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MMAB
metabolism of cobalamin associated B
The MMAB gene provides instructions for an enzyme crucial in the metabolism of vitamin B12, specifically in the formation of adenosylcobalamin. The MMAB gene encodes an enzyme that plays a vital role in cellular metabolism by facilitating the conversion of vitamin B12 into an active form called adenosylcobalamin (AdoCbl).
MMAB is located on the long (q) arm of chromosome 12, at band 12q24.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The MMAB gene, also known as "metabolism of cobalamin associated B," is responsible for producing an enzyme that is critical for vitamin B12 (cobalamin) metabolism within the body. This enzyme is primarily active within the mitochondria, the energy-producing organelles of cells.
Its main role is to help form adenosylcobalamin (AdoCbl), a derivative of vitamin B12, which is necessary for the proper function of methylmalonyl CoA mutase, an enzyme that assists in the breakdown of specific proteins, fats, and cholesterol.
What the gene does
The MMAB gene provides the blueprint for an enzyme that plays a central role in the biochemical pathway of adenosylcobalamin (AdoCbl) synthesis. Within the mitochondria, this enzyme converts a specific form of vitamin B12, known as cob(I)alamin, into AdoCbl. AdoCbl is a crucial coenzyme required by methylmalonyl CoA mutase, an enzyme responsible for metabolising various substances including certain proteins and lipids.
Beyond its role in AdoCbl formation, research indicates that the MMAB enzyme may also be involved in delivering AdoCbl directly to methylmalonyl CoA mutase, ensuring its availability for metabolic processes. This coordinated function underscores the MMAB enzyme's importance in maintaining normal mitochondrial metabolism and overall cellular health.
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Chromosome location
The MMAB gene is situated on chromosome 12, specifically at position 12q24.11. This location refers to the long (q) arm of chromosome 12, within region 24, band 11.
Protein structure
The MMAB protein consists of 250 amino acids. Its structural composition includes a Disordered region, spanning amino acids 34 to 59. This region is characterised by a lack of a fixed three-dimensional structure.
Key variants
Variants within the MMAB gene can affect the enzyme's ability to properly metabolise vitamin B12, leading to impaired adenosylcobalamin production. These genetic changes can range from single amino acid substitutions to larger deletions or duplications of genetic material within the gene. Such alterations can impact the protein's stability, activity, or its interaction with other molecules.
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.139C>T | p.Gln47Ter | Pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.220G>T | p.Glu74Ter | Pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.334G>T | p.Glu112Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.357C>A | p.Cys119Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.367del | p.Asp123fs | Pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.523G>T | p.Gly175Ter | Pathogenic | ★★☆☆ | MMAB-related disorder |
c.574_577del | p.Ala192fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.574dup | p.Ala192fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.580A>G | p.Arg194Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
c.583_584del | p.Arg195fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblB type |
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
Genetic variations in the MMAB gene are associated with inherited metabolic disorders, particularly methylmalonic acidaemia. This condition typically manifests with symptoms such as feeding difficulties and developmental delay, which can lead to long-term health problems. The inheritance pattern for conditions linked to MMAB is autosomal recessive, meaning a person must inherit two altered copies of the gene, one from each parent, to develop the condition.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MMAB 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 MMAB gene is included in several NHS Genomic Medicine Service national test panels. It is listed with a 'green' status on panels such as DDG2P, Hyperammonaemia, Intellectual disability, and Likely inborn error of metabolism (R98), indicating strong evidence for its association with these conditions in a clinical diagnostic setting. It is also found on the Undiagnosed metabolic disorders panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the MMAB gene?
The MMAB gene provides instructions for an enzyme essential in converting vitamin B12 into adenosylcobalamin (AdoCbl). This active form of B12 is vital for another enzyme, methylmalonyl CoA mutase, which helps break down certain proteins and fats.
What is methylmalonic acidaemia?
Methylmalonic acidaemia is a genetic metabolic disorder often caused by variants in genes like MMAB. It affects the body's ability to process certain proteins and fats, leading to a build-up of harmful substances that can cause feeding difficulties and developmental delays.
How is methylmalonic acidaemia inherited?
Methylmalonic acidaemia associated with MMAB gene variants is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition. Parents who carry one altered copy are typically unaffected.
References
- Hörster F, Baumgartner MR, Viardot C. Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatric research. 2007. PMID: 17597648
- Lerner-Ellis JP, Gradinger AB, Watkins D. Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Molecular genetics and metabolism. 2006. PMID: 16410054
- Zhang J, Dobson CM, Wu X. Impact of cblB mutations on the function of ATP:cob(I)alamin adenosyltransferase in disorders of vitamin B12 metabolism. Molecular genetics and metabolism. 2006. PMID: 16439175
- Chandler RJ, Venditti CP. Genetic and genomic systems to study methylmalonic acidemia. Molecular genetics and metabolism. 2005. PMID: 16182581
- Leal NA, Olteanu H, Banerjee R. Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. The Journal of biological chemistry. 2004. PMID: 15347655
- Leal NA, Park SD, Kima PE. Identification of the human and bovine ATP:Cob(I)alamin adenosyltransferase cDNAs based on complementation of a bacterial mutant. The Journal of biological chemistry. 2003. PMID: 12514191
- Dobson CM, Wai T, Leclerc D. Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Human molecular genetics. 2002. PMID: 12471062
- Adam MP, Bick S, Mirzaa GM. Isolated Methylmalonic Acidemia. 1993. PMID: 20301409