Somatic Mutations in TSC1 and TSC2 cause focal cortical dysplasia.
Low-level of somatic mutations in TSC1 and TSC2 were found in brain tissues from patients with focal cortical dysplasia (FCD), which is a major cause of intractable childhood epilepsy. Using CRISPR-Cas9 genome editing technology, we showed that identified mutations indeed caused intractable epilepsy in genome-edited mouse models. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain
Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15-25% of FCD type II (FCDII) characterized by cortical dyslamination and dysmorphic neurons.1,2 However, the genetic etiologies of individuals with FCDII who lack the MTOR mutation remain unclear. Here, we performed deep hybrid-capture and amplicon sequencing (100 – 20,012×, read depth) of 5 important mTOR pathway genes, PIK3CA, PIK3R2, AKT3, TSC1, and TSC2, using paired brain and saliva samples from 40 individuals with FCDII who were negative for MTOR mutations. Researchers at KAIST found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 and TSC2, TSC1 c.64C>T (p.Arg22Trp), TSC1 c.610C>T (p.Arg204Cys), and TSC2 c.4639G>A (p.Val1547Ile); these results were reproducible using two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1/TSC2 complex. Furthermore, in utero CRISPR/Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.
Lim JS et al, Am. J. Hum. Genet. 2017 Mar 2;100(3):454-472.
Including website for more information : http://www.cell.com/ajhg/abstract/S0002-9297(17)30031-9
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