gs.washington.edu). Published estimates suggest a somatic mutation frequency on the order of 10−9 per cell division ( Lynch, 2010b); published mutation rates from exome sequencing in humans, coupled with extrapolation of somatic mutation rates in mouse, suggest a <1 × 10−7 chance that the specific AKT3 c.49G→A mutation would occur by chance ( Awadalla et al., 2010 and Lynch, 2010a). Somatic mutations in AKT3, which encodes the serine-threonine kinase protein kinase B-gamma, have been reported in cancers, including

a p.G171R substitution mutation in a glioma ( Bamford et al., 2004). The AKT3 c.49G→A E17K mutation itself has been observed in melanoma and lung cancer, and melanoma cell lines overexpressing this exact missense mutation have been demonstrated to show increased AKT phosphorylation ( Davies et al., 2008 and Do et al., 2010).

Most remarkably though, the somatic AKT3 mutation we report is precisely click here paralogous to the recurrent E17K mutations in AKT1 associated with Proteus syndrome and recurrent E17K mutations in AKT2 associated with hypoglycemia and left-sided overgrowth, each also with varying degrees of mosaicism ( Hussain et al., 2011 and Lindhurst et al., 2011). Interestingly, despite prior reports of Proteus-associated HMG ( Griffiths et al., 1994), no brain malformations are reported in the patients with AKT1 and AKT2 mutations, consistent with the observation in mice that AKT3 may be the predominant functional member of the AKT family in the human brain ( Easton et al., 2005). AKT3 expression BGB324 concentration in the human fetal brain is higher than AKT3 expression in any other tissue sampled ( Wu et al., 2009), suggesting that its primary role is in brain development. In contrast, AKT1 and AKT2 show levels of fetal brain expression comparable to or lower than those whatever seen in other tissues ( Wu et al., 2009).

We compared the expression levels of AKT1, AKT2, and AKT3 by RNaseq analysis of the perisylvian cortex of the human brain at 9 weeks’ gestation, during active neurogenesis, and found that AKT3 is expressed at higher levels than AKT1 and AKT2 (normalized read depth, reads per kilobase-exon per million mapped reads: AKT1 = 51.90, AKT2 = 18.50, AKT3 = 90.52). Examination of published data sets reveals that AKT3 is expressed at a higher level than AKT1, and both are expressed at higher levels than AKT2, starting at 8 weeks and for the duration of human embryonic cortical development ( Kang et al., 2011). To determine the cell types in the brain that would likely be affected by activation of AKT3, we performed immunohistochemistry in sections of mouse brain by using an antiserum that recognizes all three phosphorylated forms of AKT (P-Akt). We observed widespread P-Akt localization in the developing cortex, with notable enrichment in apical progenitor cells in the ventricular zone.