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. 2016 Oct 31;2(6):e118.
doi: 10.1212/NXG.0000000000000118. eCollection 2016 Dec.

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

Rikke S Møller  1 , Sarah Weckhuysen  1 , Mathilde Chipaux  1 , Elise Marsan  1 , Valerie Taly  1 , E Martina Bebin  1 , Susan M Hiatt  1 , Jeremy W Prokop  1 , Kevin M Bowling  1 , Davide Mei  1 , Valerio Conti  1 , Pierre de la Grange  1 , Sarah Ferrand-Sorbets  1 , Georg Dorfmüller  1 , Virginie Lambrecq  1 , Line H G Larsen  1 , Eric Leguern  1 , Renzo Guerrini  1 , Guido Rubboli  1 , Gregory M Cooper  1 , Stéphanie Baulac  1
Affiliations

Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

Rikke S Møller et al. Neurol Genet. .

Abstract

Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies.

Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR.

Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother-daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy.

Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly.

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Figures

Figure 1
Figure 1. Workflow of the study
FCD = focal cortical dysplasia; MCD = malformation of cortical development.
Figure 2
Figure 2. Domain/structural organization of mTOR protein with the positions of the mutations indicated
In black: germline mutations; in blue: somatic mutations; in bold: recurrent mutations. Structural domains are composed of HEAT (huntingtin, elongation factor 3, protein phosphatase 2A, and TOR1) repeats; FAT (FRAP, ATM, TRRAP) domain; FRB (FKBP12-rapamycin binding) domain; kinase domain; and FATC (FAT C-terminal) domain.
Figure 3
Figure 3. Imaging, histopathology, and mTORC1 pathway activity of patients with focal cortical dysplasia
(A) MRI with residual lesion after the first and before the second operation because of incomplete initial resection (preoperative MRI unavailable). (D, G, J, M, P) Preoperative brain MRI; arrows indicate the dysplastic lesion. (B, E, H, K, N) Hematoxylin and eosin (H&E) staining; blue arrows indicate balloon cells, and black arrows indicate dysmorphic neurons. (C, F, I, L, O) Ser235/236 phosphorylated S6 (pS6 235/6) immunostaining counterstained with hematoxylin, showing labeling of dysmorphic neurons. Brain tissue of patient 6 was not available for further immunostaining. Scale bar: 20 μm. FCD = focal cortical dysplasia.
Figure 4
Figure 4. Unspecific MRI findings and facial dysmorphy in patients with germline variants
(A and B) T2-weighted 3T MRI images of patient 9. Axial image shows dilated lateral ventricles (A), and sagittal image shows thinning of the posterior half of the corpus callosum (B). (C and D) Pictures of identical twin pair 10a and 10b show prominent forehead, low-set ears, gingival hyperplasia, frontal bossing, and micrognathia (MRIs not available for publication). (E–G) Fluid-attenuated inversion recovery (FLAIR) weighted 1.5T MRIs of the brain, and the picture of patient 12. Axial and coronal images shows mild ventricular dilatation. Picture shows macrocephaly with frontal bossing, broad depressed nasal root, and coarse facial features.
See this image and copyright information in PMC

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