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MMADHC
metabolism of cobalamin associated D
The MMADHC gene provides instructions for a protein essential in the metabolism of vitamin B12, also known as cobalamin, influencing various critical bodily functions. The MMADHC gene is crucial for converting vitamin B12 into its active forms, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl).
MMADHC is located on the long (q) arm of chromosome 2, at band 2q23.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MMADHC gene is responsible for producing a protein involved in the intricate pathway of vitamin B12 (cobalamin) metabolism. This gene's product helps transform inactive vitamin B12 into its two biologically active coenzyme forms: adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are indispensable for several metabolic processes within the body.
Disruptions in the MMADHC gene's function can lead to impaired vitamin B12 processing, which in turn affects critical enzymatic reactions. Such impairments are associated with a spectrum of inherited metabolic conditions, including specific forms of homocystinuria and methylmalonic acidaemia.
What the gene does
The protein encoded by the MMADHC gene plays a key role in the final stages of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) formation from vitamin B12. Alongside another protein, MMACHC, the MMADHC protein facilitates the transport of vitamin B12 to specific cellular locations where these cofactors are required.
Adensosylcobalamin primarily functions within the mitochondria, the cell's energy-producing organelles, where it acts as a cofactor for methylmalonyl CoA mutase. This enzyme is crucial for breaking down certain amino acids, fatty acids, and cholesterol. Methylcobalamin, on the other hand, operates in the cytoplasm and is a cofactor for methionine synthase, an enzyme that converts homocysteine to methionine, an amino acid vital for protein synthesis and other cellular compounds. Defects in MMADHC can impair these distinct pathways, leading to a build-up of toxic metabolites.
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Chromosome location
The MMADHC gene is situated on chromosome 2, specifically at position 2q23.2. This genomic location indicates its precise address within the human genome, helping to pinpoint its position relative to other genes and genetic markers on chromosome 2.
Protein structure
The MMADHC protein consists of 296 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the MMADHC gene can alter the protein's ability to process vitamin B12 effectively. These genetic changes can range from single base pair substitutions to larger deletions or insertions, potentially affecting protein structure or function. Such alterations can impair the conversion of inactive vitamin B12 into its active forms, leading to metabolic imbalances.
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.10-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.128_129del | p.His43fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.202C>T | p.Gln68Ter | Pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.433A>T | p.Arg145Ter | Pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.538C>T | p.Gln180Ter | Pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.544dup | p.Thr182fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.646C>T | p.Arg216Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.653_654dup | p.Gly219fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.663G>A | p.Trp221Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
c.683C>G | p.Ser228Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblD |
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 MMADHC gene are associated with inherited metabolic disorders that affect vitamin B12 processing. These conditions include homocystinuria, characterised by developmental delay, neurological issues, and eye defects, which results from impaired methylcobalamin production. Variants can also cause methylmalonic acidaemia, leading to feeding difficulties, episodes of low blood glucose, and the accumulation of toxic substances, due to issues with adenosylcobalamin. Furthermore, some MMADHC variants can cause a combined condition, methylmalonic acidaemia with homocystinuria (cblD type), presenting features of both disorders.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MMADHC 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 MMADHC gene is recognised within the NHS Genomic Medicine Service, being featured on several green R-panels in PanelApp. This includes panels for DDG2P, early onset or syndromic epilepsy, foetal anomalies (R21), intellectual disability, likely inborn error of metabolism (R98), and undiagnosed metabolic disorders, indicating its clinical relevance in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the MMADHC gene?
The MMADHC gene provides instructions for a protein that helps convert vitamin B12 into its active forms, adenosylcobalamin and methylcobalamin. These active forms are crucial for several metabolic processes.
What happens if the MMADHC gene has a variant?
Variants in the MMADHC gene can lead to impaired vitamin B12 metabolism, causing a build-up of harmful substances in the body. This can result in inherited metabolic conditions such as homocystinuria and methylmalonic acidaemia.
Is MMADHC-related disease treatable?
Management for conditions related to MMADHC variants typically involves dietary modifications, vitamin B12 supplementation, and other supportive therapies tailored to the specific metabolic imbalance. Treatment plans should always be developed in consultation with a healthcare professional.
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
- Stucki M, Coelho D, Suormala T. Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. Human molecular genetics. 2012. PMID: 22156578
- Plesa M, Kim J, Paquette SG. Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B₁₂ metabolism. Molecular genetics and metabolism. 2011. PMID: 21071249
- Miousse IR, Watkins D, Coelho D. Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. The Journal of pediatrics. 2009. PMID: 19058814
- Coelho D, Suormala T, Stucki M. Gene identification for the cblD defect of vitamin B12 metabolism. The New England journal of medicine. 2008. PMID: 18385497