A FOXN1 mutation competitively displaces wild-type FOXN1 from higher order nuclear condensates to cause immunodeficiency
Rota, I. A.; Handel, A. E.; Klein, F.; Maio, S.; Dhalla, F.; Deadman, M. E.; Cheuk, S.; Newman, J. A.; Michaels, Y. S.; Zuklys, S.; Prevot, N.; Hublitz, P.; Charles, P. D.; Gkazi, A. S.; Adamopoulou, E.; Qasim, W.; Davies, E. G.; Hanson, C.; Pagnamenta, A. T.; Camps, C.; Dreau, H. M.; White, A.; James, K.; Fischer, R.; Gileadi, O.; Taylor, J. C.; Fulga, T.; Lagerholm, B. C.; Anderson, G.; Sezgin, E.; Hollander, G. A.
Show abstract
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 factors transcriptional activity. FOXN1s 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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