Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism

Abstract

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder characterised by motor and vocal tics. Despite decades of research, the aetiology of TS has remained elusive. Recent successes in gene discovery backed by rapidly advancing genomic technologies have given us new insights into the genetic basis of the disorder, but the growing collection of rare and disparate findings have added confusion and complexity to the attempts to translate these findings into neurobiological mechanisms resulting in symptom genesis. In this review, we explore a previously unrecognised genetic link between TS and a competing series of trans-synaptic complexes (neurexins (NRXNs), neuroligins (NLGNs), leucine-rich repeat transmembrane proteins (LRRTMs), leucine rich repeat neuronals (LRRNs) and cerebellin precursor 2 (CBLN2)) that links it with autism spectrum disorder through neurodevelopmental pathways. The emergent neuropathogenetic model integrates all five genes so far found to be uniquely disrupted in TS into a single pathogenetic chain of events described in context with clinical and research implications.

Figure 1

Schematic of domain architecture for a selection of neuronal leucine-rich repeat transmembrane protein families.

Figure 2

Neuropathogenetic model for Tourette syndrome (TS) implicates the full complement of known neurexin (NRXN) trans-synaptic cell-adhesion ligand gene families through multiple means of enquiry: neuroligins (NLGNs); leucine-rich repeat transmembrane proteins (LRRTMs); and the cerebellin precursors (CBLNs). The presynaptic NRXNs form trans-synaptic complexes with postsynaptic ligands NLGNs, LRRTMs and CBLNs in the formation and/or maintenance of neuronal circuitry within the brain. Vertical arrows indicate putative pathogenic dose effects. Neurexin isoforms with (+) and without (−) the 30 amino-acid insert at splice site 4 (IS4) dictate the different/competitive binding of NRXNs between the ligands. Comorbidities listed are those associated with the TS translocations and copy number variations (CNVs) affecting the respective genes.