Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.
Margot R F ReijndersM KousiG M van WoerdenMarieke KleinJ BraltenG M S ManciniT van EssenM Proietti-OnoriE E J SmeetsM van GastelA P A StegmannS J C StevensS H LelieveldChristian GilissenR PfundtP L TanT KleefstraBarbara FrankeY ElgersmaN KatsanisH G BrunnerPublished in: Nature communications (2017)
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.
Keyphrases
- intellectual disability
- autism spectrum disorder
- genome wide
- genome wide identification
- resting state
- cell proliferation
- white matter
- cerebral ischemia
- healthcare
- mental health
- functional connectivity
- endothelial cells
- copy number
- blood brain barrier
- genome wide analysis
- public health
- multiple sclerosis
- optic nerve
- nuclear factor
- transcription factor
- cell therapy
- case report
- bioinformatics analysis
- brain injury
- mesenchymal stem cells
- immune response
- climate change
- pluripotent stem cells
- human health
- optical coherence tomography