The mTOR Signaling Pathway Activity and Vitamin D Availability Control the Expression of Most Autism Predisposition Genes

• Published in: International journal of molecular sciences 2019-12, Vol.20 (24), p.6332
• Main Authors: Trifonova, Ekaterina A, Klimenko, Alexandra I, Mustafin, Zakhar S, Lashin, Sergey A, Kochetov, Alex V
• Format: Article
• Language: English
• Subjects: Autism; Autism Spectrum Disorder - genetics; Autistic Disorder - genetics; Availability; Calciferol; Chromosomes; Deregulation; Epigenetics; Fragile X syndrome; Gene Regulatory Networks - genetics; Genes; Humans; Intellectual disabilities; Kinases; Mutation; Network analysis; Phosphatase; Proteins; Rapamycin; Signal transduction; Signal Transduction - genetics; Signs and symptoms; TOR protein; TOR Serine-Threonine Kinases - genetics; Vitamin D; Vitamin D - genetics; Vitamin D3; Vitamin deficiency
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20246332

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.