Alternative titles; symbols
HGNC Approved Gene Symbol: MTHFD1
Cytogenetic location: 14q23.3 Genomic coordinates (GRCh38): 14:64,388,353-64,460,025 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q23.3 | {Neural tube defects, folate-sensitive, susceptibility to} | 601634 | Autosomal recessive | 3 |
| Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia | 617780 | Autosomal recessive | 3 |
The MTHFD1 gene encodes a trifunctional protein comprising 5,10-methylenetetrahydrofolate dehydrogenase (EC 1.5.1.5), 5,10-methenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9), and 10-formyltetrahydrofolate synthetase (EC 6.3.4.3). These 3 sequential reactions are involved in the interconversion of 1-carbon derivatives of tetrahydrofolate (THF) which are substrates for methionine, thymidylate, and de novo purine syntheses. In eukaryotes, the 3 enzymatic activities are properties of a single protein, a homodimer of 100-kD polypeptides. The eukaryotic trifunctional enzyme consists of 2 major domains, an N-terminal containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain in the C terminus (Hum et al., 1988).
See also MTHFD2 (604887).
Hum et al. (1988) isolated a cDNA clone corresponding to the human trifunctional MTHFD1 gene from a human liver cDNA library. The deduced 935-amino acid protein has a molecular mass of approximately 101 kD. The 10-formyltetrahydrofolate synthetase activity is found in the C-terminal domain. Northern blot analysis identified a 3.1-kb mRNA transcript.
By somatic cell hybridization and in situ hybridization, Rozen et al. (1989) mapped the MTHFD1 gene to chromosome 14q24.
Pseudogene
Italiano et al. (1991) demonstrated that the MTHFD sequence located on the X chromosome (Xp11) is an intronless pseudogene.
Field et al. (2015) examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency reported by Watkins et al. (2011). The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected. Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts. Field et al. (2015) concluded that these results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and severe combined immunodeficiency in MTHFD1 deficiency.
Using a genetic screen, Sdelci et al. (2019) identified human MTHFD1 as a functional partner of BRD4 (608749). BRD4 physically interacted with MTHFD1 in nucleus and recruited it to chromatin. The interaction was enhanced by binding of the BRD4 bromodomains to acetylated lysines on the surface of MTHFD1. Chromatin immunoprecipitation-sequencing analysis revealed that MTHFD1 regulated gene expression by colocalizing with BRD4 at promoter and enhancer regions, where H3K27ac was also enriched. Furthermore, BRD4 boosted the C1-tetrahydrofolate synthase activity of MTHFD1, and loss of either MTHFD1 or BRD4 resulted in similar changes in nuclear metabolite composition and gene expression, correlating BRD4-dependent epigenetic regulation and folate metabolism. Antifolates synergized with BRD4 inhibitors and impaired cancer cell proliferation without exerting general toxicity.
Neural Tube Defects
Women who take folic acid periconceptionally can substantially reduce their risk of having a child with a neural tube defect (NTD; 601634). Hol et al. (1998) identified a mutation in the MTHFD1 gene (R293H; 172460.0001) in 1 of 38 unrelated patients with familial NTD. The mutation was present in 3 unaffected family members and in none of 79 sporadic cases. Hol et al. (1998) concluded that mutations in the MTHFD1 gene may act as a risk factor for NTD.
Brody et al. (2002) analyzed 5 potential single-nucleotide polymorphisms (SNPs) in the MTHFD1 gene for an association with NTDs in the Irish population. One SNP, R653Q (172460.0002), appeared to be associated with NTD risk. They observed an excess of the MTHFD1 Q allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD, compared with control individuals (odds ratio, 1.52; p = 0.003). They concluded that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.
De Marco et al. (2006) also reported an association between the R653Q polymorphism and neural tube defects in an Italian population.
Van der Linden et al. (2007) did not find an association between the R653Q polymorphism and spina bifida among 103 Dutch patients and their mothers.
Combined Immunodeficiency and Megaloblastic Anemia with or without Hyperhomocysteinemia
In a patient, born to nonconsanguineous parents of Ashkenazi Jewish and Russian descent, with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780), Watkins et al. (2011) identified compound heterozygous mutations in the MTHFD1 gene (172460.0003-172460.0004).
In a French patient and 3 sibs in a Swedish family with CIMAH, Burda et al. (2015) identified compound heterozygous mutations in the MTHFD1 gene (172460.0005-172460.0008).
In 2 brothers with CIMAH, Ramakrishnan et al. (2016) identified compound heterozygous mutations in the MTHFD1 gene (172460.0009-172460.0010).
By whole-exome sequencing in a 34-year-old woman with CIMAH, Bidla et al. (2020) identified compound heterozygous mutations in the MTHFD1 gene (S276R, 172460.0007 and G276R, 172460.0011). The mutations, which were identified by whole-exome sequencing, were also present in the patient's affected brother. The mother was a carrier for the G276R mutation; the father was unavailable for testing. Studies in patient fibroblasts showed reduction in MTHFD1 protein expression and absence of MTHFD1 enzyme activity. Bidla et al. (2020) examined MTHFD1 protein expression and enzyme activity in fibroblasts from 3 additional patients with CIAMH and compound heterozygous variants in the MTHFD1 gene (see 172460.0003, 172460.0005, and 172460.0007) and found reduced protein content and absent enzyme activity.
Kao and Puck (1972) found that hybrids formed from an adenine-requiring Chinese hamster cell and human fibroblasts uniformly displayed new esterase activity. Hybrids that grew in selective medium showed a single extra chromosome resembling a B-group human chromosome. They postulated a human activator gene, designated esterase activator (ESAT), linked to the ade B gene, located on a B-group chromosome and capable of activating the mouse locus.
Functional complementation of mutations in the yeast Saccharomyces cerevisiae and Chinese hamster ovary cells resulting in an inability to synthesize adenine (Ade-) led to the identification of human genes involved in de novo purine biosynthesis. Two of these genes were identified as phosphoribosylglycinamide formyltransferase (GART; 138440) and phosphoribosyl formylglycinamide synthetase (PFAS; 602133), corresponding to Ade-E and Ade-B, respectively (Patterson, 1986). The human gene that complemented the defects was originally assigned to chromosome 14q22-qter, according to the findings of somatic cell hybrid studies (Kao, 1980; Kao and Puck, 1972; Jones et al., 1981; Kao et al., 1984). However, it is now known that the gene locus mapped to 14q is not GART or PFAS, but rather the MTHFD1 gene encoding enzymatic synthesis of the folate cofactor required by both enzymes. Henikoff et al. (1986) showed by direct assay of extracts of mutant cells that GART levels were normal, whereas levels of 5,10-methenyltetrahydrofolate cyclohydrolase were greatly decreased.
Schild et al. (1990) isolated a human cDNA clone complementing the yeast mutation Ade-3 (formyltetrahydrofolate synthetase). However, the cDNA clone was distinct by size and by restriction map criteria from that of the MTHFD1 clone reported by Hum et al. (1988) and was found instead to represent the MTHFD2 gene (604887).
Barton et al. (1991) gave a useful summary of the 12 enzymatic steps involved in the biosynthetic pathway for the production of AMP from phosphoribosylpyrophosphate (PRPP) as well as the 1-carbon cycle that supplies 1-carbon units for purine synthesis with 5 enzymes. The Ade(-)E mutation lies in the latter cycle, whereas the Ade(-)B mutation is at the fourth step in the pathway from PRPP to AMP. The enzymes involved have been mapped to 7 different chromosomes.
Human deficiency of the cyclohydrolase activity was proposed by Arakawa et al. (1966), but Arakawa (1970) later stated the uncertainty of this as a distinct entity.
In a boy with spina bifida (601634), Hol et al. (1998) identified a heterozygous 878G-A transition in the MTHFD1 gene, resulting in an arg293-to-his (R293H) substitution. The mutation was transmitted from the healthy maternal grandmother to the healthy mother and was also passed on to 2 other brothers, one with spina bifida occulta and the other asymptomatic. The mutation was not observed in 300 control samples. Hol et al. (1998) noted that the R293H substitution occurs in the putative interdomain region of the protein between the enzymatic regions and thus is not likely to affect enzymatic function, but may alter the structural integrity of the protein. The investigators could not evaluate the role of this mutation on plasma homocysteine concentrations.
Hol et al. (1998) identified a 1958G-A transition in the MTHFD1 gene, resulting in an arg653-to-gln (R653Q; rs2236225) substitution. The change was determined to be a polymorphism.
Brody et al. (2002) studied the R653Q polymorphism in the MTHFD1 gene in the Irish population and found an overrepresentation of QQ homozygotes in the mothers of children with neural tube defects (NTDFS; 601634) compared with control individuals.
De Marco et al. (2006) genotyped the MTHFD1 1958G-A polymorphism in 142 Italian children with NTD, 125 mothers, 108 fathers, and 523 controls. An increased risk was found for the heterozygous 1958G/A and homozygous 1958A/A genotypes in the children (OR, 1.69 and 1.91, respectively). The risk of an NTD-affected pregnancy was increased 1.67-fold only when a dominant effect (1958G/A or A/A vs G/G) was analyzed. A significant excess of transmission of the 1958A allele to affected individuals was demonstrated. De Marco et al. (2006) concluded that heterozygosity and homozygosity for the MTHFD1 1958G-A polymorphism are genetic determinants of NTD risk in the Italian population.
Parle-McDermott et al. (2006) analyzed the MTHFD1 gene in an independent sample of 245 Irish mothers with a history of NDT-affected pregnancy and 770 controls and found a significant excess of 1958AA homozygote mothers of NTD cases compared to controls (OR, 1.49; p = 0.019). Parle-McDermott et al. (2006) concluded that the 1958G-A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.
Van der Linden et al. (2007) did not find an association between the R653Q polymorphism and spina bifida among 103 Dutch patients and their mothers.
Parle-McDermott et al. (2005) genotyped 62 women with severe abruptio placentae and 184 control pregnancies and found an increased frequency of the QQ homozygote genotype in the abruptio placentae pregnancies compared to controls (OR, 2.85; p = 0.002). The authors concluded that women who are QQ homozygous for the MTHFD1 polymorphism are almost 3 times more likely to develop severe abruptio placentae than women who are RQ or RR. Zdoukopoulos and Zintzaras (2008) performed a metaanalysis of genetic risk factors for placental abruption, including the R653Q substitution.
In an infant, born to nonconsanguineous parents of Ashkenazi Jewish and Russian descent, with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780), Watkins et al. (2011) identified compound heterozygous mutations in the MTHFD1 gene: a splice site mutation in intron 8 (c.727+1G-A), and a c.517C-T transition in exon 7, resulting in an arg173-to-cys (R173C) substitution (172460.0004). The mutations segregated with the phenotype in the family. Watkins et al. (2011) noted that arg173 is in the NADP binding site of the protein and that mutations affecting this residue were shown by Pawelek et al. (2000) to affect enzyme activity. Neither mutation was identified in a panel of 93 (R173C) or 86 (c.727+1G-A) Ashkenazi Jewish control samples.
Hamosh (2017) noted that the IVS8+1G-A variant was not present in the gnomAD database (11/13/2017), whereas the R173C variant was found 10 times in 277,134 chromosomes with an allele frequency of 3.6 x 10(5). It was found most frequently among Ashkenazi Jews. The Ashkenazi Jewish frequency was 5/10,150 with an allele frequency of 4.9 x 10(-4).
For discussion of the c.517C-T transition in the MTHFD1 gene, resulting in an arg173-to-cys (R173C) substitution, that was found in compound heterozygous state in a patient with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780) by Watkins et al. (2011), see 172460.0003.
In an 18-month-old girl with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780), born to nonconsanguineous French parents, Burda et al. (2015) identified compound heterozygous mutations in the MTHFD1 gene: a c.806C-T transition, resulting in a thr296-to-ile (T296I) substitution, and a c.1674G-A transition, resulting in exon skipping (172460.0006).
Hamosh (2017) noted that the T296I variant was not reported in the gnomAD database (11/13/2017).
For discussion of the c.1674G-A transition in the MTHFD1 gene, resulting in exon skipping, that was found in compound heterozygous state in a patient with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780) by Burda et al. (2015), see 172460.0005.
In 3 patients from a nonconsanguineous Swedish family with combined immunodeficiency and megaloblastic anemia, Burda et al. (2015) identified compound heterozygous mutations in the MTHFD1 gene: a c.146C-T transition, resulting in a ser49-to-phe (S49F) substitution, and a c.673G-T transversion, resulting in a glu225-to-ter (E225X; 172460.0008) substitution.
Hamosh (2017) noted that the S49F variant was reported in 34 of 276,866 alleles in the gnomAD database (11/13/2017) for a European allele frequency of .0002368. The E225X variant was reported in heterozygous state in 4 of 246,264 alleles for an allele frequency of 1.624 x 10(-5). All 4 alleles were found in non-Finnish Europeans.
In a 34-year-old woman with CIMAH, Bidla et al. (2020) identified compound heterozygous mutations in the MTHFD1 gene: S49F, affecting a highly conserved residue in the NADP-binding site of the dehydrogenase/cyclohydrolase catalytic site, and a c.826G-C transversion, resulting in a gly276-to-arg (G276R; 172460.0011) substitution at a highly conserved residue in the dehydrogenase catalytic site. The mutations were found by whole-exome sequencing. The patient's affected brother also carried both mutations. The mother was a carrier for the G276R mutation; the father was not available for testing. Studies in patient fibroblasts showed reduction in MTHFD1 protein expression and absence of MTHFD1 enzyme activity. The G276R variant was not present in the gnomAD database. The patient was originally reported by Chery et al. (2013).
For discussion of the c.673G-T transversion in the MTHFD1 gene, resulting in a glu225-to-ter (E225X) substitution, that was found in compound heterozygous state in patients with combined immunodeficiency and megaloblastic anemia (CIMAH; 617780) by Burda et al. (2015), see 172460.0007.
In 2 brothers with combined immunodeficiency and megaloblastic anemia (CIMAH; 617780), Ramakrishnan et al. (2016) identified compound heterozygous mutations in the MTHFD1 gene: a deletion of exon 13 inherited from their father, and a c.152T-C transition (c.152T-C, NM_005956.3) in exon 3, resulting in a leu51-to-pro (L51P; 172490.0010) substitution, inherited from their mother. The exon 13 deletion was predicted to introduce a premature stop codon resulting in a truncated protein of 422 amino acids. In vitro analysis of mutant L51P predicted an adverse impact on protein function.
Hamosh (2017) noted that the L51P variant was not reported in the gnomAD database (11/13/2007).
For discussion of the c.152T-C transition in the MTHFD1 gene, resulting in a leu51-to-pro (L51P) substitution, that was found in compound heterozygous state in 2 brothers with combined immunodeficiency and megaloblastic anemia (CIMAH; 617780) by Ramakrishnan et al. (2016), see 172460.0009.
For discussion of the c.826G-C transversion (c.826G-C, NM_005956.4) in the MTHFD1 gene, resulting in a gly276-to-arg (G276R) substitution, that was found in compound heterozygous state in a patient with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780) by Bidla et al. (2020), see 172460.0007.
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