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Lyszkiewicz, Marcin; Zietara, Natalia; Frey, Laura; Pannicke, Ulrich; Stern, Marcel; Liu, Yanshan; Fan, Yanxin; Puchalka, Jacek; Hollizeck, Sebastian; Somekh, Ido; Rohlfs, Meino; Yilmaz, Tugba; Unal, Ekrem; Karakukcu, Musa; Patiroglu, Türkan; Kellerer, Christina; Karasu, Ebru; Sykora, Karl-Walter; Lev, Atar; Simon, Amos; Somech, Raz; Roesler, Joachim; Hoenig, Manfred; Keppler, Oliver T.; Schwarz, Klaus; Klein, Christoph (2020): Human FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells. In: Nature Communications, Vol. 11, No. 1, 1031
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Clathrin-mediated endocytosis (CME) is critical for internalisation of molecules across cell membranes. The FCH domain only 1 (FCHO1) protein is key molecule involved in the early stages of CME formation. The consequences of mutations in FCHO1 in humans were unknown. We identify ten unrelated patients with variable T and B cell lymphopenia, who are homozygous for six distinct mutations in FCHO1. We demonstrate that these mutations either lead to mislocalisation of the protein or prevent its interaction with binding partners. Live-cell imaging of cells expressing mutant variants of FCHO1 provide evidence of impaired formation of clathrin coated pits (CCP). Patient T cells are unresponsive to T cell receptor (TCR) triggering. Internalisation of the TCR receptor is severely perturbed in FCHO1-deficient Jurkat T cells but can be rescued by expression of wild-type FCHO1. Thus, we discovered a previously unrecognised critical role of FCHO1 and CME during T-cell development and function in humans.