Alt. symbols: MTHFC | MTHFD

Approved name: methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1
Alt. names: methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase

Location: 14q23.3: 64388031 - 64463457 (+)
Gene type: protein_coding, 34 transcripts.

Scores: LoFtool: 0.790000 | pLI: 0.60560911 | LOEUF: 0.448

HGNC: 7432

NCBI: 4522, RefSeq: NG_012450.2

Ensembl: ENSG00000100714.18

LRG_1243 | Status: public

OMIM: 172460

Expression | ProteinAtlas

This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain.

Biallelic missense, nonsense and splice-affecting mutations in MTHFD1 have been associated with 2 autosomal recessive conditions: Folate-sensitive susceptibility to neural tube defects [OMIM:601634] and combined immunodeficiency and megaloblastic anemia with or without hyper-homocysteinemia [OMIM:617780]. The latter is an inborn error of folate metabolism associated with clinical features such as atypical hemolytic uremic syndrome (aHUS), epilepsy, eczema, sensorineural hearing loss, retinopathy , and intellectual disability. Hematologic abnormalities may include megaloblastic anemia, abnormal plate count, and/or pancytopenia. Immunologic abnormalities include recurrent infections, lymphopenia involving all subsets, low T-cell receptor excision circle levels, and hypogammaglobulinemia. Biochemical studies may show elevated plasma homocysteine and low methionine levels in the setting of normal methylmalonic acid, vitamin B12 and folate levels. Patient fibroblasts show reduced MTHFD1 protein expression and absence of MTHFD1 enzyme activity. Folic or folinic acid supplementation is an effective treatment, often used in conjunction with IV hydroxocobalamin and betaine. [Load More]