Somatic mosaicism of the PI3K-AKT-MTOR pathway is associated with hemimegalencephaly in fetal brains
Kyoko Itoh1, Ritsuko Pooh2,3, Osamu Shimokawa3
1Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
Abstract:
It is known that somatic activation of PI3K-AKT-MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated-S6 ribosomal protein (P-RPS6) (Ser240/244) were observed in the polymicrogyria-like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K-AKT-MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K-AKT-MTOR pathway.
Insights
Somatic mosaic mutations in PIK3CA and AKT1 cause fetal hemimegalencephaly. These mutations disrupt neural stem cell proliferation, differentiation, and migration, leading to abnormal brain development.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Somatic activation of the PI3K-AKT-MTOR pathway is linked to cortical malformations like hemimegalencephaly.
- Fetal cases of PI3K-AKT-MTOR-related brain malformations are rarely reported.
Observation:
- Two fetal cases of hemimegalencephaly were identified, one with mosaic PIK3CA mutations and the other with mosaic AKT1 mutations.
- Brains exhibited polymicrogyria and heterotopia, indicative of abnormal neural stem/progenitor cell proliferation, differentiation, and neuroblast migration.
- Immunoreactivity for phosphorylated-S6 ribosomal protein (P-RPS6) was observed in various brain regions, confirming PI3K-AKT-MTOR pathway activation.
Findings:
- Mosaic mutations in PIK3CA and AKT1 are associated with severe fetal brain malformations.
- The PI3K-AKT-MTOR pathway is implicated in the pathogenesis of these developmental disorders.
- Abnormal neural cell behavior, including proliferation and migration, underlies the observed cortical malformations.
Implications:
- These findings enhance understanding of the mechanisms behind somatic mosaicism in brain development.
- This research provides insights into the role of the PI3K-AKT-MTOR pathway in fetal cortical development.
- Further investigation into these pathways may reveal therapeutic targets for brain malformation disorders.
