TY - JOUR

T1 - The mTOR signaling pathway activity and vitamin d availability control the expression of most autism predisposition genes

AU - Trifonova, Ekaterina A.

AU - Klimenko, Alexandra I.

AU - Mustafin, Zakhar S.

AU - Lashin, Sergey A.

AU - Kochetov, Alex V.

PY - 2019/12/15

Y1 - 2019/12/15

N2 - 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.

AB - 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.

KW - Autism spectrum disorder (ASD)

KW - Bioinformatics

KW - FMRP

KW - Genetics

KW - MTOR signaling pathway

KW - SFARI Gene database

KW - Vitamin D3

KW - mTOR signaling pathway

KW - TARGET

KW - SPECTRUM DISORDER

KW - D DEFICIENCY

KW - CYTOSCAPE

KW - SYMPTOMS

KW - GUT MICROBIOTA

KW - ANGELMAN SYNDROME

KW - TRANSLATION

KW - FEATURES

KW - genetics

KW - bioinformatics

KW - vitamin D3

KW - autism spectrum disorder (ASD)

UR - http://www.scopus.com/inward/record.url?scp=85076759513&partnerID=8YFLogxK

U2 - 10.3390/ijms20246332

DO - 10.3390/ijms20246332

M3 - Article

C2 - 31847491

AN - SCOPUS:85076759513

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 24

M1 - 6332

ER -