Adaptor protein 2 sigma subunit (AP2S1) variants associated with neurodevelopmental disorders
Author:
Stevenson MarkORCID, Bayliss Asha L., Stokes Victoria J., English Katherine A., Kooblall Kreepa G., Fischer Roman, Heilig Raphael, Vendrell Iolanda, Albers Maria E. W. A., Bartos Meghan, Begtrup Amber, Bourgois Alexia, Buchert Rebecca, Carey David J., Carere Deanna A., Carnevale Amanda, Claeys Kristl G., Cogne Benjamin, Costain Gregory, de Leeuw Nicole, Denommé-Pichon Anne-Sophie, Donner Elizabeth J., Drogouti Eftychia, Dyment David A., Gangaram Balram, Haack Tobias B., Haley Jeremy S., Heide Solveig, Husain Ralf A., Isidor Bertrand, Izatt Louise, Jacquinet Adeline, Juusola Jane, Kahle Juliette J., Keren Boris, Klee Eric W., Kokosali Evgenia, Lanpher Brendan C., Macke Erica L., Marco Elysa J., McWalter Kirsty, Mendelsohn Bryce A., Milunsky Aubrey, Osmond Matthew, Piton Amelie, Riess Angelika, Ruault Valentin, Rump Patrick, Schuhmann Sarah, Shillington Amelle L., Smelser Diane T., Snijders Blok Lot, Tran Mau-Them Frederic, Tsakalidis Christos, Turnwald Abigail, Van Gassen Koen L. I., Van Schil Kristof, Vasileiou Georgia, Vawter-Lee Marissa, Willems Marjolaine, Willemsen Marjolein H., Wong-Kisiel Lily C., Wonneberger Antje, Zaganas Ioannis, Hannan Fadil M., Lines Kate E., Thakker Rajesh V.,
Abstract
AbstractAdaptor-Related Protein Complex 2 Sigma-1 Subunit(AP2S1) encodes AP2σ2, which forms part of the heterotetrameric AP2 complex that is composed of α, β2, μ2, and σ2 subunits and has a pivotal role in clathrin-mediated endocytosis (CME)1–3.AP2S1variants involving the Arg15 residue are associated with familial hypocalciuric hypercalcaemia type 3 (FHH3)1,4–6. Here, we report 5 differentAP2S1variants (AP2σ2: 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, AP2σ2 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 AP2σ2 variants may disrupt CME and be associated with neurodevelopmental disorders.
Publisher
Cold Spring Harbor Laboratory
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