Adaptor protein 2 sigma subunit (AP2S1) variants associated with neurodevelopmental disorders

Adaptor-Related Protein Complex 2 Sigma-1 Subunit (AP2S1) encodes AP2{sigma}2, which forms part of the heterotetrameric AP2 complex that is composed of , {beta}2, 2, and {sigma}2 subunits and has a pivotal role in clathrin-mediated endocytosis (CME)1-3. AP2S1 variants involving the Arg15 residue are associated with familial hypocalciuric hypercalcaemia type 3 (FHH3)1,4-6. Here, we report 5 different AP2S1 variants (AP2{sigma}2: p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His) in 26 patients with neurodevelopmental delay, of whom >70% had epilepsy, 50% had brain abnormalities, and none had hypercalcaemia. All 5 variants decreased cell viability, 4 reduced CME transferrin uptake, and 4 disrupted interactions with other AP2 complex subunits, thereby affecting AP2 formation. Furthermore, AP2{sigma}2 p.Arg10Trp had reduced interactions with 44 human proteins including intersectin 1, a component required for clathrin-coated pit formation and synaptic vesicle dynamics in neurones. Thus, our results show that AP2{sigma}2 variants may disrupt CME and be associated with neurodevelopmental disorders.