Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder

Abstract

Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corticostriatal dysfunction. Thus, mutations that impair SLITRK5 function may contribute to the genetic risk for OCD. We re-sequenced the protein-coding sequence of the human SLITRK5 gene (SLITRK5) in three hundred and seventy seven OCD subjects and compared rare non-synonymous mutations (RNMs) in that sample with similar mutations in the 1000 Genomes database. We also performed in silico assessments and in vitro functional synaptogenesis assays on the Slitrk5 mutations identified. We identified four RNM’s among these OCD subjects. There were no significant differences in the prevalence or in silico effects of rare non-synonymous mutations in the OCD sample versus controls. Direct functional testing of recombinant SLITRK5 proteins found that all mutations identified in OCD subjects impaired synaptogenic activity whereas none of the pseudo-matched mutations identified in 1000 Genomes controls had significant effects on SLITRK5 function (Fisher’s exact test P = 0.028). These results demonstrate that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. They also highlight the importance of biological characterization of allelic effects in understanding genotype-phenotype relationships as there were no statistical differences in overall prevalence or bioinformatically predicted effects of OCD case versus control mutations. Finally, these results converge with others to highlight the role of aberrant synaptic function in corticostriatal neurons in the pathophysiology of OCD.

Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior

“…Slitrk proteins, members of the Slit and Trk-like (Slitrk) protein family, are type I transmembrane leucine-rich repeat (LRR) domain-containing proteins that are broadly expressed in the central nervous system and enriched at synapses. Interestingly, mutations in Slitrk genes have been associated with neuropsychiatric disorders (Abelson et al, 2005;Zuchner et al, 2006;Proenca et al, 2011;Piton et al, 2011;Shmelkov et al, 2010;Song et al, 2017;Cavani et al, 2011).…”

RETRACTED ARTICLE: Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism

“…Both SAPAP3 and Sltirk5 KO mice, which exhibit a high degree of OCD-like grooming behavior and anxiety-like behaviors, are considered relevant models for the corresponding human conditions, such as OCD. In fact, mutations in Sltirk5 and SAPAP3 have been linked to increased risk of OCD in humans 36,37 .…”

Leucine-rich repeat-containing synaptic adhesion molecules as organizers of synaptic specificity and diversity

“…For instance, Slitrk5 KO mice display OCD-like behavior, as they present with severe facial lesions associated with excessive grooming 55 . In relation to this, it has also been shown that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in humans 75 . SALM1 KO mice, on the other hand, exhibit autism-like behavioral abnormalities, such as social withdrawal and increased stereotyped activities 54 .…”