Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability

Sabeh P, Dumas SA, Maios C, Daghar H, Korzeniowski M, Rousseau J, Lines M, Guerin A, Millichap JJ, Landsverk M, Grebe T, Lindstrom K, Strober J, Ait Mouhoub T, Zweier C, Steinraths M, Hebebrand M, Callewaert B, Abou Jamra R, Kautza-Lucht M, Wegler M, Kruszka P, Kumps C, Banne E, Waberski MB, Dieux A, Raible S, Krantz I, Medne L, Pechter K, Villard L, Guerrini R, Bianchini C, Barba C, Mei D, Blanc X, Kallay C, Ranza E, Yang XR, O'Heir E, Donald KA, Murugasen S, Bruwer Z, Calikoglu M, Mathews JM, Lesieur-Sebellin M, Baujat G, Derive N, Pierson TM, Murrell JR, Shillington A, Ormieres C, Rondeau S, Reis A, Fernandez-Jaen A, Au PYB, Sweetser DA, Briere LC, Couque N, Perrin L, Schymick J, Gueguen P, Lefebvre M, Van Andel M, Juusola J, Antonarakis SE, Parker JA, Burnett BG, Campeau PM (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 112

Pages Range: 75-86

Journal Issue: 1

DOI: 10.1016/j.ajhg.2024.11.009

Abstract

E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.

Authors with CRIS profile

Involved external institutions

Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) Queen's University Canada (CA) Northwestern University United States (USA) (US) University Hospital Ghent Belgium (BE) Wolfson Medical Center Israel (IL) Pediatric Specialists of Virginia United States (USA) (US) Uniformed Services University United States (USA) (US) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) France (FR) Children's Hospital of Philadelphia United States (USA) (US) Université de Montréal Canada (CA) Hôpital Necker-Enfants malades France (FR) Hospital Universitario Quirónsalud Madrid Spain (ES) University of Calgary Canada (CA) Swiss Institute Of Genomic Medicine (medigenome) Switzerland (CH) University of South Dakota United States (USA) (US) Meyer Children’s Hospital Italy (IT) Phoenix Children's Hospital United States (USA) (US) BioMarin Pharmaceutical Inc. United States (USA) (US) Réseau Hospitalier Neuchâtelois Switzerland (CH) University of California San Francisco (UCSF) United States (USA) (US) Centre hospitalier universitaire de Reims (CHU de Reims) France (FR) Inselspital, Universitätsspital Bern Switzerland (CH) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) University of British Columbia Canada (CA) Red Cross War Memorial Children’s Hospital South Africa (ZA) Universität Leipzig Germany (DE) Santa Clara Valley Medical Center (SCVMC) United States (USA) (US) GCS SeqOIA France (FR) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) GeneDX United States (USA) (US) University of North Carolina at Chapel Hill United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Massachusetts General Hospital United States (USA) (US) Hôpital Universitaire Robert-Debré France (FR) Aix-Marseille University / Aix-Marseille Université France (FR) Alberta Children's Hospital Canada (CA) Hospital of the University of Pennsylvania (HUP) United States (USA) (US) Cincinnati Children's Hospital Medical Center United States (USA) (US) Centre Hospitalier Regional d'Orleans France (FR)

How to cite

APA:

Sabeh, P., Dumas, S.A., Maios, C., Daghar, H., Korzeniowski, M., Rousseau, J.,... Campeau, P.M. (2025). Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability. American Journal of Human Genetics, 112(1), 75-86. https://doi.org/10.1016/j.ajhg.2024.11.009

MLA:

Sabeh, Pascale, et al. "Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability." American Journal of Human Genetics 112.1 (2025): 75-86.

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