Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Abstract

Contactin-associated protein-like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2-related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting-up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage-gated potassium channel (VGKC) complex that is composed of TAG-1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up-to-date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2

“…For example, LGI1 antibodies can disrupt interactions between LGI1 and its receptors ADAM22/23, internalise the LGI1–ADAM complex and trigger neuronal hyperexcitability and memory deficits in vivo passive transfer models. 20 21 25 42 There is also clear evidence supporting the pathogenicity of CASPR2 antibodies with rodent passive transfer reproducing human pain manifestations, and evidence that the antibodies can disrupt CASPR2 interactions with contactin-2 22 . 43…”

Anti‐LGI1, anti‐GABABR, and Anti‐CASPR2 encephalitides in Asia: A systematic review

“…CASPR2 is a membrane protein expressed in the central and peripheral nervous system, particularly in the cortex, limbic system, basal ganglia, brainstem, thalamus, and sensory organs (Gordon et al, 2016). It is a cell adhesion molecule of the neurexin family responsible for synapse formation, regulation, and neuronal network establishment (Horresh et al, 2008;Saint-Martin et al, 2018).…”

“…Studies have shown that mutations in the gene encoding CASPR2 lead to focal epilepsy, mental retardation, schizophrenia, and other neuropsychiatric problems (Friedman et al, 2008;Saint-Martin et al, 2018;Strauss et al, 2006). Hence, comparable clinical syndrome would be justified in patients with anti-CASPR2 antibodies as well.…”

Increased densities of white matter neurons as a cross‐disease feature of neuropsychiatric disorders

“…Genetic mutations that lead to functional weakness of Reelin have been shown to cause slight cortical abnormalities, including the increase in the number of neurons in the WM and abnormal brain function, in mutant mice during their adulthood . Contactin‐associated protein‐like 2 ( Cntnap2 ) encodes a neuronal transmembrane protein, a member of the neurexin superfamily, and has been shown to be associated with the risk of development of various neuropsychiatric disorders, including ASD, intellectual disability, attention deficit hyperactivity disorder, epilepsy, and schizophrenia . Cntnap2 ‐knockout mice exhibit the core behavioral deficits of ASD and altered migration of the cortical excitatory neurons .…”

“…58,59 Contactin-associated protein-like 2 (Cntnap2) encodes a neuronal transmembrane protein, a member of the neurexin superfamily, and has been shown to be associated with the risk of development of various neuropsychiatric disorders, including ASD, intellectual disability, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. 60,61 Cntnap2-knockout mice exhibit the core behavioral deficits of ASD and altered migration of the cortical excitatory neurons. 62 Similarly, mutations in the autism susceptibility candidate 2 (AUTS2) gene have been shown to be associated with the risk of development of neurodevelopmental disorders, including ASD.…”