METTL5: The 18S rRNA Methyltransferase and Its Role in Ribosome Biogenesis and Disease
A comprehensive overview of the METTL5 gene, its protein product, expression patterns, associated diseases, and functional significance in cellular biology.
Gene Information Card
| Symbol | METTL5 |
|---|---|
| Full Name | Methyltransferase Like 5 |
| Gene Type | Protein coding |
| Chromosomal Location | 2q31.1 |
| NCBI Gene ID | 29081 ncbi.nlm.nih.gov/gene/29081 |
| Ensembl ID | ENSG00000138311 |
| UniProt ID | Q9H7H0 |
| OMIM ID | 617303 |
| HGNC ID | 25525 |
| Aliases | Methyltransferase-like protein 5 |
Description
METTL5 (Methyltransferase Like 5) is a protein-coding gene located on chromosome 2q31.1. It encodes a methyltransferase enzyme that specifically catalyzes the N6-methyladenosine (m6A) modification of 18S ribosomal RNA (rRNA) at position A1832. This modification is crucial for the proper assembly and function of the small ribosomal subunit (40S), impacting global protein synthesis. METTL5 functions as a heterodimer with the TRMT112 protein, which is essential for its stability and enzymatic activity. The gene is highly conserved across eukaryotes, underscoring its fundamental role in cellular biology. Mutations in METTL5 have been linked to autosomal recessive intellectual disability, and its dysregulation has been implicated in various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Autosomal recessive intellectual disability | Loss-of-function mutations (e.g., c.457C>T, p.Arg153*) lead to a truncated, non-functional protein, resulting in the absence of m6A modification on 18S rRNA. This impairs ribosome biogenesis and global translation, particularly affecting neurodevelopment. | ClinVar, OMIM (617303), PubMed (e.g., Richard et al., 2019) |
| Cancer (e.g., Hepatocellular carcinoma, Breast cancer) | Overexpression of METTL5 is observed in several tumor types. It promotes cancer cell proliferation, migration, and invasion, likely by enhancing the translation of oncogenic mRNAs through increased ribosome production and altered translational fidelity. | COSMIC, PubMed (e.g., Wang et al., 2022; Zhang et al., 2023) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Testis | 25.4 | Medium |
| Spleen | 15.2 | Low |
| Lymph node | 13.1 | Low |
| Bone marrow | 11.8 | Low |
| Brain (Cerebellum) | 10.5 | Low |
| Liver | 8.9 | Low |
| Kidney | 7.2 | Low |
| Heart | 5.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| HepG2 (Liver cancer) | 15.3 | Elevated expression compared to normal liver tissue, consistent with its oncogenic role. |
| MCF7 (Breast cancer) | 12.8 | High expression in this breast cancer cell line, supporting its role in tumorigenesis. |
| A549 (Lung cancer) | 9.5 | Moderate expression; its role in lung cancer is under investigation. |
| K562 (Leukemia) | 8.1 | Expression present in this myeloid leukemia cell line. |
| HeLa (Cervical cancer) | 7.9 | Basal expression level in a standard cervical cancer cell line. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| c.457C>T (p.Arg153*) | Nonsense | Rare (found in affected families) | Introduces a premature stop codon, leading to a truncated protein lacking the catalytic domain. Results in loss of function and is a cause of intellectual disability. |
| c.1A>G (p.Met1?) | Start codon loss | Rare | Disrupts the initiation of translation, likely leading to the absence of the METTL5 protein. Associated with intellectual disability. |
| c.424C>T (p.Arg142Trp) | Missense | Rare | Substitutes a highly conserved arginine with tryptophan in the SAM-binding pocket, likely impairing methyltransferase activity. Pathogenic significance is supported by functional studies. |
| c.338G>A (p.Arg113His) | Missense | Rare | Located near the dimerization interface with TRMT112; may affect protein stability or complex formation, reducing enzymatic function. |
Mutation functional classification
Loss of Function (LOF)
The primary mechanism for METTL5-associated pathology. Nonsense, frameshift, and start-loss mutations result in a non-functional protein or complete loss of expression. Missense mutations in critical domains (e.g., SAM-binding, catalytic site) also lead to loss of methyltransferase activity. This results in the absence of m6A1832 on 18S rRNA, causing defective ribosome biogenesis and impaired global translation.
Gain of Function (GOF)
Not a recognized mechanism for pathogenic METTL5 mutations. However, in cancer, overexpression of the wild-type protein acts as an oncogenic driver, representing a gain-of-function at the expression level rather than a change in the protein's intrinsic activity.
Dominant Negative (DN)
No evidence supports a dominant-negative mechanism for METTL5 mutations. The disease is inherited in an autosomal recessive pattern, indicating that a single functional allele is sufficient for normal function.
View complete mutation data：
Gene Ontology (GO)
| • mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity | • rRNA (adenine-N6-)-methyltransferase activity |
| • RNA binding | • S-adenosylmethionine-dependent methyltransferase activity |
| • ribosome biogenesis | • maturation of SSU-rRNA |
| • cytoplasm | • nucleus |
| • small-subunit processome |
Pathways
• 18S pre-rRNA processing and maturation
• Ribosome biogenesis in eukaryotes
• rRNA base methylation
Protein Summary
The METTL5 protein is a 223-amino-acid methyltransferase that forms a stable heterodimer with the TRMT112 protein. This interaction is essential for its stability and catalytic activity. The complex specifically methylates the N6 position of adenine at position 1832 (m6A1832) of the 18S rRNA. This modification occurs during the early stages of ribosome biogenesis in the nucleolus and is critical for the correct folding and processing of the 18S rRNA, as well as the subsequent assembly of the 40S small ribosomal subunit. The m6A1832 modification is located in the decoding center of the ribosome, and its absence leads to a global reduction in translation fidelity and efficiency, particularly affecting the translation of mRNAs with complex 5' UTRs. Through its role in translation, METTL5 influences cell growth, proliferation, and differentiation. Its dysregulation is linked to neurodevelopmental disorders and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| METTL5 Knockout HEK293 Cell Line | EDJ-KQ3424 | Human | 29081 | Details Get a Quote |
| METTL5 Knockout A-549 Cell Line | EDJ-KQ25141 | Human | 29081 | Details Get a Quote |
| METTL5 Knockout HCT 116 Cell Line | EDJ-KQ25142 | Human | 29081 | Details Get a Quote |
| METTL5 Knockout HeLa Cell Line | EDJ-KQ25143 | Human | 29081 | Details Get a Quote |
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