Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Abstract

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.

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

“…Common variants identified in the ICV+HC combined metaanalysis also include intronic variation in AKT3 (rs2168812) and CCND2 (rs3217870), which are related through the phosphatidylinositol 3-kinase (PI3K-AKT) pathway [44]. Disruption of PI3K-AKT pathway components causes megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome and a spectrum of related megalencephaly syndromes [45,46]. This supports previous in silico pathway analysis, which nominated PI3K-AKT as candidate pathway for intracranial volume [12].…”

A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci

“…Recently, L3MBTL3 was reported to be associated with insulin resistance and affect adipocyte differentiation (Lotta et al 2017). AKT3 encodes the AKT serine/threonine kinase 3, and mutations in this gene can cause an overgrowth of the brain, called megalencephaly (Alcantara et al 2017). AKT3 protein is part of the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway and has been shown to be stimulated by insulin (Brozinick et al 2003;Medina et al 2005;Xie et al 2016).…”

Hippocampal granule cell dispersion: a non-specific finding in pediatric patients with no history of seizures

“…The first is marked by broad, less dense GC layer, often with poorly defined borders with the molecular layer; we refer to this as "disaggregated" GCD (DA). The second subtype has a bilaminar appearance of the GC layer with cell-sparse zone in the center [3,30]; we refer to this as "tram-track" GCD (TT). By studying the H&E-stained hippocampal specimens from patients with seizure history (n = 21), we categorized the morphology of GC layer for each as compact (10/21; 47.62%, subtype equivalent to non-GCP of [8]), only DA (5/21; 23.81%), only TT (1/ 21; 4.76%), or both DA and TT (5/21; 23.81%) ( Table 1).…”

“…GCD has been reported commonly in the dentate gyrus (DG) of seizure patients and considered a hallmark of chronic epilepsy, especially TLE [3,21,30,35,55,56]. GCD was also reported to be pronounced in sudden unexplained deaths in infants [26,31].…”