PUBLICATION

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

Authors
Reijnders, M.R.F., Kousi, M., van Woerden, G.M., Klein, M., Bralten, J., Mancini, G.M.S., van Essen, T., Proietti-Onori, M., Smeets, E.E.J., van Gastel, M., Stegmann, A.P.A., Stevens, S.J.C., Lelieveld, S.H., Gilissen, C., Pfundt, R., Tan, P.L., Kleefstra, T., Franke, B., Elgersma, Y., Katsanis, N., Brunner, H.G.
ID
ZDB-PUB-180502-22
Date
2017
Source
Nature communications   8: 1052 (Journal)
Registered Authors
Katsanis, Nicholas
Keywords
none
MeSH Terms
  • Animals
  • Brain/anatomy & histology*
  • Cell Movement
  • Cell Size
  • Cells, Cultured
  • Humans
  • Intellectual Disability/genetics*
  • Intellectual Disability/pathology
  • Megalencephaly/genetics*
  • Mutation*
  • Neurons/cytology
  • Neurons/drug effects
  • Neurons/physiology
  • Organ Size
  • Ras Homolog Enriched in Brain Protein/genetics*
  • Seizures/genetics
  • Signal Transduction/genetics
  • Sirolimus/pharmacology
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • TOR Serine-Threonine Kinases/metabolism*
  • Zebrafish/genetics
PubMed
29051493 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes