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    F-BAR domain only protein 1 (FCHO1) deficiency is a novel cause of combined immune deficiency in human subjects
    (MOSBY-ELSEVIER, 2019) Calzoni, Enrica.; Platt, Craig D.; Keles, Sevgi.; Kuehn, Hye Sun.; Beaussant-Cohen, Sarah.; Zhang, Yu.; Pazmandi, Julia.; Lanzi, Gaetana.; Pala, Francesca.; Tahiat, Azzeddine.; Artac, Hasibe.; Heredia, Raul Jimenez.; Dmytrus, Jasmin.; Reisli, Ismail.; Uygun, Vedat.; Uygun, Dilara.; Bingol, Aysen.; Basaran, Erdem.; Djenouhat, Kamel.; Benhalla, Nafissa.; Bendahmane, Chafa.; Emiroglu, Melike.; Kirchhausen, Tomas.; Pasham, Mithun.; Jones, Jennifer.; Wallace, Jacqueline G..; Zheng, Lixin.; Boisson, Bertrand.; Porta, Fulvio.; Rosenzweig, Sergio D.; Su, Helen.; Giliani, Silvia.; Lenardo, Michael.; Geha, Raif S.; Boztug, Kaan.; Chou, Janet.; Notarangelo, Luigi D.
    [Abstract not Available]
  • Küçük Resim
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    F-BAR domain only protein 1 (FCHO1) deficiency is a novel cause of combined immune deficiency in humans
    (SPRINGER/PLENUM PUBLISHERS, 2019) Calzoni, Enrica.; Platt, Craig D.; Keles, Sevgi.; Kuehn, Hye Sun.; Zhang, Yu.; Pazmandi, Julia.; Lanzi, Gaetana.; Tahiat, Azzeddine.; Artac, Hasibe.; Dmytrus, Jasmin.; Reisli, Ismail.; Uygun, Dilara.; Boisson, Bertrand.; Rosenzweig, Sergio D.; Su, Helen C.; Giliani, Silvia.; Lenardo, Michael J.; Geha, Raif S.; Boztug, Kaan.; Chou, Janet.; Notarangelo, Luigi D.
    Clathrin-mediated endocytosis (CME) is the major endocytic pathway by which eukaryotic cells internalize cell-surface cargo proteins and extracellular molecules, thereby allowing for a broad range of biological processes, including cell signaling, nutrient and growth factor uptake, and cell fate and differentiation1. The FBAR domain only proteins 1 and 2 (FCHO1/FCHO2) are involved in the initiation of clathrin coat pit formation. Whether FCHO1 and FCHO2 are functionally redundant or have distinct functions is unclear. We report here the first cases of a severe immunodeficiency due to a genetic defect affecting CME. By using whole exome sequencing and genomic analysis of a targeted PID gene panel, we have identified biallelic loss-of-function FCHO1 mutations in five patients from unrelated families of Italian (P1), Turkish (P2, P3, and P5) and Algerian (P4) origin with severe T cell lymphopenia manifesting as recurrent and severe infections of bacterial, mycobacterial, viral and fungal origin. P3 developed EBV-associated diffuse large B cell lymphoma. Three patients (P3-P5) died in childhood, whereas P1 and P2 are alive with full donor chimerism at 13 and 1.5 years after allogeneic hematopoietic stem cell transplantation, respectively and have cleared pre-transplant infections. Patients P2, P3, and P4 carried homozygous frameshift mutations predicted to cause premature termination. Western-blotting analysis of HA- or FLAG-tagged FCHO1 constructs showed expression of truncated products in P2 and P3, whereas no protein was detected in P4, presumably due to mRNA decay. P1 and P5 carried homozygous splice-site mutations at the invariant -1 and +1 positions, respectively, leading to skipping of exon 6 in P1's FCHO1 cDNA. qPCR analysis demonstrated differential expression of the FCHO1 and FCHO2 genes, with the former being predominantly expressed in lymphoid cells, whereas FCHO2 was more abundantly expressed in fibroblasts and K562 cells. Analysis of T cell activation in P2 (the only patient for whom pre-transplant PBMC were available) revealed reduced T cell proliferation. While TCR internalization in response to CD3 cross-linking was normal (consistent with recent evidence that TCR internalization occurs through a clathrin-independent pathway), chase experiments demonstrated that transferrin internalization was abolished in activated T cells from P2. We had previously reported that a missense mutation in TFRC, encoding transferrin receptor 1, impairs transferrin internalization and intracellular iron delivery, causing a combined immunodeficiency with defective T cell proliferation. Our data identify the first form of severe immunodeficiency due to defects of clathrin-mediated endocytosis, and provide additional evidence in support of the critical role played by iron cellular metabolism in T cell function and homeostasis.