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

Lina Basel-Vanagaite (1, 2, 3, 4) , Bruno Dallapiccola (5) , Ramiro Ramirez-Solis (6) , Alexandra Segref (7, 8) , Holger Thiele (9) , Andrew Edwards (10) , Mark J. Arends (11) , Xavier Miro (12) , Jacqueline K. White (6) , Julie Desir (13) , Marc Abramowicz (13, 14) , Maria Lisa Dentici (5) , Francesca Lepri (5) , Kay Hofmann (15, 8) , Adi Har-Zahav (4) , Edward Ryder (6) , Natasha A. Karp (6) , Jeanne Estabel (6) , Anna-Karin B. Gerdin (6) , Christine Podrini (6, 3) , Neil J. Ingham (6) , Janine Altmueller (9) , Gudrun Nuernberg (9) , Peter Frommolt (9, 16) , Sonia Abdelhak (17, 2) , Metsada Pasmanik-Chor (18) , Osnat Konen (4, 1) , Richard I. Kelley (19) , Mordechai Shohat (2, 4, 3) , Peter Nuernberg (20, 16, 9) , Jonathan Flint (10) , Karen P. Steel (6) , Thorsten Hoppe (16, 21) , Christian Kubisch (22) , David J. Adams (6) , Guntram Borck (22)

1 Schneider Children’s Medical Center of Israel [Petah Tikva]
2 Raphael Recanati Genetics Institute [Petah Tikva]
3 Felsenstein Medical Research Center [Petah Tikva]
4 Sackler Faculty of Medicine
5 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
6 The Wellcome Trust Sanger Institute [Cambridge]
7 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)
8 Institute for Genetics [Cologne]
9 Cologne Center for Genomics
10 The Wellcome Trust Centre for Human Genetics [Oxford]
11 Addenbrooke's Hospital
12 Universität Bonn = University of Bonn
13 Department of Medical Genetics [Bruxelles]
14 IRIBHM - Instiitut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire
15 Bioinformatics Group [Bergisch-Gladbach]
16 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)
17 LR11IPT05 - Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory
18 G.S.W. Faculty of Life Sciences [Tel Aviv]
19 Kennedy Krieger Institute [Baltimore]
20 CMMC - Center for Molecular Medicine [Cologne]
21 Institute for Genetics
22 Universität Ulm - Ulm University [Ulm, Allemagne]

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.

Domaines: Sciences du Vivant [q-bio]

Lina Basel-Vanagaite, Bruno Dallapiccola, Ramiro Ramirez-Solis, Alexandra Segref, Holger Thiele, et al.. Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome. American Journal of Human Genetics, 2012, 91 (6), pp.998-1010. ⟨10.1016/j.ajhg.2012.10.011⟩. ⟨pasteur-01375146⟩