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 WT human RHEB or RHEBp.P37L and RHEBp.S68P mutations resulted in an increased head size as well as enlarged hippocampal neuron soma size. Rapamycin sufficiently and reproducibly rescued the macrocephalic phenotype and the change in hippocampal neuron size induced by both RHEBp.P37L and RHEBp.S68P.
References
Type
Title
Author, Year
Primary
Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Human WT RHEB mRNA was injected into 1- to 4-cell stage zebrafish embryos.
Allele Type: Gain-of-function
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mutant RHEB mRNA was injected into 1- to 4-cell stage zebrafish embryos.
Allele Type: Humanized GOF mutation
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mutant RHEB mRNA was injected into 1- to 4-cell stage zebrafish embryos.
Allele Type: Humanized GOF mutation
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
