Intronic Single Nucleotide Polymorphisms of &lt;i&gt;Engrailed Homeobox 2&lt;/i&gt; Modulate the Disease Vulnerability of Autism in a Han Chinese Population

Yang, Pinchen; Shu, Bih‐Ching; Hallmayer, Joachim; Lung, For‐Wey

doi:10.1159/000315441

Cited by 24 publications

(14 citation statements)

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“…Because of its roles in regulating cerebellar morphogenesis and Purkinje neuron development, and evidence of cerebellar pathology in human disease [3-6], we previously examined ENGRAILED2’s association with human autism spectrum disorder (ASD) and found evidence to support EN2 as an ASD susceptibility gene. These results, initially observed in 167 families, were subsequently replicated in two additional data sets (518 families; P = 0.00000035), and six other groups have demonstrated EN2 association with ASD [7-12]. …”

Section: Introductionmentioning

confidence: 67%

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

et al. 2014

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BackgroundThe homeobox transcription factor Engrailed2 (En2) has been studied extensively in neurodevelopment, particularly in the midbrain/hindbrain region and cerebellum, where it exhibits dynamic patterns of expression and regulates cell patterning and morphogenesis. Because of its roles in regulating cerebellar development and evidence of cerebellar pathology in autism spectrum disorder (ASD), we previously examined an ENGRAILED2 association and found evidence to support EN2 as a susceptibility gene, a finding replicated by several other investigators. However, its functions at the cell biological level remain undefined. In the mouse, En2 gene is expressed in granule neuron precursors (GNPs) just as they exit the cell cycle and begin to differentiate, raising the possibility that En2 may modulate these developmental processes.MethodsTo define En2 functions, we examined proliferation, differentiation and signaling pathway activation in En2 knockout (KO) and wild-type (WT) GNPs in response to a variety of extracellular growth factors and following En2 cDNA overexpression in cell culture. In vivo analyses of cerebellar GNP proliferation as well as responses to insulin-like growth factor-1 (IGF1) treatment were also conducted.ResultsProliferation markers were increased in KO GNPs in vivo and in 24-h cultures, suggesting En2 normally serves to promote cell cycle exit. Significantly, IGF1 stimulated greater DNA synthesis in KO than WT cells in culture, a finding associated with markedly increased phospho-S6 kinase activation. Similarly, there was three-fold greater DNA synthesis in the KO cerebellum in response to IGF1 in vivo. On the other hand, KO GNPs exhibited reduced neurite outgrowth and differentiation. Conversely, En2 overexpression increased cell cycle exit and promoted neuronal differentiation.ConclusionsIn aggregate, our observations suggest that the ASD-associated gene En2 promotes GNP cell cycle exit and differentiation, and modulates IGF1 activity during postnatal cerebellar development. Thus, genetic/epigenetic alterations of EN2 expression may impact proliferation, differentiation and IGF1 signaling as possible mechanisms that may contribute to ASD pathogenesis.

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Section: Introductionmentioning

confidence: 67%

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

et al. 2014

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“…A family-based association test (FBAT) in 151 Korean trios demonstrated a statistically significant association between autism and SNPs in the promoter region of the arginine vasopressin receptor 1A gene (Yang et al, 2010b). Intronic SNPs of engrailed homeobox 2 modulated the disease vulnerability of autism in a Chinese Han population (Yang et al, 2010a). Polymorphisms in leucine-rich repeat genes were associated with ASD susceptibility in populations of European ancestry (Sousa et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Methylenetetrahydrofolate Reductase Polymorphisms C677T and Risk of Autism in the Chinese Han Population

Guo

Chen²,

Liu³

et al. 2012

Genetic Testing and Molecular Biomarkers

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Causes of autism are still unknown. Some studies have shown that autism might be associated with metabolic abnormalities in the folate/homocysteine pathway, which is involved in DNA methylation, thus altering gene expression. The association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms and the risk of autism is still controversial and ambiguous. The purpose of this study was to examine the effect of the MTHFR C677T polymorphism on the autism risk in the Chinese Han population. A population-based case-control study was conducted in 186 children with autism and 186 controls. The MTHFR C677T polymorphisms were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of genotype MTHFR 677TT in children with autism (16.1%) was significantly higher (odds ratio [OR]=2.04; 95% confidence interval [CI]=1.07, 3.89; p=0.03] than those in controls (8.6%). When stratifying by select-item scores on the Autism Diagnostic Interview-Revised, it was found that children with current overactivity had a significantly higher frequency of the MTHFR 677TT genotype (OR=2.77, 95% CI=1.17, 6.60; p=0.02) than those without. This study suggested that MTHFR C677T is a risk factor of autism in Chinese Han children.

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“…The risk haplotype (A-C) led to higher transcription of EN2 than the opposite haplotype [102]. Remarkably, a study in Han Chinese autism cases confirmed EN2 as a susceptibility gene, but found the A-C haplotype to be protective [103]. It is conceivable that both deficits and overexpression of EN2 are disruptive for normal brain development.…”

Section: Overview Of Mutations In Wnt Pathway In Patients With Asd (Pmentioning

confidence: 99%

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

2012

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Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity.

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Intronic Single Nucleotide Polymorphisms of <i>Engrailed Homeobox 2</i> Modulate the Disease Vulnerability of Autism in a Han Chinese Population

Cited by 24 publications

References 44 publications

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

Methylenetetrahydrofolate Reductase Polymorphisms C677T and Risk of Autism in the Chinese Han Population

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

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