SHMT2 Gene: Serine Hydroxymethyltransferase 2 - Function, Disease Associations, and Expression
Comprehensive guide to SHMT2 (Serine Hydroxymethyltransferase 2): genomic location, protein function, expression, mutations, and clinical significance.
Gene Information Card
| Symbol | SHMT2 |
|---|---|
| Full Name | Serine Hydroxymethyltransferase 2 (Mitochondrial) |
| Gene Type | Protein coding |
| Chromosomal Location | 12q13.13 (GRCh38) |
| NCBI Gene ID | 6472 ncbi.nlm.nih.gov/gene/6472 |
| Ensembl ID | ENSG00000182199 |
| UniProt ID | P34897 |
| OMIM ID | 604124 |
| HGNC ID | 10851 |
| Aliases | MGC39258, SHMT, mSHMT, HEL-S-51e |
Description
SHMT2 encodes the mitochondrial isoform of serine hydroxymethyltransferase, a pyridoxal phosphate-dependent enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylene-tetrahydrofolate. This reaction is central to one-carbon metabolism, providing precursors for nucleotide synthesis, amino acid homeostasis, and redox balance. SHMT2 is essential for mitochondrial folate metabolism and is upregulated in various cancers to support rapid proliferation. Mutations in SHMT2 have been linked to neurodevelopmental disorders and cancer progression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Neurodevelopmental disorder with microcephaly, spasticity, and brain abnormalities | Biallelic loss-of-function mutations impair mitochondrial one-carbon metabolism, leading to deficient glycine and nucleotide synthesis, affecting brain development. | ClinVar (Pathogenic variants); OMIM #604124 |
| Cancer (multiple types, including colorectal, breast, lung, and glioma) | SHMT2 overexpression supports tumor growth by enhancing serine/glycine metabolism and NADPH production, promoting proliferation and survival under metabolic stress. | COSMIC (overexpression and copy number alterations); PubMed studies |
| Mitochondrial disorders (general) | Deficient SHMT2 activity disrupts mitochondrial folate metabolism, causing respiratory chain dysfunction and altered cellular redox status. | UniProt (functional annotation); OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High (e.g., 20-30 nTPM) | High |
| Kidney | Moderate (e.g., 10-20 nTPM) | Medium |
| Brain | Moderate (e.g., 10-20 nTPM) | Medium |
| Heart | Low (e.g., 5-10 nTPM) | Low |
| Skeletal Muscle | Low (e.g., 5-10 nTPM) | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver cancer) | High (e.g., 30-40 nTPM) | Overexpressed in liver cancer cell lines |
| A549 (lung cancer) | Moderate (e.g., 15-25 nTPM) | Elevated in lung cancer |
| MCF7 (breast cancer) | Moderate (e.g., 15-25 nTPM) | Upregulated in breast cancer |
| K562 (leukemia) | Low (e.g., 5-10 nTPM) | Lower expression in leukemia cell lines |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1214G>A (p.Arg405His) | Missense | Rare (0.01% in gnomAD) | Reported in neurodevelopmental disorder; reduces enzyme activity |
| c.1123C>T (p.Arg375Trp) | Missense | Rare | Pathogenic in neurodevelopmental disorder; disrupts pyridoxal phosphate binding |
| c.1A>G (p.Met1?) | Start loss | Ultra-rare | Loss of translation initiation; likely loss-of-function |
| Copy number gain/amplification | CNV | Frequent in cancers (e.g., 10-20% in certain tumors) | Overexpression promotes tumor growth |
Mutation functional classification
Loss of Function (LOF)
Biallelic loss-of-function mutations (e.g., missense, start loss) impair enzyme activity, leading to neurodevelopmental disorders due to disrupted one-carbon metabolism.
Gain of Function (GOF)
Amplification or overexpression of SHMT2 in cancers acts as a gain-of-function by increasing metabolic flux, supporting proliferation and survival.
Dominant Negative (DN)
No clear dominant-negative mutations reported; most pathogenic variants are recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• One-carbon metabolism (folate cycle)
• Glycine
• serine and threonine metabolism
• Metabolic reprogramming in cancer
• Mitochondrial amino acid metabolism
Protein Summary
SHMT2 is a mitochondrial enzyme that catalyzes the interconversion of serine and glycine, using tetrahydrofolate as a cofactor. It is a homotetramer, each subunit binding pyridoxal phosphate. The enzyme is critical for providing one-carbon units for purine and thymidylate synthesis, and for maintaining mitochondrial redox balance by generating NADPH. SHMT2 is highly expressed in proliferating cells, especially tumors, where it supports anabolic metabolism. Mutations causing loss of function lead to neurodevelopmental defects, while overexpression is associated with cancer progression.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SHMT2 Knockout HEK293 Cell Line | EDJ-KQ1040 | Human | 6472 | Details Get a Quote |
| SHMT2 Knockout A-549 Cell Line | EDJ-KQ20142 | Human | 6472 | Details Get a Quote |
| SHMT2 Knockout HCT 116 Cell Line | EDJ-KQ20143 | Human | 6472 | Details Get a Quote |
| SHMT2 Knockout HeLa Cell Line | EDJ-KQ20144 | Human | 6472 | Details Get a Quote |
| Shmt2 Knockout C2C12 Cell Line | EDJ-KZ455 | Mouse | 108037 | Details Get a Quote |
| SHMT2 Knockout PK-15 Cell Line | EDJ-KZ456 | Pig | 6472 | Details Get a Quote |
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