MMADHC metabolism of cobalamin associated D [Homo sapiens (human)] - Gene

Summary

Official Symbol: MMADHCprovided by HGNC
Official Full Name: metabolism of cobalamin associated Dprovided by HGNC
Primary source: HGNC:HGNC:25221
See related: Ensembl:ENSG00000168288 MIM:611935; AllianceGenome:HGNC:25221
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: HMAD; MACD; cblD; MAHCD; C2orf25; CL25022
Summary: This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]
Expression: Ubiquitous expression in bone marrow (RPKM 49.1), esophagus (RPKM 43.5) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2q23.2

Exon count:: 8

Annotation release	Status	Assembly	Chr	Location
RS_2025_08	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (149569637..149587775, complement)
RS_2025_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (150020083..150038221, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (150426151..150444289, complement)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

The study of genes involved in methylmalonic acidaemia with homocystinuria detected a homozygous mutation (c.748C>T) in the MMADHC gene (found in the DNA of both sisters), which generates a stop codon that results in a truncated protein, provoking the disease.
Title: Mutation of the MMADHC gene in adult-onset cobalamin D deficiency: A report of 2 potentially treatable cases.
These data show that the processing of cobalamin in cytoplasm occurs in a multiprotein complex composed of at least methionine synthase, methionine synthase reductase, MMACHC and MMADHC.
Title: Methionine synthase and methionine synthase reductase interact with MMACHC and with MMADHC.
the MMACHC-MMADHC complex is a 1:1 heterodimer, where the interaction region overlaps with the MMACHC-Cbl binding site
Title: Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking.
analysis of crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway
Title: Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.
specific regions of MMADHC are involved in differential regulation of adenosylcobalamin and methylcobalamin synthesis
Title: Characterization of functional domains of the cblD (MMADHC) gene product.
Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism.
Title: Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism.
The function of MMADHC is exerted through its structured C-terminal domain via interactions with MMACHC.
Title: Structural features of recombinant MMADHC isoforms and their interactions with MMACHC, proteins of mammalian vitamin B12 metabolism.
MMADHC mutations are associated with methylmalonic aciduria and homocystinuria.
Title: Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism.
MMADHC was confirmed as a binding partner for MMACHC both in vitro (SPR) and in vivo (bacterial two-hybrid system).
Title: Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B₁₂ metabolism.
Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.

Submit: New GeneRIF Correction See all GeneRIFs (12)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Disorders of Intracellular Cobalamin Metabolism MedGen: CN043592 GeneReviews: Disorders of Intracellular Cobalamin Metabolism	not available
Homocystinuria-megaloblastic anemia cblD type MedGen: C1848553 OMIM: 620952 GeneReviews: Not available	not available
Isolated methylmalonic aciduria cblD type MedGen: CN378546 OMIM: 620953 GeneReviews: Isolated Methylmalonic Acidemia	not available
Methylmalonic aciduria and homocystinuria type cblD MedGen: C1848552 OMIM: 277410 GeneReviews: Isolated Methylmalonic Acidemia, Disorders of Intracellular Cobalamin Metabolism	not available

EBI GWAS Catalog

Description
Genome-wide association study of liver enzymes in korean children. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interaction	Pubs
Knockdown of methylmalonic aciduria (cobalamin deficiency) cblD type, with homocystinuria (MMADHC; C2orf25) by siRNA inhibits HIV-1 replication in HeLa-derived TZM-bl cells	PubMed

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D2S2131 (e-PCR)
- UniSTS:154202

RH12678 (e-PCR)
- UniSTS:15019

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables molecular carrier activity	EXP Inferred from Experiment more info	PubMed
enables molecular carrier activity	IBA Inferred from Biological aspect of Ancestor more info
enables molecular carrier activity	IDA Inferred from Direct Assay more info	PubMed
enables molecular carrier activity	TAS Traceable Author Statement more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in cobalamin metabolic process	IBA Inferred from Biological aspect of Ancestor more info
acts_upstream_of_or_within cobalamin metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in cobalamin metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in cobalamin metabolic process	IEA Inferred from Electronic Annotation more info
involved_in cobalamin metabolic process	TAS Traceable Author Statement more info

Component	Evidence Code	Pubs
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasm	IEA Inferred from Electronic Annotation more info
is_active_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
located_in mitochondrion	HTP more info	PubMed
is_active_in mitochondrion	IBA Inferred from Biological aspect of Ancestor more info
located_in mitochondrion	IDA Inferred from Direct Assay more info	PubMed
located_in mitochondrion	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: cobalamin trafficking protein CblD

Names: methylmalonic aciduria (cobalamin deficiency) cblD type, with homocystinuria; methylmalonic aciduria and homocystinuria type D protein, mitochondrial; protein C2orf25, mitochondrial

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.