Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population

Li, Xiaoping; Hu, Zhengmao; He, Yanling; Xiong, Zhimin; Long, Zhigao; Yu, Ping; Bu, Fengxiao; Ling, Jie; Xun, Guanglei; Mo, Xiaoyun; Pan, Qian; Zhao, Jingping; Xia, Kun

doi:10.1097/ypg.0b013e32833a216f

Cited by 53 publications

(43 citation statements)

References 22 publications

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“…An FBAT and a population-based case-control test conducted by Liu et al (2010) found that the oxytocin receptor gene polymorphisms were associated with ASD in the Japanese population. The results of FBAT suggested that CNTNAP2 was a susceptibility gene of autism in the Chinese Han population (Li et al, 2010). Allelic variation in the glutamate transporter gene may be a biomarker for or modifier of anxiety symptom severity in children with ASD (Gadow et al, 2010b).…”

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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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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“…Mutations in another member of the neurexin superfamily, contactin-associated protein-like 2 ( CNTNAP2/CASPR2 ), have also been identified in individuals with autism (Alarcón et al, 2008; Arking et al, 2008; Bakkaloglu et al, 2008; Vernes et al, 2008; Li et al, 2010; Petrin et al, 2010; Poot et al, 2010; Nord et al, 2011; O’Roak et al, 2011; Peñagarikano et al, 2011; Whitehouse et al, 2011; Anney et al, 2012; Prasad et al, 2012; Girirajan et al, 2013; Sampath et al, 2013; Egger et al, 2014; Poot, 2014; Chiocchetti et al, 2015). CNTNAP2 is required for dendrite arborization and dendritic spine development and maintenance (Anderson et al, 2012; Gdalyahu et al, 2015).…”

Section: Trans-synaptic Adhesion Molecules Play Important Roles In Thmentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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“…Genotypes detected in subjects with intellectual disability include inversion of exons 11 and 12, large deletions, frameshift mutation, splice site mutation, exon deletions, deletions of the 3′ UTR, and a complex rearrangement (11). Subjects with autism have been shown to carry copy number variations, complex rearrangements, an intron deletion, a promoter deletion, and amino acid substitutions (12)(13)(14)(15)(16)(17)(18)(19)(20). Disruptions detected in schizophrenia include deletion of exons 9-24, an intron deletion, and copy number variations (21-25).…”

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confidence: 99%

Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2 /Caspr2 knockout neurons

Varea¹,

Martín-de-Saavedra²,

Kopeikina³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

125

114

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Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.A bnormalities in excitatory synapses of cortical pyramidal neurons have emerged as key cellular substrates in the pathogenesis of several psychiatric disorders. Disease-specific disruptions in synaptic morphology or number and glutamate receptors accompany several neuropsychiatric disorders, particularly those that involve deficits in information processing (1). In support of this view, postmortem neuropathological studies found altered dendritic spine density on cortical pyramidal neurons in individuals with intellectual disability (2), autism spectrum disorders (3), and schizophrenia (4). Dendritic spines are the sites of the majority of excitatory glutamatergic synapses in the mammalian brain and represent the postsynaptic compartment of these synapses. Spines are rich in actin, and their morphology changes during development and in various physiological conditions (5). Spines contain glutamate receptors, of which the AMPA subtype are the ones responsible for fast neurotransmission (6). AMPA receptors, like other membrane proteins, are processed in the endoplasmic reticulum and the Golgi complex, then delivered to synapses by forward trafficking mechanisms (7). At the synapse, they undergo constitutive and regulated exo-and endocytosis, known to modulate synapse strength (6). Together, changes in spine number and morphology, along with glutam...

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Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population

Cited by 53 publications

References 22 publications

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

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

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2 /Caspr2 knockout neurons

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