MADD (MAP Kinase Activating Death Domain) Gene
A multifunctional adaptor protein involved in MAPK signaling, vesicle trafficking, and apoptosis regulation
Gene Information Card
| Symbol | MADD |
|---|---|
| Full Name | MAP kinase activating death domain |
| Gene Type | protein-coding |
| Chromosomal Location | 11p11.2 |
| NCBI Gene ID | 8567 ncbi.nlm.nih.gov/gene/8567 |
| Ensembl ID | ENSG00000110514 |
| UniProt ID | Q8WXG6 |
| OMIM ID | 603584 |
| HGNC ID | HGNC:6766 |
| Aliases | IG20, DENN, Rab3GEP, KIAA0358 |
Description
The MADD gene encodes a multifunctional adaptor protein that activates MAP kinases (MAPK/ERK) and contains a death domain involved in apoptosis signaling. It also functions as a guanine nucleotide exchange factor (GEF) for Rab3 and Rab27, regulating vesicle trafficking and neurotransmitter release. Alternative splicing generates multiple isoforms with distinct roles in cell survival, proliferation, and secretion.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Neuroblastoma | MADD overexpression promotes tumor growth via MAPK activation | NCBI Gene, OMIM |
| Alzheimer's disease | MADD dysregulation linked to altered APP processing and apoptosis | NCBI Gene, OMIM |
| Diabetes (type 2) | MADD variants affect insulin secretion via Rab3GEF activity | ClinVar, OMIM |
| Cancer (multiple types) | MADD mutations and splice variants contribute to oncogenic signaling | COSMIC, NCBI Gene |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 25.6 | Medium |
| Adrenal gland | 18.3 | Medium |
| Pancreas | 12.1 | Low |
| Testis | 10.5 | Low |
| Lung | 8.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 32.4 | High expression |
| HEK293 (embryonic kidney) | 22.1 | Moderate expression |
| HeLa (cervical cancer) | 15.7 | Low expression |
| MCF7 (breast cancer) | 11.3 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.2260C>T (p.Arg754Trp) | Missense | <0.01% | Altered Rab3GEF activity, associated with diabetes |
| c.1234G>A (p.Glu412Lys) | Missense | <0.01% | Impaired MAPK activation, linked to neuroblastoma |
| c.789_790insA | Frameshift | Rare | Loss of function, reduced apoptosis |
| c.1567C>T (p.Arg523*) | Nonsense | <0.01% | Premature truncation, loss of death domain |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the protein, impairing Rab3GEF and MAPK activation functions.
Gain of Function (GOF)
Missense mutations that enhance MAPK signaling or alter isoform balance, promoting cell proliferation.
Dominant Negative (DN)
Certain missense variants (e.g., p.Arg754Trp) may interfere with wild-type MADD function in vesicle trafficking.
View complete mutation data：
Gene Ontology (GO)
Pathways
• MAPK signaling pathway (KEGG: hsa04010)
• Apoptosis (KEGG: hsa04210)
• Rab-regulated vesicle trafficking (Reactome: R-HSA-9007101)
• Insulin secretion (KEGG: hsa04911)
Protein Summary
The MADD protein (UniProt Q8WXG6) is a 1,589-amino-acid multidomain adaptor that includes a death domain, a DENN domain, and a Rab3GEF domain. It activates MAPK/ERK signaling and regulates exocytosis via Rab3 and Rab27. Isoform diversity (e.g., IG20, MADD-DENN) modulates its roles in cell survival, apoptosis, and neurotransmitter release. The protein is widely expressed, with highest levels in brain and endocrine tissues.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MADD Knockout HEK293 Cell Line | EDJ-KQ2650 | Human | 8567 | Details Get a Quote |
| MADD Knockout A-549 Cell Line | EDJ-KQ22049 | Human | 8567 | Details Get a Quote |
| MADD Knockout HCT 116 Cell Line | EDJ-KQ23419 | Human | 8567 | Details Get a Quote |
| MADD Knockout HeLa Cell Line | EDJ-KQ23420 | Human | 8567 | Details Get a Quote |
