Intragenic CNTNAP2 Deletions: A Bridge Too Far?

Abstract

Intragenic deletions of the contactin-associated protein-like 2 gene (CNTNAP2) have been found in patients with Gilles de la Tourette syndrome, intellectual disability (ID), obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, stuttering, and attention deficit hyperactivity disorder. A variety of molecular mechanisms, such as loss of transcription factor binding sites and perturbation of penetrance and expressivity, have been proposed to account for the phenotypic variability resulting from CNTNAP2 mutations. Deletions of both CNTNAP2 alleles produced truncated proteins lacking the transmembrane or some of the extracellular domains, or no protein at all. This observation can be extended to heterozygous intragenic deletions by assuming that such deletion-containing alleles lead to expression of a Caspr2 protein lacking one or several extracellular domains. Such altered forms of Capr2 proteins will lack the ability to bridge the intercellular space between neurons by binding to partners, such as CNTN1, CNTN2, DLG1, and DLG4. This presumed effect of intragenic deletions of CNTNAP2, and possibly other genes involved in connecting neuronal cells, represents a molecular basis for the postulated neuronal hypoconnectivity in autism and probably other neurodevelopmental disorders, including epilepsy, ID, language impairments and schizophrenia. Thus, CNTNAP2 may represent a paradigmatic case of a gene functioning as a node in a genetic and cellular network governing brain development and acquisition of higher cognitive functions.

Keywords: CNTNAP2; Intragenic deletions; Neurodevelopmental disorders.

Fig. 1

Diagram depicting the putative in solution structure of the extracellular domains of Caspr2 [for details, see Rubio-Marrero et al., 2016]. FBG, fibrinogen-like region; F5/8, discoidin/neuropilin homology domain; LG, laminin G-binding domains.

Fig. 2

Postulated proteins in patients with homozygous CNTNP2 mutations. The yellow bar represents the PDZ interaction domain. CDFE, cortical dysplasia/focal epilepsy; E, EGF-like domain; FBG, fibrinogen-like region; F5/8, discoidin/neuropilin homology domain; LG, laminin G-binding domains; SP, signal peptide; TM, transmembrane domain.

Fig. 3

Intragenic CNTNAP2 deletions. Orange bars: heterozygous de novo deletions. Purple bar: homozygous deletion inherited from both heterozygous carrier parents. Cross-hatched bars: inherited heterozygous deletions. The arrows indicate the breakpoints of CNTNAP2 disruptions in translocation and inversion patients. The double black arrow connects a maternally inherited deletion of exon 1 and a paternally inherited deletion of exons 4–20 in a patient reported by Smogavec et al. [2016]. ADHD, attention deficit hyperactivity disorder; GTS, Gilles de la Tourette syndrome; ID, intellectual disability; Schizo, schizophrenia.

Fig. 4

Proteins binding to Caspr2. The black bar on the left-hand side represents the extracellular domain to which CNTN1, CNTN2, DLG1, and DLG4 bind. The black bar on the right-hand side represents the intracellular domain to which ADAM22, LGI1, and KCNA1 bind. For abbreviations, see Figure 2.

Fig. 5

Associating SNPs (green), DNA methylation site (orange) [Schneider et al., 2012], and transcription binding sites (blue) are shown. The downward arrow indicates inhibition, and the upward arrows indicate stimulation of transcription by binding of the transcription factor.