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Nat Commun. 2017 Oct 20;8(1):1052. doi: 10.1038/s41467-017-00933-6.

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

Author information

1
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, 6500 GA, The Netherlands.
2
Center for Human Disease Modeling, Duke University, Durham, NC, 27701, USA.
3
Department of Neuroscience and ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, 3015 CN, Rotterdam, The Netherlands.
4
Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, 3000 CA, Rotterdam, The Netherlands.
5
Department of Genetics, University of Groningen, University Medical Center of Groningen, 9700 RB, Groningen, The Netherlands.
6
Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ, Maastricht, The Netherlands.
7
Department of Medical Care, SWZ zorg, 5691 AG, Son, The Netherlands.
8
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 GA, Nijmegen, The Netherlands.
9
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 GA, Nijmegen, The Netherlands.
10
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, 6500 GA, The Netherlands. han.brunner@radboudumc.nl.
11
Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ, Maastricht, The Netherlands. han.brunner@radboudumc.nl.

Abstract

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.

PMID:
29051493
PMCID:
PMC5648772
DOI:
10.1038/s41467-017-00933-6
[Indexed for MEDLINE]
Free PMC Article

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