Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

Hanai, Sae; Sukigara, Sayuri; Dai, Hongmei; Owa, Tomoo; Horike, Shin-ichi; Otsuki, Taisuke; Saito, Takashi; Nakagawa, Eiji; Ikegaya, Naoki; Kaido, Toshimi; Sato, Noriko; Takahashi, Akio; Sugai, Kenji; Saito, Yuko; Sasaki, Masayuki; Hoshino, Mikio; Goto, Yu‐ichi; Koizumi, Schuichi; Itoh, Masayuki

doi:10.1016/j.ajpath.2017.01.015

Cited by 25 publications

(24 citation statements)

References 40 publications

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“…These findings are reminiscent to what has been observed for mutations of MTOR itself. Constitutive activation of mTORC1 causes enlarged neuronal somata in rodent neurons, and focal cortical expression of MTOR mutations has been reported to disrupt neuronal migration and to cause spontaneous seizures by in utero electroporation in mice 40 , 41 , 53 . This observation shows that activating mutations in different genes of the mTORC1 branch of the mTOR pathway act through convergent mechanisms and have similar phenotypic outcomes.…”

Section: Discussionmentioning

confidence: 99%

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

et al. 2017

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De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

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Section: Discussionmentioning

confidence: 99%

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

et al. 2017

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“…Incidentally, the role of signals that regulate hamartin and tuberin activity as well as the mTORC1 substrates responsible for specific developmental events are only now being determined. Perhaps most striking is the fact that somatic mutations that cause mTORC1 pathway activation have been identified as a cause of a plethora of neurological diseases (Lee et al, 2012 ; Poduri et al, 2012 ; Parker et al, 2013 ; Lal et al, 2014 ; Baek et al, 2015 ; Baulac et al, 2015 ; Crino, 2015 ; D’Gama et al, 2015 , 2017 ; Leventer et al, 2015 ; Lim et al, 2015 ; Baulac, 2016 ; Korenke et al, 2016 ; Møller et al, 2016 ; Hanai et al, 2017 ; Park et al, 2018 ; Iffland and Crino, 2019 ; Kim et al, 2019 ; Pelorosso et al, 2019 ; Salinas et al, 2019 ; Zhao et al, 2019 ; Garcia et al, 2020 ). Thus, what has been learned by studying the TSC pathway may now be applied to an expanding number of patients.…”

Section: The Molecular Genetics Of Tscmentioning

confidence: 99%

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

Feliciano

2020

Front. Neuroanat.

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Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gainof-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.

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“…This study demonstrated that the change of the conserved aspartic acid in position 2412 to valine is a gain-of-function variant (GOF) since it was able to activate the mTOR pathway (Fig. 3) [17]. Thus, the phosphorylation of the mTORC1 substrates 4EBP1 and S6K, and phosphorylation of AKT, the substrate of mTORC2, were increased in patient, indicating activation of both complexes.…”

Section: Discussionmentioning

confidence: 81%

A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome

et al. 2019

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We report the clinical, biochemical and genetic findings from a Spanish girl of Caucasian origin who presented with macrocephaly, dysmorphic facial features, developmental delay, hypotonia, combined oxidative phosphorylation (OxPhos) deficiency, epilepsy and anti-phospholipid antibodies (aPL). Whole-exome sequencing (WES) uncovered a heterozygous variant in the MTOR gene (NM_004958.3: c.7235A>T: p.(Asp2412Val)) that encodes for the Serine/threonine-protein kinase mTOR. The substrates phosphorylation experiments demonstrated that this variant exerts its effect by gain-offunction (GOF) and autosomal dominant mechanism. GOF variants in this protein have been associated with Smith-Kingsmore syndrome (SKS), a rare autosomal dominant disorder characterized by intellectual disability, macrocephaly, seizure, developmental delay and dysmorphic facial features. Furthermore, the mTOR pathway has been demonstrated previously to be involved in many types of endothelium injuries including the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by the production of aPL with recurrent vascular thrombosis. Therefore, our patient is the first one with an mTOR variant and diagnosed with SKS and APS. In conclusion, our data expand both the genetic and phenotypic spectrum associated with MTOR gene variants.

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Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

Cited by 25 publications

References 40 publications

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome

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