy", "Foetal anomalies", "Hereditary ataxia", "Hereditary neuropathy", "Intellectual disability", "Likely inborn error of metabolism", "Retinal disorders", and "Undiagnosed metabolic disorders". The gene is also listed in the DDG2P database.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the MMACHC protein?
The MMACHC protein's main function is to process vitamin B12 (cobalamin), preparing it for conversion into active cofactors. These cofactors are crucial for enzymes involved in breaking down specific amino acids and fatty acids, as well as synthesising methionine.
What condition is linked to MMACHC gene variants?
Variants in the *MMACHC* gene are primarily associated with methylmalonic acidaemia with homocystinuria, cblC type. This is a metabolic disorder that can lead to developmental delay, neurological problems, and other health issues.
How does the MMACHC protein interact with other proteins?
The MMACHC protein is known to interact with MMADHC, another protein involved in vitamin B12 metabolism. Together, they transport processed vitamin B12 to specific cellular locations where it can be converted into its active cofactor forms.
References
- Froese DS, Kopec J, Fitzpatrick F. Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking. The Journal of biological chemistry. 2015. PMID: 26483544
- Lerner-Ellis JP, Anastasio N, Liu J. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Human mutation. 2009. PMID: 19370762
- Hannibal L, Kim J, Brasch NE. Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Molecular genetics and metabolism. 2009. PMID: 19447654
- Kim J, Gherasim C, Banerjee R. Decyanation of vitamin B12 by a trafficking chaperone. Proceedings of the National Academy of Sciences of the United States of America. 2008. PMID: 18779575
- Lerner-Ellis JP, Tirone JC, Pawelek PD. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nature genetics. 2006. PMID: 16311595