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Ebstein, F.* ; Latypova, X.* ; Hung, K.Y.S.* ; Prado, M.A.* ; Lee, B.H.* ; Möller, S.* ; Wendlandt, M.* ; Zieba, B.A.* ; Florenceau, L.* ; Vignard, V.* ; Poirier, L.* ; Toutain, B.* ; Moroni, I.* ; Dubucs, C.* ; Chassaing, N.* ; Horvath, J.* ; Prokisch, H. ; Küry, S.* ; Bézieau, S.* ; Paulo, J.A.* ; Finley, D.* ; Krüger, E.* ; Ghezzi, D.* ; Isidor, B.*

Biallelic USP14 variants cause a syndromic neurodevelopmental disorder.

Genet. Med. 26:101120 (2024)

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PURPOSE: Imbalances in protein homeostasis affect human brain development, with the ubiquitin-proteasome system (UPS) and autophagy playing crucial roles in neurodevelopmental disorders (NDD). This study explores the impact of biallelic USP14 variants on neurodevelopment, focusing on its role as a key hub connecting UPS and autophagy. METHODS: Here, we identified biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. Functional studies were conducted using SDS-PAGE, Western blotting, and mass spectrometry analyses in both patient-derived and CRISPR-Cas-generated cells. RESULTS: Our investigations indicated that the USP14 variants correlated with reduced N-terminal methionine excision, along with profound alterations in proteasome, autophagy, and mitophagy activities. CONCLUSION: Biallelic USP14 variants in NDD patients perturbed protein degradation pathways, potentially contributing to disorder etiology. Altered UPS, autophagy, and mitophagy activities underscore the intricate interplay, elucidating their significance in maintaining proper protein homeostasis during brain development.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords N-terminal Methionine Excision ; Neurodevelopmental Disorders ; Usp14 ; Loss-of-function Variants ; Ubiquitin-proteasome System; Deubiquitinating Enzyme; Intellectual Disability; Proteins; Ubiquitination; Association; Degradation; Mutations; Autophagy; Variants

ISSN (print) / ISBN 1530-0366

e-ISSN 1098-3600

Journal Genetics in Medicine

Quellenangaben Volume: 26, Issue: 6, Article Number: 101120

Publisher Lippincott Williams & Wilkins

Publishing Place Baltimore, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants I-site Nantes Excellence Trajectory (NExT) Junior Talent Chair
COST (European Cooperation in Science and Technology)
German Research Foundation
Instituto de Salud Carlos III (ISCIII) - European Union
National Institutes of Health
National Research Foundation of Korea (NRF) of the Ministry of Science and ICT
European Research Area PerMed project