Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome
Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome
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DOI：
10.1016/j.ajhg.2012.10.011
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发表时间：
2012-12-07
影响因子：
9.8
通讯作者：
Borck, Guntram
中科院分区：
文献类型：
--
作者：
Basel-Vanagaite, Lina;Dallapiccola, Bruno;Borck, Guntram
泛素化在神经发育中起着至关重要的作用，例如Angelman综合征，其由编码泛素连接酶的UBE 3A基因的遗传改变引起。虽然UBE 3A的功能已被广泛研究，但对其亚型UBE 3B知之甚少。通过使用外显子组和毛细管测序，我们在这里确定双等位基因UBE 3B突变的4例患者来自三个不相关的家庭，提出了常染色体隐性眼睑裂-上睑下垂-智力残疾综合征的特点是发育迟缓，生长迟缓，头围小，面部畸形，和低胆固醇水平。UBE 3B编码一种未表征的E3泛素连接酶。鉴定的UBE 3B变体包括一个移码和两个剪接位点突变以及影响高度保守的HECT结构域的错义取代。小鼠Ube 3b的破坏导致生存能力降低，并重演了人类疾病的关键方面，例如体重和大脑大小减少以及胆固醇合成下调。我们建立了可能的秀丽隐杆线虫直系同源物UBE 3B，oxi-1，在体内的泛素/蛋白酶体系统的功能，特别是在氧化应激条件下所需的。我们的数据揭示了UBE 3B缺陷的多效性效应，并加强了泛素化在哺乳动物神经元发育和功能中的生理重要性。
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.