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

M. R. F. Reijnders, M. Kousi, G. M. Woerden, M. Klein, J. Bralten, G. M. S. Mancini, T. Essen, M. Proietti-Onori, E. E. J. Smeets, M. Gastel, A. P. A. Stegmann, S. J. C. Stevens, S. H. Lelieveld, C. Gilissen, R. Pfundt, P. L. Tan, T. Kleefstra, B. Franke, Y. Elgersma, N. Katsanis and H. G. Brunner ()
Additional contact information
M. R. F. Reijnders: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
M. Kousi: Duke University
G. M. Woerden: Erasmus University Medical Center
M. Klein: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
J. Bralten: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
G. M. S. Mancini: Erasmus MC, Sophia Children’s Hospital
T. Essen: University of Groningen, University Medical Center of Groningen
M. Proietti-Onori: Erasmus University Medical Center
E. E. J. Smeets: Maastricht University Medical Center
M. Gastel: SWZ zorg
A. P. A. Stegmann: Maastricht University Medical Center
S. J. C. Stevens: Maastricht University Medical Center
S. H. Lelieveld: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
C. Gilissen: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
R. Pfundt: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
P. L. Tan: Duke University
T. Kleefstra: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
B. Franke: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
Y. Elgersma: Erasmus University Medical Center
N. Katsanis: Duke University
H. G. Brunner: Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00933-6

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