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

Autor:	Sabeh P; Department of Genetics, CHU Sainte-Justine, Montréal, QC, Canada., Dumas SA; Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814, USA., Maios C; Department of Neuroscience, Université de Montréal, CRCHUM, Montréal, QC, Canada., Daghar H; Department of Neuroscience, Université de Montréal, CRCHUM, Montréal, QC, Canada., Korzeniowski M; Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814, USA., Rousseau J; Department of Genetics, CHU Sainte-Justine, Montréal, QC, Canada., Lines M; Department of Clinical and Metabolic Genetics, Alberta Children's Hospital, Calgary, AB, Canada., Guerin A; Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, ON, Canada., Millichap JJ; Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Landsverk M; Sanford Research, Pediatrics and Rare Diseases Group, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA., Grebe T; Department of Genetics and Metabolism, Phoenix Children Hospital, Phoenix, AZ, USA., Lindstrom K; BioMarin Pharmaceutical, Inc., 105 Digital Dr., Novato, CA 94949, USA., Strober J; Department of Child Neurology, University of California, San Francisco, San Francisco, CA, USA., Ait Mouhoub T; Department of Genetic, University Hospital Center of Reims, Reims, France., Zweier C; Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland., Steinraths M; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada., Hebebrand M; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Callewaert B; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Abou Jamra R; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Kautza-Lucht M; Institute of Human Genetics, University Hospital of Schleswig-Holstein, Kiel, Germany., Wegler M; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Kruszka P; GeneDx, Gaithersburg, MD, USA., Kumps C; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Banne E; The Genetic Institute, Wolfson Medical Center, Holon, Israel., Waberski MB; Pediatric Specialists of Virginia, Fairfax, VA, USA., Dieux A; Service de génétique clinique du CHU de Lille, Lille, France., Raible S; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Krantz I; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Medne L; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Pechter K; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Villard L; Aix Marseille University, INSERM, Marseille Medical Genetics Center, MMG, Marseille, France; University of Florence, Florence, Italy., Guerrini R; Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy., Bianchini C; Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy., Barba C; Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy., Mei D; Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, Italy., Blanc X; Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland., Kallay C; Réseau Hospitalier Neuchâtelois, Neuchâtel, Switzerland., Ranza E; Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland., Yang XR; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., O'Heir E; Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Donald KA; Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa., Murugasen S; Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa., Bruwer Z; Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Rondebosch, South Africa., Calikoglu M; University of North Carolina, Department of Pediatrics, Division of Genetics and Metabolism, Chapel Hill, NC, USA., Mathews JM; University of North Carolina, Department of Pediatrics, Division of Genetics and Metabolism, Chapel Hill, NC, USA., Lesieur-Sebellin M; Service de médecine génomique des maladies rares, Necker Hospital, Paris, France., Baujat G; University of North Carolina, Department of Pediatrics, Division of Genetics and Metabolism, Chapel Hill, NC, USA., Derive N; Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France., Pierson TM; Departments of Pediatrics and of Neurology, Guerin Children's Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Murrell JR; Department of Pathology and Laboratory Medicine, Children's Hospital of the University of Pennsylvania, Philadelphia, PA, USA., Shillington A; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Ormieres C; Service de médecine génomique des maladies rares, Necker Hospital, Paris, France., Rondeau S; Service de médecine génomique des maladies rares, Necker Hospital, Paris, France., Reis A; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Fernandez-Jaen A; Department of Pediatric Neurology, Hospital Universitario Quirónsalud, Madrid, Spain., Au PYB; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Sweetser DA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Briere LC; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Couque N; Département de Génétique - UF de Génétique Moléculaire Hôpital Robert Debré, Paris, France., Perrin L; Département de Génétique - UF de Génétique Moléculaire Hôpital Robert Debré, Paris, France., Schymick J; Santa Clara Valley Medical Center, San Jose, CA, USA., Gueguen P; Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France., Lefebvre M; UF de génétique clinique, Centre Hospitalier Régional d'Orléans, Orléans, France., Van Andel M; Santa Clara Valley Medical Center, San Jose, CA, USA., Juusola J; GeneDx, Gaithersburg, MD, USA., Antonarakis SE; Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland., Parker JA; Department of Neuroscience, Université de Montréal, CRCHUM, Montréal, QC, Canada., Burnett BG; Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Herbert School of Medicine, Bethesda, MD 20814, USA. Electronic address: barrington.burnett@usuhs.edu., Campeau PM; Department of Genetics, CHU Sainte-Justine, Montréal, QC, Canada. Electronic address: p.campeau@umontreal.ca.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2025 Jan 02; Vol. 112 (1), pp. 75-86. Date of Electronic Publication: 2024 Dec 24.
DOI:	10.1016/j.ajhg.2024.11.009
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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