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Publication Detail
A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency
  • Publication Type:
    Working discussion paper
  • Authors:
    Rota I, Handel A, Klein F, Maio S, Dhalla F, Deadman M, Cheuk S, Newman J, Michaels Y, Zuklys S, Prevot N, Hublitz P, Charles P, Gkazi AS, Adamopoulou E, Qasim W, Davies G, Hanson C, Pagnamenta A, Camps C, Dreau H, White A, James K, Fischer R, Gileadi O, Taylor J, Fulga T, Lagerholm C, Anderson G, Sezgin E, Holländer G
  • Publication date:
  • Status:
The transcription factor FOXN1 is a master regulator of thymic epithelial cell development and function. Here we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multi-molecular nuclear condensates essential for the factor’s transcriptional activity. FOXN1’s C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are significantly altered in a patient with a mutant FOXN1 which is modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog, selectively impairs mouse thymic epithelial cell (TEC) differentiation revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect.
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