The role of trace elements thiamin e and transketolase in autism and autistic spectrum disorder

Abstract Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder. The copy number variation (CNV) of genes in the X-chromosome is speculated to play a critical role in ASD. The HECT, UBA and WWE domain containing the E3 ubiquitin protein ligase 1 (HUWE1) gene is located on the X-chromosome and is associated with neurodevelopment. However, the CNV of HUWE1 has not been linked to ASD. In this study, we identified increased copy numbers of HUWE1 in ASD patients compared to the controls. Moreover, an elevated severity of ASD phenotype was observed in patients with more HUWE1 copy numbers. In vitro, overexpression HUWE1 could decrease the proliferation of nervous system derived cells and promote their apoptosis, declining the G2/M phase transition. The functional assay showed that HUWE1, an E3 ubiquitin protein ligase, regulated the ubiquitination degradation of key mediators in the Wnt/β-catenin signaling pathway, which is involved in neurodevelopment. Consistent with the ASD patients, overexpression of huwe1 in zebrafish embryos caused defective brain development, small eyes, cardiac edema and a curly spinal cord, supporting the pivotal role of the HUWE1 CNV in neurodevelopmental disorders. In this study, we demonstrated the role of the HUWE1 CNV for complement pathway factors in the origin of ASD for the first time. Genetic analysis of the HUWE1 copy number could inform the clinical counseling of ASD patients.

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Association of Allelic Variants of the Reelin Gene with Autistic Spectrum Disorder: A Systematic Review and Meta-Analysis of Candidate Gene Association Studies

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17218010 ◽

2020 ◽

Vol 17 (21) ◽

pp. 8010

Author(s):

Ignacio Hernández-García ◽

Antonio-Javier Chamorro ◽

Hugo Guillermo Ternavasio-de la Vega ◽

Cristina Carbonell ◽

Miguel Marcos ◽

...

Keyword(s):

Systematic Review ◽

Genetic Variants ◽

Autistic Spectrum Disorder ◽

Association Studies ◽

Meta Analysis ◽

Spectrum Disorder ◽

Current Evidence ◽

Triplet Repeat ◽

Autistic Spectrum

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disability with a genetic basis, and several studies have suggested a potential role of the reelin gene (RELN) in ASD susceptibility. Accordingly, genetic association studies have explored this potential association, but the results have been controversial thus far. For this reason, we assessed the association of four genetic variants of RELN (the 5′UTR CGG triplet repeat and polymorphisms rs736707, rs362691, and rs2229864) with ASD by means of a systematic review and meta-analysis. We retrieved studies comparing the distribution of the above-mentioned genetic variants between ASD patients and healthy controls. A meta-analysis was conducted using a random effects model, and calculations of the odds ratios (ORs) and confidence intervals (CIs) were performed. A sensitivity analysis and tests to determine the heterogeneity of the results were also performed. Eleven previous studies fulfilled the inclusion criteria and analyzed the association of the above-mentioned genetic variants and ASD. We did not find any significant association between the allele or genotype frequencies of the analyzed polymorphisms and ASD, and large heterogeneity was found for the rs736707 polymorphism. Moreover, no significant differences were found between the 5′UTR triplet repeat and this disorder. In light of current evidence, no single genetic variant within this gene is clearly associated with the development of ASD, and ethnic differences may explain part of the observed heterogeneity. Larger studies among different ethnic groups are needed to establish the role of specific genetic variants within RELN in the etiology of this disorder.

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