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, 19 Richard I. Kelley 20 Mordechai Shohat 2, 4, 3 Peter Nuernberg 21, 16, 9 Jonathan Flint 22 Karen P. Steel 6 Thorsten Hoppe 16, 23 Christian Kubisch 24 David J. Adams 6 Guntram Borck 24
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.
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American Journal of Human Genetics, Elsevier (Cell Press), 2012, 91 (6), pp.998-1010. 〈10.1016/j.ajhg.2012.10.011〉
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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, Elsevier (Cell Press), 2012, 91 (6), pp.998-1010. 〈10.1016/j.ajhg.2012.10.011〉. 〈pasteur-01375146〉

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