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MMAA
metabolism of cobalamin associated A
The MMAA gene provides instructions for a protein crucial in vitamin B12 (cobalamin) metabolism, particularly in the formation of adenosylcobalamin, which is vital for breaking down certain fats and proteins. The MMAA gene encodes a protein that facilitates the production of adenosylcobalamin (AdoCbl), a derivative of vitamin B12.
MMAA is located on the long (q) arm of chromosome 4, at band 4q31.21. Arm ratio per GRCh38 - banding schematic.
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Overview
The MMAA gene, also known as metabolism of cobalamin associated A, plays a key role in the body's utilisation of vitamin B12, or cobalamin. Specifically, the protein produced from this gene is involved in the complex biochemical pathway that converts vitamin B12 into its active form, adenosylcobalamin (AdoCbl). AdoCbl is a crucial coenzyme required for the proper function of certain metabolic enzymes.
Inherited changes in the MMAA gene are associated with an autosomal recessive form of methylmalonic acidaemia, a metabolic disorder. This condition can lead to difficulties in breaking down specific amino acids and fatty acids, resulting in the accumulation of harmful substances in the body.
What the gene does
The MMAA gene provides the genetic blueprint for a protein that is integral to the synthesis of adenosylcobalamin (AdoCbl). AdoCbl is a biologically active form of vitamin B12 that serves as a coenzyme for the methylmalonyl CoA mutase enzyme. This enzyme is responsible for metabolising specific fats, proteins, and cholesterol, converting them into energy or other essential molecules.
Research indicates that the MMAA protein may be involved in one of the final steps of AdoCbl formation, potentially facilitating the transport of vitamin B12 into mitochondria, the cell's energy-producing organelles. Within the mitochondria, further chemical reactions convert vitamin B12 into AdoCbl. Additionally, evidence suggests the MMAA protein might contribute to the stability of methylmalonyl CoA mutase, helping to protect it from inactivation and ensuring its continuous function in metabolic processes.
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Chromosome location
The MMAA gene is located on chromosome 4, specifically at position 4q31.21. This indicates its precise band on the long arm ('q') of chromosome 4. The gene contains multiple exons, which are the coding segments of a gene that are ultimately translated into protein.
Protein structure
The MMAA protein comprises 418 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the MMAA gene can disrupt its normal function, leading to impaired vitamin B12 metabolism. These genetic changes can include insertions, deletions, duplications, or single amino acid substitutions, all of which may alter the structure or abundance of the MMAA protein. Over 25 different variants have been identified that are associated with clinical conditions.
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.1087C>T | p.Gln363Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.1098G>A | p.Trp366Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.1114C>T | p.Gln372Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.1117G>T | p.Glu373Ter | Pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.365T>C | p.Leu122Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.388del | p.His130fs | Pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.639del | p.Arg214fs | Pathogenic/Likely pathogenic | ★★☆☆ | MMAA-related disorder |
c.733+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.756del | p.Val253fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA type |
c.963_969+4del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria, cblA 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
Pathogenic variants in the MMAA gene are primarily associated with methylmalonic acidaemia, an inherited metabolic disorder. This condition is characterised by the body's inability to properly process certain proteins and fats, leading to an accumulation of methylmalonic acid. Symptoms often include feeding difficulties, developmental delay, and a range of long-term health problems.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MMAA 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 MMAA gene is included in several expert-curated panels within the UK's NHS Genomic Medicine Service's PanelApp. It is rated as 'green' for conditions such as DDG2P, Hyperammonaemia, Intellectual disability, and Undiagnosed metabolic disorders, indicating strong evidence for its association with these conditions. It is also listed under 'Likely inborn error of metabolism' (R98), further highlighting its clinical relevance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is methylmalonic acidaemia?
Methylmalonic acidaemia is an inherited metabolic disorder where the body cannot properly break down certain proteins and fats. This leads to a build-up of methylmalonic acid, which can cause serious health problems, particularly affecting brain development and overall growth.
How does the MMAA gene relate to vitamin B12?
The MMAA gene produces a protein essential for converting vitamin B12 (cobalamin) into its active form, adenosylcobalamin. This active form is crucial for the function of an enzyme that breaks down specific fats and proteins in the body.
Is methylmalonic acidaemia caused by MMAA gene variants inherited?
Yes, methylmalonic acidaemia associated with the MMAA gene is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
References
- Froese DS, Kochan G, Muniz JR. Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. The Journal of biological chemistry. 2010. PMID: 20876572
- 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
- Chandler RJ, Venditti CP. Genetic and genomic systems to study methylmalonic acidemia. Molecular genetics and metabolism. 2005. PMID: 16182581
- Korotkova N, Lidstrom ME. MeaB is a component of the methylmalonyl-CoA mutase complex required for protection of the enzyme from inactivation. The Journal of biological chemistry. 2004. PMID: 14734568
- Yang X, Sakamoto O, Matsubara Y. Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B(12)-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation. Molecular genetics and metabolism. 2004. PMID: 15308131
- Lerner-Ellis JP, Dobson CM, Wai T. Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism. Human mutation. 2004. PMID: 15523652
- Dobson CM, Wai T, Leclerc D. Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. Proceedings of the National Academy of Sciences of the United States of America. 2002. PMID: 12438653
- Adam MP, Bick S, Mirzaa GM. Isolated Methylmalonic Acidemia. 1993. PMID: 20301409