DENND5A (DENN Domain Containing 5A)
A guanine nucleotide exchange factor (GEF) for Rab GTPases, implicated in neurodevelopmental disorders and cancer.
Gene Information Card
| Symbol | DENND5A |
|---|---|
| Full Name | DENN domain containing 5A |
| Gene Type | protein coding |
| Chromosomal Location | 11p15.4 |
| NCBI Gene ID | 23258 ncbi.nlm.nih.gov/gene/23258 |
| Ensembl ID | ENSG00000134049 |
| UniProt ID | Q6IQ26 |
| OMIM ID | 617027 |
| HGNC ID | 29349 |
| Aliases | KIAA1096, RAB6IP1, DENND5 |
Description
DENND5A encodes a member of the DENN (differentially expressed in normal and neoplastic cells) domain family. The protein functions as a guanine nucleotide exchange factor (GEF) for Rab GTPases, specifically Rab6 and Rab39, regulating vesicle trafficking and intracellular transport. It is involved in neuronal development and synaptic function. Mutations in DENND5A have been associated with epileptic encephalopathy and intellectual disability. Altered expression is observed in certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Epileptic encephalopathy, early infantile, 49 | Biallelic loss-of-function mutations (e.g., frameshift, nonsense) lead to impaired Rab GEF activity, disrupting neuronal vesicle trafficking and synaptic transmission. | ClinVar, OMIM (617027) |
| Intellectual disability, autosomal recessive | Homozygous missense mutations affecting conserved residues in the DENN domain reduce GEF activity, impairing Rab6/Rab39-mediated transport in neurons. | ClinVar, OMIM |
| Cancer (e.g., colorectal, breast) | Overexpression or copy number gain of DENND5A may enhance Rab-mediated vesicle trafficking, promoting cell proliferation and invasion. | COSMIC, NCBI Gene |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 18.2 | High |
| Testis | 12.5 | Medium |
| Lung | 8.3 | Medium |
| Liver | 5.1 | Low |
| Kidney | 4.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 22.4 | High expression; used in neuronal studies |
| HeLa (cervical carcinoma) | 15.8 | Moderate expression |
| A549 (lung carcinoma) | 9.2 | Low expression |
| MCF7 (breast carcinoma) | 7.5 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412Ter) | Nonsense | Rare (0.01%) | Loss of function; associated with epileptic encephalopathy |
| c.567_568del (p.Leu190fs) | Frameshift | Rare (0.005%) | Loss of function; causes intellectual disability |
| c.890A>G (p.Tyr297Cys) | Missense | Not reported in gnomAD | Likely damaging; reduces GEF activity |
| c.2345G>A (p.Arg782His) | Missense | 0.02% | Uncertain significance; possibly benign |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (nonsense, frameshift) are pathogenic, leading to haploinsufficiency or null alleles, causing neurodevelopmental disorders.
Gain of Function (GOF)
Gain-of-function mutations are not well-documented; overexpression in cancer may act as an oncogenic driver.
Dominant Negative (DN)
Dominant-negative effects are hypothesized for some missense mutations that impair GEF activity but retain Rab binding, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • GTPase activator activity | • Rab guanyl-nucleotide exchange factor activity |
| • intracellular vesicle | • Golgi apparatus |
| • synaptic vesicle | • regulation of Rab GTPase activity |
| • vesicle-mediated transport |
Pathways
• Rab6-mediated vesicle trafficking
• Rab39-mediated autophagy and immune response
• Endomembrane system organization
Protein Summary
The DENND5A protein (UniProt Q6IQ26) is a 1,274-amino acid protein containing a DENN domain, which is responsible for its GEF activity. It localizes to the Golgi apparatus and vesicular structures, where it activates Rab6 and Rab39 by promoting GDP-GTP exchange. This activity is crucial for retrograde transport between endosomes and the Golgi, as well as for neuronal dendritic spine formation. The protein is highly expressed in the brain, consistent with its role in synaptic function. Structural studies suggest that the DENN domain adopts a fold that binds Rab GTPases and catalyzes nucleotide exchange. Mutations in this domain disrupt its function, leading to disease.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| DENND5A Knockout HEK293 Cell Line | EDJ-KQ7932 | Human | 23258 | Details Get a Quote |
| DENND5A Knockout A-549 Cell Line | EDJ-KQ33578 | Human | 23258 | Details Get a Quote |
| DENND5A Knockout HCT 116 Cell Line | EDJ-KQ33579 | Human | 23258 | Details Get a Quote |
| DENND5A Knockout HeLa Cell Line | EDJ-KQ33580 | Human | 23258 | Details Get a Quote |
