MTHFR
methylenetetrahydrofolate reductase
Theoretical — per Powers
Gene summary
A protein-coding gene on chromosome 1 (methylation and one-carbon metabolism). The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.
Source: NCBI Gene, accessed 2026-10-07.
Protein reference (UniProt)
- Protein
Methylenetetrahydrofolate reductase (NADPH)
- Function
Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Represents a key regulatory connection between the folate and methionine cycles (Probable).
- Pathway
One-carbon metabolism; tetrahydrofolate interconversion.
- Associated conditions
Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity (MTHFRD); Ischemic stroke (ISCHSTR); Neural tube defects, folate-sensitive (NTDFS); Schizophrenia (SCZD).
Source: UniProtKB/Swiss-Prot P42898, release 2026_03, licensed CC BY 4.0. This is the protein’s normal biology, not evidence about post-drug syndromes; associated conditions are inherited disorders of the gene, not PFS, PSSD or PRSD.
Why its pathway is in the library
One-carbon metabolism supplies methyl groups for DNA/histone methylation — the epigenetic layer implicated in persistent post-drug changes.
Written for the whole methylation / one-carbon family, not for MTHFR specifically.
Powers’ note (his unpublished theorizing)
Named by Powers in adjacent (non-PFS) work (unpublished): reported high rates of MTHFR variants in his patient population and himself (“two bad copies”); hypothesized methylation defects amplify mild steroid-synthesis enzyme defects.
Narrative library record
Function
Rate-limiting enzyme of folate metabolism that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for remethylating homocysteine to methionine and ultimately producing S-adenosylmethionine - the universal methyl donor for DNA, RNA, and protein methylation. The common C677T variant (A222V) substantially reduces enzyme activity.
Corpus relevance
Powers described mining patient genomes for shared variants and trialing methylated B vitamins (L-methylfolate, methylcobalamin) with self-reported benefit (DWP-006) - MTHFR is the canonical gene behind that methylation-support rationale. It connects the corpus's epigenetic theme (DNA methylation in PFS-002, PFS-011) to one-carbon metabolism. Attribution: Powers' clinical anecdote (unpublished); MTHFR biochemistry is established, its PFS relevance is not.
Powers’ claims naming MTHFR
- Powers gene claim
MTHFR — "two bad copies" (self-reported); common MTHFR SNPs (e.g., rs1801131, rs1801133) in patients
Confidence: direct (adjacent)
Powers reported finding MTHFR mutations at high rates in his transgender patient population and in himself (two bad copies), and trialed L-methylfolate plus methylcobalamin with self-reported mental-health benefit. He hypothesized methylation defects amplify…
MTHFRPGL-MTHFRcirca 2023PFS
Mentioned in 2 corpus records
- Powers · Reddit post
Have gender dysphoria, hypermobile, ADHD or autism… / The non-AD of trans…
u/drwillpowers · r/DrWillPowers
Powers described a striking comorbidity cluster in his transgender patient population — autism, ADHD, hypermobility, POTS/dysautonomia, congenital adrenal hyperplasia, Hashimoto's thyroiditis, and GI issues — and reported discovering relevant mutations in his…
MTHFRDWP-0062023PFSPSSDCore corpus - Peer-reviewed paper
Association between MTHFR C677T polymorphism and depression: An updated meta-analysis of 26 studies
Yile Wu, Xiuxiu Ding, Yehuan Sun, Huiyun Yang, Jian Chen, Xue Yan Zhao, Yuhong Jiang, Xiaoling Lv, Zhenqiang Wu · Progress in Neuro-Psychopharmacology and Biological Psychiatry
Prior studies of the MTHFR C677T polymorphism and depression had given inconclusive results, so the authors pooled 26 studies comprising 4,992 depression cases and 17,082 controls. The T allele was associated with increased depression risk overall (TT vs CC…
MTHFRMECH-0412013Systems review · Oct 2026
Also in methylation and one-carbon metabolism
All 5 genes- AHCY
adenosylhomocysteinase
chr 20· Methylation / one-carbon· Pathway candidate - BHMT
betaine--homocysteine S-methyltransferase
chr 5· Methylation / one-carbon· Pathway candidate - MTR
5-methyltetrahydrofolate-homocysteine methyltransferase
chr 1· Methylation / one-carbon· Pathway candidate - MTRR
5-methyltetrahydrofolate-homocysteine methyltransferase reductase
chr 5· Methylation / one-carbon· Pathway candidate
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