Somatic mutation, such as by the mobilization of retrotransposons during neurogenesis (Muotri and Gage, 2006 and Singer et al., 2010) or by copy number variation in neurons (Rehen et al.,
2005), has been proposed as a source of normal neuronal diversity. However, neurogenetic disease has also been attributed to somatic, postzygotic mutations in TSC2, NF1, and DCX that are detectable in some, but not all, blood cells and appear to be present in some, but not all, brain cells ( Gleeson et al., 2000, Messiaen et al., 2011, Qin et al., 2010 and Vogt et al., 2011). On the other hand, it has been essentially impossible to study potential roles of mutations that are limited to brain cells, because such mutations are by definition absent from blood and VX-770 in vivo other tissues typically available for genetic study. Such somatic mutations could conceivably play important roles in complex neurogenetic disorders, such as epilepsy, intellectual disability, and psychiatric disease, for which prominent selleck inhibitor roles for de novo mutations have been well documented ( Awadalla et al., 2010,
Poduri and Lowenstein, 2011 and Ropers, 2008). Here we describe a highly epileptic disorder, hemimegalencephaly (HMG, literally, enlargement of one brain hemisphere), as a model to characterize the role of somatic mutation in the developing brain. HMG is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere (Flores-Sarnat et al., 2003). The clinical presentation typically includes intellectual disability and severe, intractable epilepsy, often necessitating surgical removal or disconnection of the abnormal hemisphere for seizure control (Gowda et al., 2010). L-NAME HCl Although no specific genetic causes have been identified for isolated HMG, HMG has been reported in association with
Proteus syndrome (Griffiths et al., 1994)—another multisystem overgrowth disorder that has recently been associated with somatic activating mutations in the gene AKT1 ( Lindhurst et al., 2011)—as well as other rare neurocutaneous syndromes ( Mochida et al., 2013). There are also rare reports of HMG associated with tuberous sclerosis complex (TSC) ( Cartwright et al., 2005), a syndrome in which multiple organ systems display disordered and sometimes cancerous growths. The striking asymmetry of the brain in individuals with HMG has long suggested that HMG reflects spontaneous, somatic, clonal mutation limited to the brain, analogous to cancer but without cellular transformation and ongoing proliferation. We hypothesized that the somatic mutations causing HMG might be essentially restricted to the brain and detectable by direct study of affected brain tissue.