Role ofp53, Mitochondrial DNA Deletions, and Paternal Age in Autism: A Case-Control Study

Abstract

The tumor suppressor p53 responds to a variety of environmental stressors by regulating cell cycle arrest, apoptosis, senescence, DNA repair, bioenergetics and mitochondrial DNA (mtDNA) copy number maintenance. Developmental abnormalities have been reported in p53-deficient mice, and altered p53 and p53-associated pathways in autism (AU). Furthermore, via the Pten-p53 crosstalk, Pten haploinsufficient-mice have autisticlike behavior accompanied by brain mitochondrial dysfunction with accumulation of mtDNA deletions.

Circulating Non-Coding RNAs as a Signature of Autism Spectrum Disorder Symptomatology

“…A total of three significant molecular networks were identified by Fisher’s exact test in the IPA system, with additional criteria specifying that a pathway’s score was at least 20 and each pathway had at least 10 molecules ( Supplementary Table ) observed sixteen ASD miRNAs candidates, enriched by the functions of neurological and psychological disorders. We highlighted Dickkopf WNT Signaling Pathway Inhibitor 1 ( DKK1 ), EPH Receptor B6 ( EPHB6 ), Neurotrophic Receptor Tyrosine Kinase 3 ( NRTK3 ), and Tumor Protein P53 ( TP53 ), which were previously described as being regulated by these miRNAs and involved in either brain disorders or ASD [ 24 , 25 , 26 , 27 ].…”

“…Furthermore, a genetic association was found between the NTRK3 gene and both autism and Asperger syndrome [ 27 ]. Additionally, altered P53 and p53-dependent pathways have been reported in autism [ 24 ]. AGO2 mutations in some patients contribute to disturbances in terms of neurological development and the outcome of ASD [ 28 , 29 ].…”

Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder

“…mtDNA lineages or haplogroups significantly contribute to overall ASD risk in some studies [ 117 , 118 ], while other studies have not confirmed a major role for mtDNA variation in ASD susceptibility [ 119 , 120 ]. Increased mtDNA copy number in leukocytes from children with ASD has been reported in six studies [ 121 – 126 ], while increased mtDNA damage and deletions in leukocytes from children with ASD have been reported in four studies [ 121 , 122 , 126 , 127 ]. Interestingly, Wong et al also found an increase in microdeletions of p53, which is a regulator of mtDNA integrity [ 126 ], leading others to suggest that changes in mtDNA may be an epiphenomenon of genetic abnormalities in nuclear DNA (nDNA) mutations [ 128 ].…”

Mitochondrial DNA Variants in Autism Spectrum Disorder: A Systematic Review

“…Chen et al (2015) examined the mtDNA copy number in peripheral blood cells from ASD subjects and healthy controls, found a signi cant increased mtDNA copy number of MT-ND1, MT-ND4 and MT-CYB genes in ASD subjects as compared to healthy controls, but it was not related to clinical features of ASD. Wong et al(2016) quanti ed the mtDNA copy number in peripheral blood monocytic cells from 66 children with ASD and 46 typically developing children, found a signi cant higher number of mtDNA copies in children with ASD relative to typically children. Also one study reported a decreased mtDNA copy number in ASD subjects relative to controls.…”

“…The search yielded 6 studies that linked mtDNA deletions to ASD only presented the length of mtDNA deletions in ASD subjects without describing the exactly genomic location. Wong et al(2016) evaluated the role of mtDNA deletions in the development of ASD, found a signi cant higher incidence of mtDNA deletion in ASD cases as compared to healthy controls. An exploratory study of the correlation between mtDNA changes and ASD carried out by Varga et al(2018) analyzed common mtDNA variants in 60 ASD patients and 60 healthy controls, found that 16.6% of ASD subjects presented mtDNA deletions when compared with healthy controls.…”