IQ motif and SEC7 domain-containing protein 1

IQSEC1 (IQ motif and SEC7 domain-containing protein 1) is a guanine nucleotide exchange factor that activates ARF1 and ARF6 GTPases, with activity enhanced by lipid binding (UniProt: Q6DN90). In neurons, it regulates vesicle formation and endocytic cargo control, and mediates ARF6-dependent internalization of synaptic AMPA receptors during long-term depression. The protein is involved in neuronal development and plays a role in dendritic spine plasticity.

IQSEC1 is associated with intellectual developmental disorder with short stature and behavioral abnormalities (IDDSSBA, MIM 618687), an autosomal recessive condition featuring intellectual disability, developmental delay, and seizures (UniProt: Q6DN90).

In Alzheimer's disease, IQSEC1 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2FC: −0.94, Chaparral AD proteomics). This downregulation was observed in a TMT-labeled quantitative proteomics study examining multiple subcellular fractions from AD and control brain samples. The reduced expression of this synaptic-regulating protein may contribute to alterations in glutamate receptor trafficking and synaptic dysfunction characteristic of AD pathology.