A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder

François Lecoquierre*, A. Mattijs Punt, Frédéric Ebstein, Ilse Wallaard, Rob Verhagen, Maja Studencka-Turski, Yannis Duffourd, Sébastien Moutton, Frédédic Tran Mau-Them, Christophe Philippe, John Dean, Stephen Tennant, Alice S. Brooks, Marjon A. van Slegtenhorst, Julie A. Jurgens, Brenda J. Barry, Wai Man Chan, Eleina M. England, Mayra Martinez Ojeda, Elizabeth C. EngleCaroline D. Robson, Michelle Morrow, A. Micheil Innes, Ryan Lamont, Matthea Sanderson, Elke Krüger, Christel Thauvin, Ben Distel, Laurence Faivre, Ype Elgersma, Antonio Vitobello

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Purpose:
Fem1 homolog B (FEM1B) acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CULLIN 2-based E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive.

Methods:
To understand the involvement of FEM1B in human disease, we made use of Matchmaker exchange platforms to identify individuals with de novo variants in FEM1B and performed their clinical evaluation. We performed functional validation using primary neuronal cultures and in utero electroporation assays, as well as experiments on patient's cells.

Results:
Five individuals with a recurrent de novo missense variant in FEM1B were identified: NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln) (FEM1BR126Q). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells. In addition, the individuals’ cells exhibited signs of oxidative stress and induction of type I interferon signaling.

Conclusion:
Overall, our data indicate that p.(Arg126Gln) induces aberrant FEM1B activation, resulting in a gain-of-function mechanism associated with a severe syndromic developmental disorder in humans.

Original languageEnglish
Article number101119
Number of pages15
JournalGenetics in Medicine
Volume26
Issue number6
Early online date7 Mar 2024
DOIs
Publication statusPublished - Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

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