Basel-Vanagaite, Lina, Dallapiccola, Bruno ORCID: 0000-0002-5031-1013, Ramirez-Solis, Ramiro ORCID: 0000-0003-4182-173X, Segref, Alexandra ORCID: 0000-0001-8095-4469, Thiele, Holger, Edwards, Andrew, Arends, Mark J., Miro, Xavier, White, Jacqueline K., Desir, Julie, Abramowicz, Marc ORCID: 0000-0003-0623-8768, Dentici, Maria Lisa, Lepri, Francesca, Hofmann, Kay, Har-Zahav, Adi, Ryder, Edward ORCID: 0000-0002-1799-9899, Karp, Natasha A., Estabel, Jeanne, Gerdin, Anna-Karin B., Podrini, Christine ORCID: 0000-0002-5391-3378, Ingham, Neil J., Altmueller, Janine, Nuernberg, Gudrun, Frommolt, Peter ORCID: 0000-0002-1966-8014, Abdelhak, Sonia ORCID: 0000-0001-8466-5525, Pasmanik-Chor, Metsada, Konen, Osnat, Kelley, Richard I., Shohat, Mordechai, Nuernberg, Peter, Flint, Jonathan, Steel, Karen P., Hoppe, Thorsten ORCID: 0000-0002-4734-9352, Kubisch, Christian ORCID: 0000-0003-4220-0978, Adams, David J. and Borck, Guntram (2012). Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome. Am. J. Hum. Genet., 91 (6). S. 998 - 1011. CAMBRIDGE: CELL PRESS. ISSN 0002-9297

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Basel-Vanagaite, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dallapiccola, BrunoUNSPECIFIEDorcid.org/0000-0002-5031-1013UNSPECIFIED
Ramirez-Solis, RamiroUNSPECIFIEDorcid.org/0000-0003-4182-173XUNSPECIFIED
Segref, AlexandraUNSPECIFIEDorcid.org/0000-0001-8095-4469UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edwards, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arends, Mark J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miro, XavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, Jacqueline K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Desir, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abramowicz, MarcUNSPECIFIEDorcid.org/0000-0003-0623-8768UNSPECIFIED
Dentici, Maria LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lepri, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, KayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Har-Zahav, AdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryder, EdwardUNSPECIFIEDorcid.org/0000-0002-1799-9899UNSPECIFIED
Karp, Natasha A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Estabel, JeanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerdin, Anna-Karin B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Podrini, ChristineUNSPECIFIEDorcid.org/0000-0002-5391-3378UNSPECIFIED
Ingham, Neil J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frommolt, PeterUNSPECIFIEDorcid.org/0000-0002-1966-8014UNSPECIFIED
Abdelhak, SoniaUNSPECIFIEDorcid.org/0000-0001-8466-5525UNSPECIFIED
Pasmanik-Chor, MetsadaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konen, OsnatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelley, Richard I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shohat, MordechaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flint, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steel, Karen P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ThorstenUNSPECIFIEDorcid.org/0000-0002-4734-9352UNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
Adams, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-476857
DOI: 10.1016/j.ajhg.2012.10.011
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 91
Number: 6
Page Range: S. 998 - 1011
Date: 2012
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 0002-9297
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MENTAL-RETARDATION; CAENORHABDITIS-ELEGANS; HECT-DOMAIN; OXIDATIVE STRESS; OHDO SYNDROME; GENOME-WIDE; GENE; EVOLUTION; E3; DEGRADATIONMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47685

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