Association of<i>MTOR</i>Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism

Mirzaa, Ghayda; Campbell, Catarina D.; Solovieff, Nadia; Goold, Carleton P.; Jansen, Laura A.; Menon, Suchithra; Timms, Andrew E.; Conti, Valerio; Biag, Jonathan; Olds, Carissa; Boyle, Evan A.; Collins, Sarah; Ishak, Gisele E.; Poliachik, Sandra L.; Girisha, Katta M.; Yeung, Kit San; Chung, Brian Hon Yin; Rahikkala, Elisa; Gunter, Sonya A.; McDaniel, Sharon S.; Macmurdo, Colleen; Bernstein, Jonathan A.; Martin, Beth; Leary, Rebecca J.; Mahan, Scott; Liu, Shanming; Weaver, Molly; Dorschner, Michael O.; Jhangiani, Shalini N.; Muzny, Donna M.; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.; Shendure, Jay; Saneto, Russell P.; Novotny, Edward J.; Wilson, Christopher J.; Sellers, William R.; Morrissey, Michael; Hevner, Robert F.; Ojemann, Jeffrey G.; Guerrini, Renzo; Murphy, Leon O.; Winckler, Wendy; Dobyns, William B.

doi:10.1001/jamaneurol.2016.0363

Cited by 237 publications

(253 citation statements)

References 33 publications

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“…The recurrent variants p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro were considered to be pathogenic as they have already been linked to FCD. 15,16,18 These mosaic variants were detected across several studies using distinct technologies and sequencing platforms, excluding that they might correspond to sequencing artifacts.…”

Section: Resultsmentioning

confidence: 97%

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

et al. 2016

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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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Section: Resultsmentioning

confidence: 97%

“…Our results are consistent with previous studies reporting individuals with megalencephaly and seizures due to germline activating mutations in MTOR . 18–22 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…For example, for patients carrying the p.S2215Y/F mutation in MTOR , fourteen patients with FCD, mostly FCD IIb, carry the mutation in 2.1–18.6% of cells, and two patients with HME carry the mutation in 14.2–41.2% of cells (Lim et al, 2015; Mirzaa et al, 2016; Moller et al, 2016; Nakashima et al, 2015). In fact, analyzing all of the somatic mutations reported in the literature associated with FCD and HME reveals that the average AAF for somatic mutations associated with FCD, 3.76 ± 2.89%, is significantly lower than the average AAF for somatic mutations associated with HME, 16.35 ± 9.26% (p<0.0001, two-tailed t test) (Table S6).…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

et al. 2017

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Summary Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27/66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA, and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional PIK3CA activation in mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

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“…Mutations in PIK3R2, PIK3CA, AKT3, CCND2 and MTOR, involved in the mTOR pathway, have also been associated with PMG [243][244][245][246][247][248][249]. Mutations in these genes also cause hemimegalencephaly (HMG), which is a developmental disorder characterized by the enlargement and malformation of a cerebral hemisphere [250].…”

Section: 25a Polymicrogyria (Pmg)mentioning

confidence: 99%

Genetics and mechanisms leading to human cortical malformations

Romero

Bahi‐Buisson

Francis

2018

Seminars in Cell & Developmental Biology

109

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Association ofMTORMutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism

Cited by 237 publications

References 33 publications

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

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

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Genetics and mechanisms leading to human cortical malformations

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