Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome

Autor: Basel-Vanagaite, L, Dallapiccola, B, Ramirez-Solis, R, Segref, A, Thiele, H, Edwards, A, Arends, MJ, Miró, X, White, JK, Désir, J, Abramowicz, M, Dentici, ML, Lepri, F, Hofmann, K, Har-Zahav, A, Ryder, E, Karp, NA, Estabel, J, Gerdin, AKB, Podrini, C, Ingham, NJ, Altmüller, J, Nürnberg, G, Frommolt, P, Abdelhak, S, Pasmanik-Chor, M, Konen, O, Kelley, RI, Shohat, M, Nürnberg, P, Flint, J, Steel, KP, Hoppe, T, Kubisch, C, Adams, DJ, Borck, G
Přispěvatelé: Schneider Children’s Medical Center of Israel [Petah Tikva], Raphael Recanati Genetics Institute [Petah Tikva], Rabin Medical Center, Felsenstein Medical Research Center [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], The Wellcome Trust Sanger Institute [Cambridge], Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Institute for Genetics [Cologne], Cologne Center for Genomics, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Addenbrooke's Hospital, Cambridge University NHS Trust, University of Bonn, Department of Medical Genetics [Bruxelles], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Instiitut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles (ULB), Bioinformatics Group [Bergisch-Gladbach], Miltenyi Biotec GmbFl, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), G.S.W. Faculty of Life Sciences [Tel Aviv], Schneider Children's Medical Center of Israel, Kennedy Krieger Institute [Baltimore], Center for Molecular Medicine [Cologne] (CMMC), Institute for Genetics, Universität Ulm - Ulm University [Ulm, Allemagne]
Rok vydání: 2012
Předmět:
Zdroj: American journal of human genetics, 91 (6
American Journal of Human Genetics
American Journal of Human Genetics, Elsevier (Cell Press), 2012, 91 (6), pp.998-1010. ⟨10.1016/j.ajhg.2012.10.011⟩
ISSN: 0002-9297
1537-6605
Popis: Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis- ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals. © 2012 The American Society of Human Genetics.
SCOPUS: ar.j
info:eu-repo/semantics/published
Databáze: OpenAIRE
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