Somatic Mutations in the <scp><i>MTOR</i></scp> gene cause focal cortical dysplasia type <scp>II</scp>b

Nakashima, Mitsuko; Saitsu, Hirotomo; Takei, Nobuyuki; Tohyama, Jun; Kato, Mitsuhiro; Kitaura, Hiroki; Shiina, Masaaki; Shirozu, Hiroshi; Masuda, Hiroshi; Watanabe, Keisuke; Ohba, Chihiro; Tsurusaki, Yoshinori; Miyake, Noriko; Zheng, Yingjun; Sato, Tatsuhiro; Takebayashi, Hirohide; Ogata, Kazuhiro; Kameyama, Shigeki; Kakita, Akiyoshi; Matsumoto, Naomichi

doi:10.1002/ana.24444

Cited by 178 publications

(188 citation statements)

References 42 publications

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“…TSC is naturally a mutation of either TSC1 or TSC2 in 85%, whereas more than half of those cases show also mosaicism 43. Recent studies found somatic (mosaic) mutations affecting the mTOR signaling also in focal lesions of FCD II patients 4, 8, 21, 25, 32, 36. This is a very important aspect since as far as we know, in FCD, the mutations are localized and show profound variability in cellular expression.…”

Section: Discussionmentioning

confidence: 99%

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

et al. 2017

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Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug‐resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy‐associated pathologies show myelin deficiencies in seizure‐related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter‐pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects. We analyzed epilepsy surgery specimens of FCD IIB (n = 22), TSC (n = 8), and other malformations of cortical development MCD (n = 12), and compared them to autopsy and biopsy cases (n = 15). The entire lesional pathology was assessed using digital immunohistochemistry, immunofluorescence and western blotting for oligodendroglial lineage, myelin and mTOR markers, and findings were correlated to clinical parameters. White matter pathology with depleted myelin and oligodendroglia were found in 50% of FCD IIB and 62% of TSC cases. Other MCDs had either a normal content or even showed reactive oligodendrolial hyperplasia. Furthermore, myelin deficiency was associated with increased mTOR expression and the lower amount of oligodendroglia was linked with their precursor cells (PDGFRa). The relative duration of epilepsy (normalized to age) also correlated positively to mTOR activation and negatively to myelination. Decreased content of oligodendroglia and missing precursor cells indicated insufficient oligodendroglial development, probably mediated by mTOR, which may ultimately lead to severe myelin loss. In terms of disease management, an early and targeted treatment could restore normal myelin development and, therefore, alter seizure threshold and improve cognitive outcome.

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Section: Discussionmentioning

confidence: 99%

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

et al. 2017

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“…Because the molecular genetic etiology of FCD has remained elusive, genetically validated drug targets in individuals with FCD are poorly understood. Recently, we and another group have shown that somatic activating mutations in MTOR (MIM: 601231) in the brain account for 15%-25% of individuals with FCDII 8,9 and that inhibition of hyperactivated mTOR kinase reverses epilepsy and the development of cytomegalic neurons. 8 However, the genetic causes underlying the development of FCDII in individuals who are negative for MTOR mutations remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Lim

Gopalappa

Kim

et al. 2017

The American Journal of Human Genetics

167

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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. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 1003-20,0123) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on 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.

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“…Recently, somatic mutations have been associated with hyperactivation of the mTOR pathway in FCD type II 9, 10, 11, 12. In our cohort, 28.5% of the tested patients harbored brain somatic mutations in genes belonging to the mTOR pathway.…”

Section: Discussionmentioning

confidence: 74%

“…The somatic missense mutations identified in MTOR and TSC2 are probably deleterious, because they are classified as damaging, by 2 (Polyphen2 and SNPs&GO) of the 3 mutation prediction programs used. In addition, rs1057519779 in MTOR has been previously reported in patients with FCD type II 21. Variation identified in AKT1 is a glutamic acid in‐frame deletion.…”

Section: Resultsmentioning

confidence: 88%

“…Although recent literature points to the involvement of the mTOR pathway in FCD type II,9, 10, 11, 12 the exact molecular mechanism leading to this type of cortical malformation, especially to the presence of aberrant cells, remains undetermined 13, 14. As the development of the cerebral cortex is a sophisticated process, requiring the fine‐tuning of gene expression, we decided to analyze the expression of microRNAs as a shortcut to gain a better understanding of the mechanisms involved in the pathogenesis of FCD type II.…”

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confidence: 99%

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Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

Avansini

Torres

Vieira

et al. 2018

Annals of Neurology

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ObjectiveFocal cortical dysplasias (FCDs) are an important cause of drug‐resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II.MethodsWe used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study.Resultshsa‐let‐7f (p = 0.039), hsa‐miR‐31 (p = 0.0078), and hsa‐miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2‐target, is upregulated (p < 0.001). In vitro experiments showed that hsa‐miR‐34a downregulates NEUROG2 by binding to its 5′‐untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway.InterpretationOur findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa‐miR‐34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623–635

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Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb

Abstract: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.

Cited by 178 publications

References 42 publications

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

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