Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly
Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly
复制标题
DOI：
10.1093/brain/awx203
复制
发表时间：
2017-10-01
期刊：
影响因子：
14.5
通讯作者：
Mirzaa, Ghayda M.
中科院分区：
文献类型：
--
作者：
Alcantara, Diana;Timms, Andrew E.;Mirzaa, Ghayda M.
磷脂酰肌醇-3-激酶（PI 3 K）-AKT-MTOR途径内的基因突变是脑过度生长（巨脑畸形）以及节段性皮质发育不良（例如半侧巨脑畸形、局灶性皮质发育不良和多小脑回症）的众所周知的原因。迄今为止，AKT 3基因突变已在少数脑畸形患者中报道。因此，我们对与该关键基因突变相关的临床和分子谱的理解是有限的，没有明确的基因型-表型相关性。我们试图进一步描绘这一谱，研究镶嵌水平，并确定AKT 3相关疾病的基因型-表型相关性。我们通过分子倒位探针和/或桑格测序对具有这些表型的个体进行AKT 3的靶向测序，以确定突变的镶嵌性的类型和水平。我们分析了突变阳性个体的所有临床和脑成像数据，包括一例神经病理学分析。我们对用患者突变工程化的AKT 3进行了离体激酶测定，并检查了普列克底物蛋白同源结构域定位突变的磷脂结合谱。我们确定了14个新的AKT 3突变的个人与几个表型依赖于突变的类型和镶嵌水平。我们全面的临床特征，以及对所有先前发表的患者的回顾，将AKT 3突变的个体大致分为两组：患有由常见p.E17K突变引起的高度不对称皮质发育不良的患者，以及具有表现出更多可变表型的体质性AKT 3突变的患者，包括双侧皮质畸形，多小脑回，脑室周围结节性异位和弥漫性巨脑畸形，无皮质发育不良。所有突变增加激酶活性，和pleckstrin同源结构域突变体表现出增强磷脂结合。总的来说，我们的研究表明，关键AKT 3基因的激活突变与广泛的脑受累相关，范围从主要由嵌合型AKT 3突变引起的局灶性或节段性脑畸形（如半侧巨脑畸形和多小脑回畸形）到由体质性AKT 3突变引起的弥漫性双侧皮质畸形、巨脑畸形和异位。我们还提供了第一个详细的神经病理学检查的极端巨脑畸形的儿童由于宪法AKT 3突变。据我们所知，这个孩子有着最大的儿科大脑尺寸。最后，我们的数据显示，体质AKT 3突变与巨脑畸形相关，有或没有自闭症，类似于PTEN相关疾病。认识到AKT 3突变的这种广泛的临床和分子谱对于提供受影响个体的早期诊断和适当管理是重要的，并且将促进使用PI 3 K-AKT通路抑制剂的未来人类临床试验的靶向设计。
Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p. E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.