2/26/2023 0 Comments Fcho1 f bar![]() ![]() ![]() In an 18-month-old boy (P2), born of consanguineous Turkish parents, with immunodeficiency-76 (IMD76 619164), Calzoni et al. (2020) concluded that FCHO1 and clathrin-mediated endocytosis play an important role in T-cell development and function, and that these loss-of-function mutations impair TCR internalization and subsequent signaling during immune responses. Patient fibroblasts showed normal endocytic internalization of the transferrin receptor, suggesting that the mutation does not alter global endocytosis. None of the mutants colocalized with endogenous clathrin, and all failed to facilitate the formation of clathrin-coated pits and vesicles. Two mutations affecting the C-terminal mu-HD domain (R679P and Stop687) reduced the interaction with partner proteins, whereas a mutation affecting the N-terminal F-BAR domain (A34P) resulted in the formation of large aggregates that were not associated with the plasma membrane. Further in vitro functional expression studies in HEK293 cells transfected with 3 of the mutant proteins showed variable effects depending on the location of the mutation. These defects could be rescued by wildtype FCHO1, but not mutant FCHO1. Deletion of FCHO1 in a T-cell line disrupted endocytic internalization of the CD3:TCR complex, possibly due to impaired calcium mobilization. T cells derived from 1 patient (kindred C) with a frameshift mutation designated Stop687 ( 613437.0002) showed impaired proliferation and poor cytokine production after TCR stimulation. There were 2 missense, 2 splice site, a nonsense, and a frameshift mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In 10 affected patients from 7 unrelated families with IMD76, Lyszkiewicz et al. In contrast, endocytic internalization of the T-cell receptor (TCR)/CD3, which the authors stated is clathrin-independent, was preserved in activated T cells from P2. Patient cells also showed decreased internalization of the transferrin receptor (TFRC 190010), consistent with defective clathrin-mediated endocytosis. (2019) noted that clathrin-mediated endocytosis is important for mitosis. T cells derived from 1 patient (P2) showed impaired proliferation and increased apoptosis upon CD3/CD28 stimulation compared to controls. All were absent from the gnomAD database. There were 2 splice site mutations, 2 frameshift mutations, and an in-frame deletion. The mutations, which were found by whole-exome or candidate gene sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Four of the families were consanguineous. In 5 unrelated probands with immunodeficiency-76 (IMD76 619164), Calzoni et al. ![]()
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