De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly

Abstract

De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8–40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…A heterozygous deletion in 15q11.2-15q13.1 has been recently detected in the affected hemisphere in a single case of isolated HME [254]. More recently, de novo somatic mutations in PIK3CA, AKT3, and MTOR genes, encoding wellknown regulators of the mTOR signaling pathway, have been reported [255]. These mutations were identified in 8-40 % of sequenced alleles in various brain regions and have been shown to be associated with the expression of pS6 (marker of mTOR pathway activation; Fig.…”

“…1o). Thus, on the basis of these recent observations, HEM can be considered a genetically mosaic disease caused by overactivation in phosphatidylinositol 3-kinase-Akt3-mTOR signaling [255].…”

A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

“…10 Although we did not observe any significant change in the expression level of TSC2 or mTORC1 in skin fibroblast of the patient (Figure 2b), we cannot discard that the involvement of HERC1 in the mTOR pathway could be tissue-specific. Given that the megalencephaly phenotype is largely attributed to misregulation of the mTOR pathway, [3][4][5] it is likely that loss of HERC1 could impair this pathway early in brain development. Loss of HERC1 protein may also affect intracellular membrane trafficking.…”

“…2 The PI3K/AKT/mTOR (phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin) pathway controls key cellular responses such as cell growth and proliferation, survival, migration and metabolism; mutations in various core members and upstream regulators of this pathway are responsible for a large proportion of megalencephaly-related disorders. 2 De novo mutations in PIK3CA, AKT3 and MTOR are found in 30% of cases of hemimegalencephaly, 3 whereas de novo and postzygotic mutations in AKT3, PIK3R2, PIK3CA and CCND2 cause 74% of cases of megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus. 4,5 Moreover, mutations in other components of mTOR could manifest neurological symptoms without megalencephaly, such as ID, autism or epilepsy, as seen in patients with mutations in TSC1 (tuberous sclerosis complex 2), TSC2, PINK1 and DISC1.…”

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

“…11,12 Recently, variants in the PI3K-AKT pathway have been described to be associated with megalencephaly and overgrowth syndromes, such as MCAP and MPPH, 5-7 but also CLOVES (congenital lipomatous asymmetric overgrowth, epidermal naevi, skeletal and spinal anomalies) syndrome, 13,14 as well as hemimegalencephaly 15 and isolated macrodactyly. 16 Although both the RAS-MAPK pathway and the PI3K-AKT pathway are very complex and still only partly understood, interactions between these two signaling pathways are well known: most importantly but not exclusively, activated GTP-bound RAS not only induces the MAP-kinase cascade through association with RAF, but can also bind to PI3K to increase the generation of PIP3 out of PIP2, thereby activating several downstream effectors such as mTOR, BAX or FOXO-each directing to distinct cellular results leading to inhibition of apoptosis, initiation of translation, cell proliferation and loss of cell differentiation (see Figure 2).…”