Somatic activation of AKT3 causes hemispheric developmental brain malformations

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Hemimegalencephaly (HMG) is a congenital brain malformation characterized by an enlarged cerebral hemisphere.
• HMG often leads to intractable epilepsy requiring surgical intervention.

Purpose of the Study:

• To investigate the role of somatic mutations in the etiology of hemimegalencephaly.
• To identify specific genes and genetic alterations associated with HMG development.

Main Methods:

• Analysis of resected hemimegalencephaly brain tissue.
• Genetic analysis including chromosomal analysis (trisomy) and mutation screening of key developmental genes.
• Comparison of mutations in tissue versus patient blood samples.

Main Results:

• Two of eight HMG samples exhibited trisomy of chromosome 1q, which contains the AKT3 gene.
• A third HMG case presented with a specific activating mutation (p.E17K) in AKT3, absent in blood DNA.
• AKT3 was identified as the most abundant AKT paralog during brain neurogenesis, with abundant phosphorylated AKT in cortical progenitor cells.

Conclusions:

• Somatic mutations in AKT3 are a potential cause of hemimegalencephaly.
• Brain-specific genetic alterations, particularly in AKT3, may underlie complex neurodevelopmental disorders.
• These findings highlight the significance of somatic mutations in the pathogenesis of HMG.