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

Area of Science:

• Neurogenetics
• Molecular Psychiatry

Background:

• Obsessive compulsive disorder (OCD) has a significant heritable component, yet its genetic underpinnings remain largely elusive.
• Mouse models lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) exhibit OCD-like behaviors and corticostriatal dysfunction, suggesting SLITRK5's role in the disorder.

Purpose of the Study:

• To investigate the role of rare non-synonymous mutations (RNMs) in the human SLITRK5 gene as potential genetic risk factors for obsessive compulsive disorder.
• To functionally characterize identified SLITRK5 mutations using in silico and in vitro assays.

Main Methods:

• Re-sequencing of the SLITRK5 gene in 377 OCD subjects and comparison of RNMs with the 1000 Genomes database.
• In silico prediction of mutation effects and in vitro synaptogenesis assays to assess the functional impact of SLITRK5 variants.

Main Results:

• Four RNMs were identified in OCD subjects; however, no significant differences in RNM prevalence or predicted in silico effects were observed between OCD patients and controls.
• In vitro functional assays demonstrated that all SLITRK5 mutations found in OCD subjects impaired synaptogenic activity, while control mutations did not.
• Fisher's exact test indicated a significant difference in functional effects between OCD-associated and control mutations (P = 0.028).

Conclusions:

• Rare functional mutations in SLITRK5 are implicated in the genetic risk for obsessive compulsive disorder.
• Direct biological characterization of allelic effects is crucial for understanding genotype-phenotype relationships in OCD, as in silico predictions alone were insufficient.
• Aberrant synaptic function in corticostriatal neurons is highlighted as a key factor in the pathophysiology of OCD, supported by these findings.