Roohi J. et al. Disruption of contactin 4 in three subjects with autism spectrum disorder. J. Med. Genet. 46, 176-182

Stony Brook University, United States.
Journal of Medical Genetics (Impact Factor: 6.34). 04/2008; 46(3):176-82. DOI: 10.1136/jmg.2008.057505
Source: PubMed


Autism spectrum disorder (ASD) is a developmental disorder of the central nervous system of largely unknown aetiology. The prevalence of the syndrome underscores the need for biological markers and a clearer understanding of pathogenesis. For these reasons, a genetic study of idiopathic ASD was undertaken.
Array based comparative genomic hybridisation identified a paternally inherited chromosome 3 copy number variation (CNV) in three
a deletion in two siblings and a duplication in a third, unrelated individual. These variations were fluorescence in situ hybridisation (FISH) validated and the end points further delineated using a custom fine tiling oligonucleotide array. Polymerase chain reaction (PCR) products unique to the rearrangements were amplified and sequence analysis revealed the variations to have resulted from Alu Y mediated unequal recombinations interrupting contactin 4 (CNTN4).
CNTN4 plays an essential role in the formation, maintenance, and plasticity of neuronal networks. Disruption of this gene is known to cause developmental delay and mental retardation. This report suggests that mutations affecting CNTN4 function may be relevant to ASD pathogenesis.

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    • "Recently, 2 SNPs at CNTN4 were associated with measures of human brain network connectivity (Jahanshad et al., 2013) indicating that genetic variants at CNTN4 have the potential to affect brain function. Indeed, evidence has shown that CNTN4 is associated with developmental disorders including 3p deletion syndrome (Fernandez et al., 2004) and autism (Roohi et al., 2009). In summary, evidence indicates that CNTN4 is of critical importance for human brain development and function and, when disrupted, can lead to neurodevelopmental disorders. "
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    ABSTRACT: Methylome-wide association (MWAS) studies present a new way to advance the search for biological correlates for alcohol use. A challenge with methylation studies of alcohol involves the causal direction of significant methylation-alcohol associations. One way to address this issue is to combine MWAS data with genomewide association study (GWAS) data. Here, we combined MWAS and GWAS results for alcohol use from 619 individuals. Our MWAS data were generated by next-generation sequencing of the methylated genomic DNA fraction, producing over 60 million reads per subject to interrogate methylation levels at ~27 million autosomal CpG sites in the human genome. Our GWAS included 5,571,786 single nucleotide polymorphisms (SNPs) imputed with 1000 Genomes. When combining the MWAS and GWAS data, our top finding was a region in an intron of CNTN4 (p = 2.55 × 10(-8) ), located between chr3: 2,555,403 and 2,555,524, encompassing SNPs rs1382874 and rs1382875. This finding was then replicated in an independent sample of 730 individuals. We used bisulfite pyrosequencing to measure methylation and found significant association with regular alcohol use in the same direction as the MWAS (p = 0.021). Rs1382874 and rs1382875 were genotyped and found to be associated in the same direction as the GWAS (p = 0.008 and p = 0.009). After integrating the MWAS and GWAS findings from the replication sample, we replicated our combined analysis finding (p = 0.0017) in CNTN4. Through combining methylation and SNP data, we have identified CNTN4 as a risk factor for regular alcohol use. Copyright © 2015 by the Research Society on Alcoholism.
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    • "This puts MDGA2 in line with other neuronal cell adhesion molecules of the immunoglobulin family, such as RESEARCH ARTICLE Biology Open (2015) 000, 1–9 doi:10.1242/bio.20148482 contactins, NRCAM, CADM1 and LRFN5 that are implicated in axon migration and guidance and were associated with autism (Berglund et al., 1999; Fernandez et al., 2004; Glessner et al., 2009; Roohi et al., 2009; Cottrell et al., 2011; Morrow et al., 2008; van Daalen et al., 2011; Bonora et al., 2005; Marui et al., 2009; Zhiling et al., 2008; de Bruijn et al., 2010). In summary, the association of truncated MDGA2 variants with ASD, and the notion that a number of neuronal cell adhesion factors are implicated in ASD, supports also a role of human MDGA2 as a cell adhesion molecule important in neuronal positioning and axon guidance. "
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    ABSTRACT: The formation of functional neuronal circuits relies on accurate migration and proper axonal outgrowth of neuronal precursors. On the route to their targets migrating cells and growing axons depend on both, directional information from neurotropic cues and adhesive interactions mediated via extracellular matrix molecules or neighbouring cells. The inactivation of guidance cues or the interference with cell adhesion can cause severe defects in neuronal migration and axon guidance. In this study we have analyzed the function of the MAM domain containing glycosylphosphatidylinositol anchor 2A (MDGA2A) protein in zebrafish cranial motoneuron development. MDGA2A is prominently expressed in distinct clusters of cranial motoneurons, especially in the ones of the trigeminal and facial nerves. Analyses of MDGA2A knockdown embryos by light sheet and confocal microscopy revealed impaired migration and aberrant axonal outgrowth of these neurons; suggesting that adhesive interactions mediated by MDGA2A are required for the proper arrangement and outgrowth of cranial motoneuron subtypes. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jan 2015 · Biology Open
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    • "Genetic studies of neuropsychiatric disorders have sparked off new interests in human contactins (CNTNs) and contactin associated proteins (CNTNAPs) because of their involvement in diseases such as autism spectrum disorders (ASD) (Burbach and van der Zwaag, 2009). Genetic alterations including copy number variants (CNVs) for CNTN3 (Morrow et al., 2008) CNTN4 (Glessner et al., 2009; Roohi et al., 2009; Cottrell et al., 2011), CNTN5 and CNTN6 (Saus et al., 2010; van Daalen et al., 2011) have been reported in ASD patients. Several reports have also linked the CNTNAP2 gene, encoding for contactinassociated protein-like 2 (CASPR2), with ASD (Alarcón et al., 2008; Bakkaloglu et al., 2008). "
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    ABSTRACT: The neural cell-adhesion molecules contactin 4, contactin 5 and contactin 6 are involved in brain development, and disruptions in contactin genes may confer increased risk for autism spectrum disorders (ASD). We describe a co-culture of rat cortical neurons and HEK293 cells overexpressing and delivering the secreted forms of rat contactin 4-6. We quantified their effects on the length and branching of neurites. Contactin 4-6 effects were different depending on the contactin member and duration of co-culture. At 4 days in culture, contactin 4 and -6 increased the length of neurites, while contactin 5 increased the number of roots. Up to 8 days in culture, contactin 6 progressively increased the length of neurites while contactin 5 was more efficient on neurite branching. We studied the molecular sites of interaction between human contactin 4, -5 or -6 and the human Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a contactin partner, by modeling their 3D structures. As compared to contactin 4, we observed differences in the Ig2 and Ig3 domains of contactin 5 and -6 with the appearance of an omega loop that could adopt three distinct conformations. However, interactive residues between human contactin 4-6 and PTPRG were strictly conserved. We did not observe any differences in PTPRG binding on contactin 5 and -6 either. Our data suggest that the differential contactin effects on neurite outgrowth do not result from distinct interactions with PTPRG. A better understanding of the contactin cellular properties should help elucidate their roles in ASD.
    Full-text · Article · Mar 2013 · Biology Open
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