Disruption of contactin 4 in three subjects with autism spectrum disorder

Abstract

Background: 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. Methods and results: Array based comparative genomic hybridisation identified a paternally inherited chromosome 3 copy number variation (CNV) in three subjects: 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). Conclusion: 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.Autism spectrum disorder (ASD) (Online Mendelian Inheritance in Man (OMIM) 209850) is a severe developmental disorder of the central nervous system characterised by impairments in three behavioural areas: (1) social interaction; (2) verbal and non-verbal communication; and (3) range of interests, activities and patterns of behaviour.

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

“…It identified 471 loci with significant changes in histone modification rates in human (enrichment, 410; loss, 61) when compared with the two nonhuman primate species. Additionally, the investigators detected 33 human specifically enriched loci that were selectively methylated in neuronal versus nonneuronal cells (Shulha et al 2012), among which they pinpoint DPP10 (chromosomal band 2q14.1), CNTN4, and CHL1 (both at 3p26.3), three genes conferring susceptibility to neurological disease (Sakurai et al 2002;Fernandez et al 2004;Marshall et al 2008;Glessner et al 2009;Roohi et al 2009;Salyakina et al 2011). They describe and further analyze the DPP10 and 16p11.2-12.2 loci, the latter among the 410 loci with human-specific enrichment in H3K4me3 modifications.…”

AFM Force Spectroscopy and Steered Molecular Dynamics Simulation of Protein Contactin 4

“…The human CNTN4 (locus 3p26.2-3p26.3) was identified as a candidate gene responsible for 3p deletion syndrome, rare contiguous--gene disorder [2]. Mutations affecting CNTN4 function may be also relevant to autism spectrum disorder (ASD) pathogenesis [3]. Thus understanding nanoscale mechanical properties of contactins has a great medical significance.…”

“…New experimental results were compared with steered molecular dynamics (SMD) simulations, reported for the first time here. As a recent study suggests a connection between contactin 4 and autism [12], we hope that better understanding of its mechanical fingerprint may open possibility of the diagnosis in a truly nanomedical fashion -one molecule at a time.…”

Mutant Mouse Models of Autism Spectrum Disorders

“…Several rare variants have been described in the CNTN4 gene in association with neurodevelopmental disorders including ASD [59,122]. Contactin4 (CNTN4), also known as BIG2 (brain-derived immunoglobulin superfamily molecule 2), is an axonal cell adhesion molecule that belonging to the contactin family.…”