Gene & protein function
SLITRK3(SLIT and NTRK-like family member 3) encodes a transmembrane protein with extracellular leucine-rich repeats (LRRs) that interacts with synaptic partners to regulate inhibitory synapse formation, particularly through binding to presynaptic PTPδ (a receptor protein tyrosine phosphatase) and intracellular scaffolding proteins.
In mice, loss of Slitrk3 leads to decreased inhibitory synapse density (without affecting excitatory synapses), increased seizure susceptibility, and spontaneous epileptiform activity.
Types of mutations identified
• Missense variants (e.g. C566R) affecting protein folding or trafficking
• Truncating / nonsense variants (e.g. E606X) that abolish function, likely by removing transmembrane or cytoplasmic domains
• Both homozygous (biallelic) and heterozygous de novo variants have been reported
Pathophysiologic mechanism
Variants in SLITRK3 lead to impaired GABAergic synapse development (loss-of-function), resulting in reduced inhibitory input, neuronal hyperexcitability, and predisposition to seizures and neurodevelopmental impairment.
Some mutant proteins are trapped intracellularly (e.g. in the Golgi) rather than properly localized to the neuronal membrane, impairing synaptic targeting.
Diagnostic testing
• Exome or genome sequencing with variant interpretation (following ACMG/AMP guidelines)
• Segregation studies (parental testing)
• Functional assays (cellular localization, electrophysiology) may help classify variants of uncertain significance
• In some cases, animal or neuronal models (e.g. knockout mice, patient-derived neurons) can assist in determining pathogenicity
SLITRK3