Editors' ChoiceNeurology

Patchwork people: A role for somatic mutations in brain malformations

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ec55
DOI: 10.1126/scitranslmed.aaa8319

Like a patchwork quilt, humans are mosaics—every cell does not have the same genetic material. Although the embryo starts with a single genome, errors can occur during the DNA replication that occurs when a cell divides. These errors are referred to as post-zygotic or somatic mutations and can be passed on to daughter cells in subsequent cell divisions. Whereas some errors that sneak past the DNA repair machinery—perhaps most—have no effect on the health of the cell or the individual, others may be detrimental. The clearest examples of disease-causing somatic mutations are those that cause cancer, but somatic mosaic mutations are increasingly recognized as an important mutation mechanism for genetic disease other than cancer. Focal cortical dysplasia (FCD), a developmental malformation that affects the cerebral cortex, usually appears as one or a few discrete lesions in the brain. Because of this, it has been hypothesized that FCD is caused by somatic mutation, and Lim and colleagues recently tested this hypothesis.

Because somatic mutations affect only some cells and tissues, they are often not detectable in the blood. Even in the tissue where the mutation arises, only a subset of cells may be affected, making these mutations difficult to detect. To detect somatic mutations in the affected brain tissue, Lim and colleagues performed deep whole-exome sequencing in samples from four individuals with FCD. For each individual, they sequenced DNA from blood and from brain, hypothesizing that somatic mutations that are present only in the brain tissue may be relevant to disease. Indeed, they detected and confirmed rare variants in the MTOR gene in brain tissue, but not blood, for two individuals. Based on this initial discovery, the authors performed deep sequencing of the MTOR gene in affected brain tissue from an additional 73 patients with FCD. They identified somatic mosaic MTOR mutations in 10 cases that were present in brain tissue at a level of <2% to 13%, but not in blood or saliva. Overall, 15% of cases carried a mosaic MTOR mutation.

Importantly, the mTOR pathway has been well studied, and rapamycin, an approved drug, is known to modify activity of the pathway. Lim and colleagues showed that, in mice, administration of rapamycin to mice who had mosaic MTOR mutations in the brain almost completely rescued seizures and led to an improvement of brain cell morphology. If this holds true in humans, rapamycin may become a new therapy for the intractable epilepsy that patients with FCD experience. This study provides important evidence for the role of somatic mutation in developmental malformations of the brain. Further exploration of the role of somatic mutation in other development abnormalities may yield similar exciting results.

J. S. Lim et al., Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat. Med. 10.1038/nm.3824 (2015). [Abstract]

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