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Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.

ABSTRACT: BACKGROUND: There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype. METHODS: We analysed a cohort of 148 patients with idiopathic ASD for a number of mutations proposed in the literature as pathogenic in ASD. We also carried out a case control association study for the most common European haplogroups (hgs) and their diagnostic single nucleotide polymorphisms (SNPs) by comparing cases with 753 healthy and ethnically matched controls. RESULTS: We did not find statistical support for an association between mtDNA mutations or polymorphisms and ASD. CONCLUSIONS: Our results are compatible with the idea that mtDNA mutations are not a relevant cause of ASD and the frequent observation of concomitant mitochondrial dysfunction and ASD could be due to nuclear factors influencing mitochondrion functions or to a more complex interplay between the nucleus and the mitochondrion/mtDNA.

SUBMITTER: Alvarez-Iglesias V

PROVIDER: S-EPMC3080282 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.

Álvarez-Iglesias Vanesa V Mosquera-Miguel Ana A Cuscó Ivón I Carracedo Ángel Á Pérez-Jurado Luis Alberto LA Salas Antonio A

BMC medical genetics 20110406

<h4>Background</h4>There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype.<h4>Methods</h4>We analysed a cohort of 148 patients ...[more]

PMID: 21470425

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Project description:Autism spectrum disorder (ASD) is characterized by phenotypic heterogeneity and a complex genetic architecture which includes distinctive epigenetic patterns. We report differential DNA methylation patterns associated with ASD in South African children. An exploratory whole-epigenome methylation screen using the Illumina 450 K MethylationArray identified differentially methylated CpG sites between ASD and controls that mapped to 898 genes (P ≤ 0.05) which were enriched for nine canonical pathways converging on mitochondrial metabolism and protein ubiquitination. Targeted Next Generation Bisulfite Sequencing of 27 genes confirmed differential methylation between ASD and control in our cohort. DNA pyrosequencing of two of these genes, the mitochondrial enzyme Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12), revealed a wide range of methylation levels (9-49% and 0-54%, respectively) in both ASD and controls. Three CpG loci were differentially methylated in PCCB (P ≤ 0.05), while PCDHA12, previously linked to ASD, had two significantly different CpG sites (P ≤ 0.001) between ASD and control. Differentially methylated CpGs were hypomethylated in ASD. Metabolomic analysis of urinary organic acids revealed that three metabolites, 3-hydroxy-3-methylglutaric acid (P = 0.008), 3-methyglutaconic acid (P = 0.018), and ethylmalonic acid (P = 0.043) were significantly elevated in individuals with ASD. These metabolites are directly linked to mitochondrial respiratory chain disorders, with a putative link to PCCB, consistent with impaired mitochondrial function. Our data support an association between DNA methylation and mitochondrial dysfunction in the etiology of ASD. Autism Res 2020, 13: 1079-1093. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Epigenetic changes are chemical modifications of DNA which can change gene function. DNA methylation, a type of epigenetic modification, is linked to autism. We examined DNA methylation in South African children with autism and identified mitochondrial genes associated with autism. Mitochondria are power-suppliers in cells and mitochondrial genes are essential to metabolism and energy production, which are important for brain cells during development. Our findings suggest that some individuals with ASD also have mitochondrial dysfunction.

Dataset Information

Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.

Publications

Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.

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