Mthfd1 methylenetetrahydrofolate dehydrogenase (NADP+ dependent), methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthase [Mus musculus (house mouse)] - Gene

Summary

Official Symbol: Mthfd1provided by MGI
Official Full Name: methylenetetrahydrofolate dehydrogenase (NADP+ dependent), methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthaseprovided by MGI
Primary source: MGI:MGI:1342005
See related: Ensembl:ENSMUSG00000021048 AllianceGenome:MGI:1342005
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Mus musculus
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus
Also known as: Dcs; Mthfd; E430024A07Rik
Summary: This gene encodes a trifunctional cytoplasmic enzyme. The encoded protein functions as a methylenetetrahydrofolate dehydrogenase, a methenyltetrahydrofolate cyclohydrolase, and a formyltetrahydrofolate synthase. The encoded enzyme functions in de novo synthesis of purines and thymidylate and in regeneration of methionine from homocysteine. [provided by RefSeq, Oct 2009]
Expression: Ubiquitous expression in kidney adult (RPKM 44.6), liver adult (RPKM 41.3) and 27 other tissues See more
Orthologs: human all
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Genomic context

Location:: 12 C3; 12 33.52 cM

Exon count:: 28

Annotation release	Status	Assembly	Chr	Location
RS_2024_02	current	GRCm39 (GCF_000001635.27)	12	NC_000078.7 (76301180..76366594)
108.20200622	previous assembly	GRCm38.p6 (GCF_000001635.26)	12	NC_000078.6 (76254406..76319820)

Chromosome 12 - NC_000078.7 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

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Expression

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See details

Project title: Mouse ENCODE transcriptome data
Description: RNA profiling data sets generated by the Mouse ENCODE project.
BioProject: PRJNA66167
Publication: PMID 25409824
Analysis date: n/a

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma.
Title: MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma.
Deletion of Mthfd1l causes decreased density in the cranial mesenchyme and this defect is improved with formate supplementation. This study reveals a mechanistic link between folate-dependent mitochondrially produced formate, head mesenchyme formation and neural tube defects.
Title: Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density.
MTHFD1 synthetase-deficient mice are more sensitive to low folate intake than wild-type mice during pregnancy.
Title: Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects.
Study evaluated cognitive function in Mthfd1(gt/+) male and female mice using a behavioral battery composed of eight different tests, found that these mice display impaired cue-conditioned learning, while other behaviors remain intact.
Title: Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice.
Study observed decreased tumor growth in mice with reduced MTHFD1-synthetase activity, a model for the decreased metabolic activity of the human R653Q variant. These results propose that synthetase deficiency does not contribute to tumor initiation in the normal colon, but it limits tumor growth by reducing purine pools and altering expression of genes involved in cell proliferation and inflammation.
Title: Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors.
Moderately higher folate intake and MTHFD1-synthetase deficiency in pregnant mice result in a lower methylation potential in maternal liver and embryos and a greater incidence of defects in embryos.
Title: Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development.
Deficiency of the MTHFD1 10-formyltetrahydrofolate synthetase activity in embryos is associated with increased incidence of congenital heart defects
Title: MTHFD1 formyltetrahydrofolate synthetase deficiency, a model for the MTHFD1 R653Q variant, leads to congenital heart defects in mice.
methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis.
Title: Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency.
Mthfd1gt/+ mice exhibited attentional dysfunction and a blunted affective response to committing an error. They also showed decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor.
Title: Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice.
Data suggest that decreased MTHFD1 activity (here, insertional mutant heterozygotes) has greater impact on one-carbon metabolism compared with folate-deficient diet; no interaction was observed between MTHFD1 genotype and folate deficiency.
Title: Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration.

Submit: New GeneRIF Correction See all GeneRIFs (15)

Variation

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Alleles

Alleles of this type are documented at Mouse Genome Informatics (MGI)

Gene trapped (2) 1 citation
Targeted (3) 1 citation

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

Mthfd1 (e-PCR), detects polymorphism
- UniSTS:526047

Gene Ontology Provided by MGI

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables formate-tetrahydrofolate ligase activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables formate-tetrahydrofolate ligase activity	ISO Inferred from Sequence Orthology more info
enables methenyltetrahydrofolate cyclohydrolase activity	IBA Inferred from Biological aspect of Ancestor more info
enables methenyltetrahydrofolate cyclohydrolase activity	ISO Inferred from Sequence Orthology more info
enables methenyltetrahydrofolate cyclohydrolase activity	ISS Inferred from Sequence or Structural Similarity more info
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity	IDA Inferred from Direct Assay more info	PubMed
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity	IBA Inferred from Biological aspect of Ancestor more info
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity	ISO Inferred from Sequence Orthology more info
enables methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity	ISO Inferred from Sequence Orthology more info

Process	Evidence Code	Pubs
involved_in 10-formyltetrahydrofolate biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in 10-formyltetrahydrofolate biosynthetic process	ISO Inferred from Sequence Orthology more info
involved_in L-histidine biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in heart development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in methionine biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in methionine biosynthetic process	ISO Inferred from Sequence Orthology more info
involved_in methionine metabolic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in neural tube closure	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in neutrophil homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in one-carbon metabolic process	ISO Inferred from Sequence Orthology more info
involved_in purine nucleotide biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
acts_upstream_of purine nucleotide biosynthetic process	ISO Inferred from Sequence Orthology more info
acts_upstream_of purine ribonucleotide biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in serine family amino acid biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in serine family amino acid biosynthetic process	ISO Inferred from Sequence Orthology more info
involved_in serine family amino acid metabolic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in somite development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in tetrahydrofolate interconversion	IBA Inferred from Biological aspect of Ancestor more info
involved_in tetrahydrofolate interconversion	IEA Inferred from Electronic Annotation more info
involved_in tetrahydrofolate interconversion	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in tetrahydrofolate interconversion	ISO Inferred from Sequence Orthology more info
involved_in transsulfuration	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
is_active_in cytosol	IBA Inferred from Biological aspect of Ancestor more info
located_in cytosol	IEA Inferred from Electronic Annotation more info
located_in cytosol	ISO Inferred from Sequence Orthology more info
located_in mitochondrion	HDA more info	PubMed

General protein information

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Preferred Names: C-1-tetrahydrofolate synthase, cytoplasmic

Names: C1-THF synthase; C1-tetrahydrofolate synthase

NP_620084.2

EC 1.5.1.5

EC 3.5.4.9

EC 6.3.4.3

XP_030102369.1

EC 1.5.1.5

EC 3.5.4.9

EC 6.3.4.3

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.

mRNA and Protein(s)

NM_138745.2 → NP_620084.2 C-1-tetrahydrofolate synthase, cytoplasmic

See identical proteins and their annotated locations for NP_620084.2

Status: REVIEWED

Source sequence(s)

AK042958, AK159812, AW536566, CD545120

Consensus CDS

CCDS25990.1

UniProtKB/Swiss-Prot

Q8R013, Q922D8

UniProtKB/TrEMBL

Q3TW74

Related

ENSMUSP00000021443.6, ENSMUST00000021443.7

Conserved Domains (4) summary

cd01080
Location:120 → 292

NAD_bind_m-THF_DH_Cyclohyd; NADP binding domain of methylene-tetrahydrofolate dehydrogenase/cyclohydrolase

PLN02759
Location:309 → 935

PLN02759; Formate--tetrahydrofolate ligase

COG0190
Location:6 → 294

FolD; 5,10-methylene-tetrahydrofolate dehydrogenase/Methenyl tetrahydrofolate cyclohydrolase [Coenzyme transport and metabolism]

pfam00763
Location:6 → 125

THF_DHG_CYH; Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain

RefSeqs of Annotated Genomes: GCF_000001635.27-RS_2024_02

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCm39 C57BL/6J

Genomic

NC_000078.7 Reference GRCm39 C57BL/6J

Range

76301180..76366594

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_030246509.1 → XP_030102369.1 C-1-tetrahydrofolate synthase, cytoplasmic isoform X1

UniProtKB/TrEMBL

A0A1W2P733, Q3TW74

Related

ENSMUSP00000151500.2, ENSMUST00000220046.2

Conserved Domains (2) summary

cd01080
Location:1 → 112

NAD_bind_m-THF_DH_Cyclohyd; NADP binding domain of methylene-tetrahydrofolate dehydrogenase/cyclohydrolase

PLN02759
Location:129 → 755

PLN02759; Formate--tetrahydrofolate ligase