title: Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome.
abstract: 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.
authors.affiliation: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel. basel@post.tau.ac.il
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Ramiro
authors.initials: R
authors.lastname: Ramirez-Solis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Segref
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Andrew
authors.initials: A
authors.lastname: Edwards
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: Xavier
authors.initials: X
authors.lastname: Miró
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.forename: Julie
authors.initials: J
authors.lastname: Désir
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.forename: Maria Lisa
authors.initials: ML
authors.lastname: Dentici
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.forename: Adi
authors.initials: A
authors.lastname: Har-Zahav
authors.forename: Edward
authors.initials: E
authors.lastname: Ryder
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Karp
authors.forename: Jeanne
authors.initials: J
authors.lastname: Estabel
authors.forename: Anna-Karin B
authors.initials: AK
authors.lastname: Gerdin
authors.forename: Christine
authors.initials: C
authors.lastname: Podrini
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ingham
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.forename: Sonia
authors.initials: S
authors.lastname: Abdelhak
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.forename: Osnat
authors.initials: O
authors.lastname: Konen
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hoppe
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016569:Blepharophimosis / Q000175:diagnosis / Q000235:genetics*; D001763:Blepharoptosis / Q000175:diagnosis / Q000235:genetics*; D001921:Brain / Q000473:pathology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002490:Central Nervous System; D002648:Child; D002675:Child, Preschool; D059472:Exome; D019066:Facies; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D018384:Oxidative Stress; D013577:Syndrome; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*
chemical_list: C482647:UBE3B protein, human; D044767:Ubiquitin-Protein Ligases