Analysis of 101 mTOR-related genes in a cohort of 826 patients with intellectual disability (ID) identified three individuals from two families with de novo missense variants in the RHEB gene that, in addition to ID, presented with macrocephaly and autism spectrum disorder/autistic features; functional analysis of both RHEB missense variants in animal models revealed increased head size in zebrafish and aberrant neuronal migration and induction of seizures in mice (Reijnders et al., 2017).
Molecular Function
This gene is a member of the small GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. This protein is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.
Overexpression of Rheb resulted in significant enlargement of musroom body lobe size, as well as neuropil volume, Kenyon cell size, and Kenyon cell cluster volume. It had no change on immediate memory, but long-term memory (when measured 3 hours after training) was significantly impaired. When conditionally expressed in insulin-producing cells (IPCs) only, Rheb overexpression increased IPCs cell body size, IPCs nucleolus size, IPCs projecting neurite diameter, and IPCs axon bundle size.
References
Type
Title
Author, Year
Primary
The small GTPase Rheb affects central brain neuronal morphology and memory formation in Drosophila.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To generate flies overexpressing both Rheb and GFP in the mushroom bodies, the authors crossed y w mcd8GFP; +, and y w mcd8GFP; UAS-Rheb (generated from Bloomington Stock Center stocks) to w*; OK107-Gal4, respectively.
Allele Type: Overexpression
Strain of Origin: Not reported
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To generate flies overexpressing both Rheb and GFP in the insulin producing cells, the authors crossed w*; UAS-Rheb to w*; dilp2-Gal4.A UASmcd8-GFP/CyO.
Allele Type: Overexpression
Strain of Origin: Not reported
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Rheb morphants showed a significantly lower learning index compared to controls, suggesting a memory deficit.
Exp Paradigm: Sucrose conditioning; measured 3 hours after training
Description: Rheb morphants showed an increase in the the diameter of the individual neurites projecting from the insulin-producing cell (IPC) bodies compared to controls.
