Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly
Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly
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DOI：
10.1016/j.ajhg.2010.01.011
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发表时间：
2010-02-12
影响因子：
9.8
通讯作者：
D'Adamo, Patrizia
中科院分区：
文献类型：
--
作者：
Giannandrea, Maila;Bianchi, Veronica;D'Adamo, Patrizia
人类智力低下(MR)是一种常见的高度异质性的儿科疾病，约占总人口的3%；至少有21种S X连锁MR(XI，MR)的情况已被描述，并已在83个不同的基因上发现突变，编码具有多种功能的蛋白质，如染色质重塑、突触功能和细胞内转运。RAB家族的小GTP酶在细胞内囊泡运输中起着重要作用，已被证明参与了这一过程。我们在这里报告了两例男性患者小GTP酶RAB39B基因的突变。X家族中的一个突变(D-23)在起始密码子(c.21C>；A；p.Y7X)后引入了一个终止密码子。MRX72家族中的第二个突变改变了5‘剪接点(c.215+1G>；A)和正常剪接。这两个例子都没有产生蛋白质。在家族中，突变与疾病分离，在一些家庭成员中，智力障碍与自闭症谱系障碍、癫痫发作和巨头畸形有关。我们发现RAB39B是一种新的功能未知的RAB GTP酶，是一种定位于高尔基体室的神经元特异性蛋白。它的下调导致突触生长锥体的数量和形态的改变，突触前按钮的显著减少，提示RAB39B是突触形成和维持所必需的。我们的结果证明了RAB39B下调导致的发育和功能神经元的变化，并强调了囊泡运输在神经元发育和人类智能能力中的关键作用。
Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 21 S X-linked MR (XI,MR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, Such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5' splice site (c.215+1 G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.