Shining a light on CNTNAP2: complex functions to complex disorders

Abstract

The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions.

Insights into the Genetic Foundations of Human Communication

“…Common SNPs across CNTNAP2 were tested for association with quantitative language measures in families with SLI, which revealed association with a cluster of intronic SNPs (Vernes et al 2008). These same variants have been associated with language measures in other samples, and there is also evidence that heterozygous loss-of-function mutations and common SNPs in CNTNAP2 represent a risk factor for neurodevelopmental disorders (Whitehouse et al 2011a;Luciano et al 2013;Rodenas-Cuadrado et al 2014).…”

Genetics and the Language Sciences

“…As discussed above, some proteins also act to regulate gene transcription and splicing of genes, and such proteins are, of course, themselves encoded by genes. Thus, genes and proteins interact with each other to form complicated networks, which can be carefully traced out and studied through a variety of experimental methods (Fisher 2006, Vernes & Fisher 2009, Fogel et al 2012, CarrionCastillo et al 2013, Rodenas-Cuadrado et al 2014. But how might defined functions of genes and proteins at cellular levels affect the building of brain circuitry, or influence neural processing?…”

“…CNTNAP2 is a gene that has been implicated in SLI and associated with a number of other disorders involving language disruptions, such as autism and epilepsy (Alarcón et al 2008, Vernes et al 2008, Rodenas-Cuadrado et al 2014). CNTNAP2 expression is tightly controlled, and it has been found at high levels in brain circuits involved in higher-order cognitive functions.…”

A Molecular Genetic Perspective on Speech and Language

“…CNTNAP2 is a member of the neurexin superfamily that encodes a transmembrane protein that has been implicated in multiple fundamental processes in the developing and mature nervous system (Rodenas-Cuadrado, Ho, & Vernes, 2013). It helps to cluster potassium channels at nodes of Ranvier in myelinated axons, and it has also been linked to mechanisms of neuronal migration, dendritic arborization, and spine formation during development .…”

“…It helps to cluster potassium channels at nodes of Ranvier in myelinated axons, and it has also been linked to mechanisms of neuronal migration, dendritic arborization, and spine formation during development . Diverse CNTNAP2 variants (rare mutations and common polymorphisms) have been associated with a range of neurodevelopmental disorders, including not only SLI and autism but also epilepsy, schizophrenia, Tourette syndrome, and intellectual disability (Rodenas-Cuadrado et al, 2013).…”