TY - JOUR
T1 - Deficiency for the ubiquitin ligase ube3b in a blepharophimosis-ptosis- intellectual-disability syndrome
AU - Basel-Vanagaite, Lina
AU - Dallapiccola, Bruno
AU - Ramirez-Solis, Ramiro
AU - Segref, Alexandra
AU - Thiele, Holger
AU - Edwards, Andrew
AU - Arends, Mark J.
AU - Miró, Xavier
AU - White, Jacqueline K.
AU - Désir, Julie
AU - Abramowicz, Marc
AU - Dentici, Maria Lisa
AU - Lepri, Francesca
AU - Hofmann, Kay
AU - Har-Zahav, Adi
AU - Ryder, Edward
AU - Karp, Natasha A.
AU - Estabel, Jeanne
AU - Gerdin, Anna Karin B
AU - Podrini, Christine
AU - Ingham, Neil J.
AU - Altmüller, Janine
AU - Nürnberg, Gudrun
AU - Frommolt, Peter
AU - Abdelhak, Sonia
AU - Pasmanik-Chor, Metsada
AU - Konen, Osnat
AU - Kelley, Richard I.
AU - Shohat, Mordechai
AU - Nürnberg, Peter
AU - Flint, Jonathan
AU - Steel, Karen P.
AU - Hoppe, Thorsten
AU - Kubisch, Christian
AU - Adams, David J.
AU - Borck, Guntram
PY - 2012/12/7
Y1 - 2012/12/7
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2012.10.011
DO - 10.1016/j.ajhg.2012.10.011
M3 - Article
C2 - 23200864
AN - SCOPUS:84870882024
VL - 91
SP - 998
EP - 1010
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -