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.
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
In utero electroporation at E14.5 was performed to induce the in vivo expression of RHEB-WT in the developing somatosensory cortex.
Allele Type: Conditional overexpresion
Strain of Origin: Female FvB/NHsD and male C57Bl6/J
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
In utero electroporation at E14.5 was performed to induce the in vivo expression of RHEBp.P37L in the developing somatosensory cortex.
Allele Type: Conditional overexpresion
Strain of Origin: Female FvB/NHsD and male C57Bl6/J
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
In utero electroporation at E14.5 was performed to induce the in vivo expression of RHEBp.S68P in the developing somatosensory cortex.
Allele Type: Conditional overexpresion
Strain of Origin: Female FvB/NHsD and male C57Bl6/J
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Rheb-wt mice show abnormal patterns of neuronal migration compared to mice transfected with control vector. while cells transfected with the control vector efficiently migrated to the cortical plate (cp), cells transfected with rheb-wt could be found in all the layers of the cortex.
Exp Paradigm: NA
Description: Rhebp.p37l mice show abnormal patterns of neuronal migration compared to mice transfected with control vector. the majority of cells transfected with rhebp.p37l remained in the subplate (sp), indicating more severe migration deficits compared to rheb-wt overexpression.
Exp Paradigm: NA
Description: Rhebp.p37l mice show occurrence of spontaneous tonic-clonic seizures. rhebp.p37l mice show significantly earlier onset of tonic-clonic seizures compared with mice transfected with rheb-wt and mice transfected with rhebp.s68p.
Exp Paradigm: NA
Description: Rhebp.s68p mice show abnormal patterns of neuronal migration compared to mice transfected with control vector. the majority of cells transfected with rhebp.s68p remained in the subplate (sp), indicating more severe migration deficits compared to rheb-wt overexpression.
Exp Paradigm: NA
