IQSEC1: A Key Regulator of Vesicular Trafficking and Neuronal Function
Comprehensive genomic and proteomic overview of IQSEC1, a guanine nucleotide exchange factor for ARF GTPases, implicated in intellectual disability and cancer.
Gene Information Card
| Symbol | IQSEC1 |
|---|---|
| Full Name | IQ motif and Sec7 domain 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 3p25.2 |
| NCBI Gene ID | 9922 ncbi.nlm.nih.gov/gene/9922 |
| Ensembl ID | ENSG00000144713 |
| UniProt ID | Q6DN90 |
| OMIM ID | 610166 |
| HGNC ID | 28955 |
| Aliases | ARFGEF, BRAG2, GEP100, IQSEC1L |
Description
IQSEC1 encodes a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor (ARF) GTPases, specifically activating ARF1 and ARF6. The protein contains an IQ calmodulin-binding motif and a Sec7 catalytic domain. It plays a critical role in vesicular trafficking, cytoskeletal organization, and receptor endocytosis. Mutations in IQSEC1 are associated with X-linked intellectual disability (though the gene is autosomal, the protein interacts with X-linked pathways) and have been implicated in cancer progression through ARF6-mediated signaling.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Intellectual disability, autosomal dominant 79 (MRD79) | Loss-of-function mutations impair ARF6 activation, disrupting synaptic vesicle cycling and neuronal connectivity. | ClinVar, OMIM #619602 |
| Breast cancer | Overexpression of IQSEC1 (GEP100) promotes ARF6 activation, leading to increased cell migration and invasion via E-cadherin downregulation. | COSMIC, PubMed: 22926525 |
| Lung cancer | Amplification and overexpression of IQSEC1 correlate with poor prognosis; ARF6-dependent signaling enhances metastasis. | COSMIC, PubMed: 25605248 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | High |
| Testis | 8.3 | Medium |
| Lung | 6.1 | Medium |
| Breast | 4.7 | Low |
| Colon | 3.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.2 | Neuronal model; high expression |
| MCF7 (breast cancer) | 8.9 | Overexpressed in some breast cancer lines |
| A549 (lung cancer) | 7.4 | Moderate expression |
| HEK293 (embryonic kidney) | 6.5 | Baseline expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.226C>T (p.Arg76Trp) | Missense | Rare | Loss of GEF activity; associated with intellectual disability |
| c.1483G>A (p.Gly495Arg) | Missense | Rare | Impaired calmodulin binding; reduced ARF6 activation |
| c.1960_1962del (p.Lys654del) | In-frame deletion | Rare | Disrupts Sec7 domain; dominant-negative effect |
| Amplification (3p25.2) | Copy number gain | Frequent in breast cancer | Increased IQSEC1 expression; promotes invasion |
Mutation functional classification
Loss of Function (LOF)
Missense mutations in the Sec7 domain (e.g., p.Arg76Trp) reduce or abolish GEF activity toward ARF6, leading to impaired vesicular trafficking and neuronal dysfunction.
Gain of Function (GOF)
Gene amplification and overexpression in cancers result in hyperactivation of ARF6, enhancing cell migration and invasion.
Dominant Negative (DN)
Deletion mutations in the Sec7 domain (e.g., p.Lys654del) produce a protein that binds ARF6 but fails to catalyze nucleotide exchange, blocking downstream signaling.
View complete mutation data：
Gene Ontology (GO)
| • ARF guanyl-nucleotide exchange factor activity (GO:0005086) | • calmodulin binding (GO:0005516) |
| • intracellular protein transport (GO:0006886) | • endosomal transport (GO:0016197) |
| • actin cytoskeleton organization (GO:0030036) | • positive regulation of GTPase activity (GO:0043547) |
Pathways
• ARF6 signaling pathway
• Endocytosis
• Vesicle-mediated transport
• E-cadherin trafficking and cell adhesion
Protein Summary
IQSEC1 (BRAG2/GEP100) is a 130 kDa multidomain protein containing an N-terminal IQ motif that binds calmodulin and a central Sec7 domain that catalyzes GDP-GTP exchange on ARF1 and ARF6. The protein localizes to the plasma membrane and endosomes, regulating receptor internalization, cell adhesion, and cytoskeletal dynamics. In neurons, IQSEC1 is essential for synaptic vesicle recycling and dendritic spine morphogenesis. Dysregulation of IQSEC1 contributes to neurodevelopmental disorders and cancer metastasis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| IQSEC1 Knockout HEK293 Cell Line | EDJ-KQ6819 | Human | 9922 | Details Get a Quote |
| IQSEC1 Knockout A-549 Cell Line | EDJ-KQ31345 | Human | 9922 | Details Get a Quote |
| IQSEC1 Knockout HCT 116 Cell Line | EDJ-KQ31346 | Human | 9922 | Details Get a Quote |
| IQSEC1 Knockout HeLa Cell Line | EDJ-KQ31347 | Human | 9922 | Details Get a Quote |
