Abstract
Autism spectrum disorder (ASD) has a strong and complex genetic component with an estimate of more than 1000 genes implicated cataloged in SFARI (Simon′s Foundation Autism Research Initiative) gene database. A significant part of both syndromic and idiopathic autism cases can be attributed to disorders caused by the mechanistic target of rapamycin (mTOR)-dependent translation deregulation. We conducted gene-set analyses and revealed that 606 out of 1053 genes (58%) included in the SFARI Gene database and 179 out of 281 genes (64%) included in the first three categories of the database (“high confidence”, “strong candidate”, and “suggestive evidence”) could be attributed to one of the four groups: 1. FMRP (fragile X mental retardation protein) target genes, 2. mTOR signaling network genes, 3. mTOR-modulated genes, 4. vitamin D3 sensitive genes. The additional gene network analysis revealed 43 new genes and 127 new interactions, so in the whole 222 out of 281 (79%) high scored genes from SFARI Gene database were connected with mTOR signaling activity and/or dependent on vitamin D3 availability directly or indirectly. We hypothesized that genetic and/or environment mTOR hyperactivation, including provocation by vitamin D deficiency, might be a common mechanism controlling the expressivity of most autism predisposition genes and even core symptoms of autism.
Highlights
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with complex genetic, environmental, and epigenetic components
Dysregulation of the mammalian or mechanistic target of rapamycin pathway has been identified in numerous syndromes, such as fragile X syndrome, tuberous sclerosis, PTEN hamartoma tumor syndrome, a set of syndromes named RASopathy, Angelman syndrome, Rett syndrome, and Phelan–McDermid syndrome
We attempted to quantify the percentages of the mechanistic target of rapamycin (mTOR) signaling network members, the extremely sensitive to mTOR pathway activity targets, FMRP targets, and vitamin D targets among the genes cataloged in the SFARI Gene database
Summary
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with complex genetic, environmental, and epigenetic components. Higher activity of mTOR, ERK, and p70S6 kinase and lower activity of GSK3α and tuberin (TSC2) have been observed in cells from children with non-syndromic autism that suggests an increased Akt/mTOR pathway activity in idiopathic ASD [8]. MTORC1 affects global protein synthesis, a subset of mRNAs appears to be exceptionally sensitive to changes in mTOR activity [10]. Vitamin D3 is a fat-soluble substance that is converted to its biologically active form 1,25-dihydroxyvitamin D (calcitriol), a steroid hormone that appears to regulate the expression of approximately 900 different genes, a large number of which impact brain development and function [15,16]. We attempted to quantify the percentages of the mTOR signaling network members, the extremely sensitive to mTOR pathway activity targets, FMRP targets, and vitamin D targets among the genes cataloged in the SFARI Gene database
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
