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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Persistent URL dx.doi.org/10.1038/s41467-017-00933-6, hdl.handle.net/1765/102540
Journal Nature Communications
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/602805 - Aggression subtyping for improved insight and treatment innovation in psychiatric disorders (AGGRESSOTYPE), This work was funded by the European Commission 7th Framework Programme; grant id fp7/602450 - IMAging GEnetics for MENtal Disorders (IMAGEMEND), This work was funded by the European Commission 7th Framework Programme; grant id h2020/643051 - Mastering skills in the training Network for attention deficit hyperactivity and autism spectrum Disorders (MiND)
Citation
Reijnders, M.R.F, Kousi, M. (M.), van Woerden, G.M, Klein, M, Bralten, L.B.C, Mancini, G.M.S, … Brunner, H.G. (2017). Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Nature Communications, 8(1). doi:10.1038/s41467-017-00933-6