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Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly
Brain ( IF 14.5 ) Pub Date : 2017-09-07 , DOI: 10.1093/brain/awx203
Diana Alcantara 1 , Andrew E Timms 2 , Karen Gripp 3, 4 , Laura Baker 3, 4 , Kaylee Park 5 , Sarah Collins 5 , Chi Cheng 5 , Fiona Stewart 6 , Sarju G Mehta 7 , Anand Saggar 8 , László Sztriha 9 , Melinda Zombor 9 , Oana Caluseriu 10 , Ronit Mesterman 11 , Margot I Van Allen 12, 13 , Adeline Jacquinet 14 , Sofia Ygberg 15 , Jonathan A Bernstein 16 , Aaron M Wenger 16 , Harendra Guturu 16 , Gill Bejerano 16, 17, 18 , Natalia Gomez-Ospina 16 , Anna Lehman 12 , Enrico Alfei 19 , Chiara Pantaleoni 19 , Valerio Conti 20 , Renzo Guerrini 20, 21 , Ute Moog 22 , John M Graham Jr. 23 , Robert Hevner 5, 24 , William B Dobyns 5, 25 , Mark O’Driscoll 1 , Ghayda M Mirzaa 5, 25
Affiliation  

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.

中文翻译:

AKT3突变与广泛的发育障碍有关,包括极端巨脑

磷脂酰肌醇3-激酶(PI3K)-AKT-MTOR途径内的基因突变是众所周知的导致大脑过度生长(巨头畸形)以及部分皮质发育不良(例如半巨头畸形,局灶性皮质发育异常和多菌核)的原因。迄今为止,已经报道了少数患有脑畸形的个体的AKT3基因突变。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该谱图,研究镶嵌水平,并鉴定与AKT3相关的疾病的基因型与表型的相关性。我们进行了AKT3的靶向测序通过分子倒置探针和/或Sanger测序对具有这些表型的个体进行检测,以确定突变的镶嵌类型和水平。我们在一个实例中分析了突变阳性个体的所有临床和脑成像数据,包括神经病理学分析。我们对用患者突变改造的AKT3进行了离体激酶测定,并检查了pleckstrin同源域定位突变的磷脂结合特性。我们确定了14个具有AKT3突变的新个体,这些个体具有取决于突变类型和镶嵌水平的几种表型。我们全面的临床特征以及对所有先前发表过的患者的回顾,广泛地将AKT3个体隔离开来。突变分为两组:由常见的p.E17K突变引起的高度不对称皮层发育不良的患者,以及具有AKT3突变的患者表现出更多可变的表型,包括双侧皮质畸形,多微神经节,脑室结节性异位症和无皮质发育不良的弥漫性大头畸形。所有突变均增加激酶活性,而pleckstrin同源结构域突变体显示出增强的磷脂结合。总体而言,我们的研究表明,关键性AKT3基因的激活突变与广泛的脑部受累相关,范围广泛,主要是由于镶嵌AKT3引起的局灶性或节段性脑畸形(例如半大脑畸形和多小脑小脑畸形)。突变,以弥散双体皮质畸形,巨头畸形和异位症,这是由于AKT3突变引起的。我们还提供了由于体质性AKT3突变而导致患有极端巨脑症的儿童的首次详细神经病理学检查。据我们所知,这个孩子有最大的儿科大脑记录之一。最后,我们的数据表明,与PTEN相关的疾病相似,体质性AKT3突变与巨脑畸形(伴有或不伴自闭症)相关。认识到AKT3的广泛临床和分子谱 突变对于提供受影响的个体的早期诊断和适当的管理很重要,并且将有助于使用PI3K-AKT途径抑制剂进行有针对性的未来人类临床试验设计。
更新日期:2017-09-07
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