Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy
Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy
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DOI：
10.1016/j.ajhg.2016.01.016
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发表时间：
2016-04-07
影响因子：
9.8
通讯作者：
Doherty, Dan
中科院分区：
文献类型：
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作者：
Chong, Jessica X.;Caputo, Viviana;Doherty, Dan
婴儿脑病是一组临床和生物学异质性疾病，其遗传基础在很大程度上仍然未知。在这里，我们报告了一个以深度发育障碍、严重张力低下、癫痫发作、需要机械通气的呼吸驱动减弱、脑萎缩、胼胝体发育不良、小脑蚓发育不全和面部畸形为特征的综合征新生儿脑病。通过全外显子组测序，在四个不相关的家族中独立鉴定了TBCK（含TBCK结构域激酶）双等位基因失活突变是导致这种情况的原因。在最近发布的基于网络的工具（Geno(2)MP）中，表型谱和WES数据的共享促进了这些家族的匹配，该工具将表型信息与具有孟德尔特征的家族中的罕见变异联系起来。TBCK是一种推定的gtase激活蛋白（GAP），用于Rab家族的小gtase，并已被证明可以控制细胞生长和增殖，肌动蛋白-细胞骨架动力学和mTOR信号传导。三个突变中的两个(c.376C>T] p。[a] [b] [j]。Lys455*])预计会截断该蛋白，并且在一个受影响个体的原代成纤维细胞中证实了主要TBCK亚型的缺失。第三个突变是c.1532G>A (p.a g511his)，改变了TBC1结构域内的一个保守残基。结构分析表明Arg511是raba -GAP功能的必需残基，并在硅同源性模型中预测相应突变体的GAP功能受损。这些结果表明，Rab-GAP活性的丧失是疾病的潜在机制。与其他与局灶性或全脑过度生长相关的mTOR信号失调引起的疾病相反，TBCK功能受损导致脑容量的进行性损失。
Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno(2)MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126*] and c.1363A>T [p.Lys455*]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.