Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is characterized by impaired social interaction, language delay and repetitive or restrictive behaviors. With increasing prevalence, ASD is currently estimated to affect 0.5–2.0% of the global population. However, its etiology remains unclear due to high genetic and phenotypic heterogeneity. Copy number variations (CNVs) are implicated in several forms of syndromic ASD and have been demonstrated to contribute toward ASD development by altering gene dosage and expression. Increasing evidence points toward the p-arm of chromosome 3 (chromosome 3p) as an ASD risk locus. Deletions occurring at chromosome 3p result in 3p-deletion syndrome (Del3p), a rare genetic disorder characterized by developmental delay, intellectual disability, facial dysmorphisms and often, ASD or ASD-associated behaviors. Therefore, we hypothesize that overlapping molecular mechanisms underlie the pathogenesis of Del3p and ASD. To investigate which genes encoded in chromosome 3p could contribute toward Del3p and ASD, we performed a comprehensive literature review and collated reports investigating the phenotypes of individuals with chromosome 3p CNVs. We observe that high frequencies of CNVs occur in the 3p26.3 region, the terminal cytoband of chromosome 3p. This suggests that CNVs disrupting genes encoded within the 3p26.3 region are likely to contribute toward the neurodevelopmental phenotypes observed in individuals affected by Del3p. The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4). CNVs disrupting these neuronal IgCAMs may contribute toward ASD phenotypes as they have been associated with key roles in neurodevelopment. CHL1, CNTN6, and CNTN4 have been observed to promote neurogenesis and neuronal survival, and regulate neuritogenesis and synaptic function. Furthermore, there is evidence that these neuronal IgCAMs possess overlapping interactomes and participate in common signaling pathways regulating axon guidance. Notably, mouse models deficient for these neuronal IgCAMs do not display strong deficits in axonal migration or behavioral phenotypes, which is in contrast to the pronounced defects in neuritogenesis and axon guidance observed in vitro. This suggests that when CHL1, CNTN6, or CNTN4 function is disrupted by CNVs, other neuronal IgCAMs may suppress behavioral phenotypes by compensating for the loss of function.

Patient brain organoids identify a link between the 16p11.2 copy number variant and the RBFOX1 gene

“…Notably, in hemideletion hCOs DPP6, RBFOX1, and TCERG1L were each downregulated in several cell types and are previously associated with ASD and attention-deficit hyperactive disorder (ADHD) (Figure 5) [68][69][70] . Furthermore, we found downregulated genes grouped across cell types that play a role in neuronal cell adhesion and were previously associated with ASD including CHL1, CNTN4, and NLGN1 [71][72][73][74] (Figure 5). Interestingly, independent studies showed pathogenic CNVs within RBFOX1, DPP6, CNTN4, NLGN1, and CHL1 in patients suffering from several different neurodevelopmental disorders 5,[75][76][77] .…”

Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period

“…In humans three of the contactin family genes, CNTN3 , CNTN4 and CNTN6 are located on the short arm of the chromosome 3. Deletions in this region frequently result in the 3p-deletion syndrome – a genetic disorder associated with ASD, schizophrenia, epilepsy and accompanied by developmental delay and intellectual disability [ 10 ]. Copy number variations in 3p-deletion syndrome often occur at the 3p26 locus (which contains CNTN4 , CNTN6 ) and one case report of a child with a proximal interstitial 3p deletion that included CNTN3 (located at 3p12) also demonstrated neurodevelopmental delay, growth retardation and dysmorphic facial features among other abnormalities [ 31 ].…”

“…Such structural similarity may confer overlapping and redundant functions on these CAMs. It has been observed that larger copy number variations, affecting multiple genes in 3p-deletion syndrome, show a higher penetrance with more severe phenotypes [ 10 ]. Based on our RNAseq data, down-regulation in CNTN1 , CNTN4 and CNTN5 is also present in cortical tubers to some degree, albeit to a lesser extent than CNTN3 .…”

“…The pathogenesis of neurodevelopmental disorders has been linked to dysfunction in cell adhesion, mediated by neural cell adhesion molecules (CAMs) [ 8 – 10 ]. These molecules orchestrate the interactions between neurons during brain development, regulate synaptogenesis, synaptic plasticity and influence the processes of learning and memory [ 11 , 12 ].…”

A Comprehensive Review of Receptor-Type Tyrosine-Protein Phosphatase Gamma (PTPRG) Role in Health and Non-Neoplastic Disease

“…In the present case, PTPRG has a precise distribution in the brain and is characteristic of a group of neurons [ 14 , 15 ]. Its high affinity for contactin members, which are involved in autism spectrum disorder (ASD), suggest a potential role in this disease [ 57 , 58 ]. Various evidence indeed suggesting PTPRG as a susceptible gene involved also in neuropsychiatric disorders.…”