SIRT4 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the sirtuin 4 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | SIRT4 |
|---|---|
| Full Name | Sirtuin 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 12q24.31 |
| NCBI Gene ID | 23409 ncbi.nlm.nih.gov/gene/23409 |
| Ensembl ID | ENSG00000107833 |
| UniProt ID | Q9Y6E7 |
| OMIM ID | 604141 |
| HGNC ID | 14933 |
| Aliases | SIR2L4 |
Description
SIRT4 is a member of the sirtuin family of NAD+-dependent deacetylases and ADP-ribosyltransferases. Unlike other sirtuins, SIRT4 lacks deacetylase activity and primarily functions as an ADP-ribosyltransferase and lipoamidase. It is localized to the mitochondria and plays a key role in metabolic regulation, particularly in amino acid metabolism, insulin secretion, and fatty acid oxidation. SIRT4 also participates in the DNA damage response and has been implicated in tumor suppression and aging.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various types) | SIRT4 acts as a tumor suppressor by inhibiting glutamine metabolism and mitochondrial function, thereby reducing tumor cell proliferation. | Multiple studies show reduced SIRT4 expression in various cancers; overexpression inhibits tumor growth. |
| Type 2 Diabetes | SIRT4 regulates insulin secretion by modulating glutamate dehydrogenase (GDH) activity in pancreatic beta cells. | Animal models and cell studies demonstrate altered SIRT4 expression affects insulin secretion. |
| Metabolic Syndrome | SIRT4 influences lipid metabolism and fatty acid oxidation, contributing to metabolic homeostasis. | Association studies link SIRT4 variants with metabolic traits. |
| Aging | SIRT4 modulates mitochondrial function and oxidative stress, potentially affecting lifespan. | Experimental evidence in model organisms suggests SIRT4 involvement in aging. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 5.6 | Medium |
| Kidney | 4.2 | Low |
| Heart | 3.1 | Low |
| Skeletal Muscle | 2.8 | Low |
| Pancreas | 6.0 | Medium |
| Brain | 1.5 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | 7.2 | High expression |
| A549 (lung) | 3.4 | Moderate |
| MCF7 (breast) | 2.1 | Low |
| K562 (leukemia) | 1.0 | Very low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs3748980 | SNV (intronic) | 0.23 (global) | Associated with altered SIRT4 expression in some populations. |
| rs2807834 | SNV (intronic) | 0.31 (global) | Potential link to metabolic traits. |
| c.311C>T (p.Ala104Val) | Missense | Rare | Reported in cancer samples; functional impact unknown. |
| c.457G>A (p.Gly153Ser) | Missense | Rare | Found in COSMIC; may affect protein stability. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in SIRT4 are rare but may lead to increased glutamine metabolism and tumorigenesis, as seen in some cancer cell lines.
Gain of Function (GOF)
Gain-of-function mutations are not well characterized; overexpression of wild-type SIRT4 is generally tumor-suppressive.
Dominant Negative (DN)
No dominant-negative mutations have been reported for SIRT4.
View complete mutation data：
Gene Ontology (GO)
| • NAD+ ADP-ribosyltransferase activity | • Protein lipoamidase activity |
| • Zinc ion binding | • Mitochondrion |
| • Regulation of insulin secretion | • Cellular response to DNA damage stimulus |
Pathways
• Glutamate metabolism
• Insulin signaling
• Fatty acid oxidation
• Mitochondrial stress response
Protein Summary
SIRT4 is a 314-amino acid mitochondrial protein that belongs to the sirtuin family. It possesses NAD+-dependent ADP-ribosyltransferase and lipoamidase activities, but lacks deacetylase activity. SIRT4 primarily targets glutamate dehydrogenase (GDH) and other mitochondrial enzymes, regulating amino acid metabolism, insulin secretion, and fatty acid oxidation. It also plays a role in the DNA damage response by inhibiting mitochondrial glutamine metabolism. SIRT4 is widely expressed in metabolically active tissues such as liver, kidney, and pancreas. Its expression is often downregulated in cancers, suggesting a tumor suppressor role. SIRT4 has been implicated in metabolic diseases and aging.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SIRT4 Knockout HEK293 Cell Line | EDJ-KQ15265 | Human | 23409 | Details Get a Quote |
| SIRT4 Knockout A-549 Cell Line | EDJ-KQ45954 | Human | 23409 | Details Get a Quote |
| SIRT4 Knockout HCT 116 Cell Line | EDJ-KQ45955 | Human | 23409 | Details Get a Quote |
| SIRT4 Knockout Hep-G2 Cell Line | EDJ-KZ463 | Human | 23409 | Details Get a Quote |
| SIRT4 Knockout HeLa Cell Line | EDJ-KQ55727 | Human | 23409 | Details Get a Quote |
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