Gene Name: SLIT and NTRK like family member 2 Aliases: CXorf1, CXorf2, SLITL1, TMEM257 Chromosome No: X Chromosome Band: Xq27.3 Genetic Category: Rare single gene variant-Functional-Syndromic/Functional-Syndromic
El Chehadeh et al., 2022 reported eight individuals from seven unrelated families presenting a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and behavioral/neuropsychiatric manifestations (including ASD in 4/8 individudals) and harboring rare potential disease-causing variants in SLITRK2; functional studies subsequently showed that some of these variants caused impaired surface trafficking in transfected HEK293T cells and impaired dendritic targeting in cultured hippocampal neurons, as well as an inability to rescue deficits in excitatory synapse development and transmission in Slitrk2-cKO hippocampal neurons. El Chehadeh et al., 2022 also demonstrated that Slitrk2 conditional knockout mice were found to exhibit impaired long-term memory and abnormal gait. Slitrk2 knockout mice had previously been shown to exhibit increased locomotor activity in novel environments, antidepressant-like behaviors, enhanced vestibular function, and increased plasticity at mossy fiber-CA3 synapses with reduced sensitivity to serotonin (Katayama et al., 2022). The protein encoded by the SLITRK2 gene has been shown to interact with the protein products of the ASD-associated genes SHANK3, DLG2, and DLG4, and these interactions are required for SLITRK2-mediated excitatory synapse development (Han et al., 2019; Loomis et al., 2020). A maternally-inherited SLITRK2 missense variant (p.Val89Met) that was originally identified as being transmitted to three sisters with schizophrenia in Piton et al., 2011 was experimentally shown in Kang et al., 2016 to compromise synapse formation activity in cultured hippocampal neurons.
Molecular Function
This gene encodes an integral membrane protein that contains two N-terminal leucine-rich repeats domains and contains C-terminal regions similar to neurotrophin receptors. The encoded protein may play a role in modulating neurite activity. It is involved in synaptogenesis and promotes excitatory synapse differentiation (Beaubien et al., 2016; Kang et al., 2016).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
Rescue Type:
RESCUE-Pharmaceutical
Rescue Paradigm:
A targeting vector containing the 1.4-kb 5' and 5.7-kb 3' homology regions replaced the entire 5.8-kb fragment containing the open-reading frame of Slitrk2 with a floxed neo. Lithium was administered in the diet at a concentration of 2.4 g Li2CO3 per 1 kg dry food for 4 weeks.
Treatment does not improve measured phenotype (was expected to do so)
Ameliorated
Treatment provides partial correction or improvement of measured phenotype
No adverse effect
Treatment does not affect the parameter adversely
Sustained effect
Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect
Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Description: Chronic lithium treatment did not significantly alter the locomotor activity in the open field test of Slitrk2 knockout mice compared to wildtype mice.
Description: Slitrk2 knockout mice displayed greater total distance traveled, distance per bin, moving speed duration per movement, and distance per movement, but decreased movement episode number during the social preference test compared to wildtype mice.
Description: Slitrk2 knockout mice exhibited greater total distance traveled, moving speed, and movement duration compared to wildtype mice, but decreased number of movement episodes compared to wildtype mice.
Description: Slitrk2 knockout mice exhibited decreased latency to walk across both the 5 mm and 9 mm width beam, but higher hindlimb slipping tendency compared to wildtype mice.
Description: PSD-95+ particle sizes were increased in the tegmental reticular nuclei (TRN) and pontine nuclei of Slitrk2 knockout mice. PSD-95+/VGlut1+ particle sizes were increased in the pontine gray of Slitrk2 knockout mice. PSD-95+ signal intensity was increased in the pontine gray of Slitrk2 knockout mice. Exp Paradigm: PSD-95, VGLUT1
Description: The SERT positive fiber count was increased in the CA3 stratum radiatum region, but no significant differences were observed in either the hippocampus or dentate gyrus stratum of Slitrk2 knockout mice. After staining for serotonergic cell markers Tph2 and Slitrk2, analysis showed that serotonergic neurons were sparsely present in TRN that expressed Slitrk2. Exp Paradigm: SERT
Description: There were fewer serotonergic neurons in the dorsal and median raphe nuclei of Slitrk2 knockout mice compared with the dorsal raphe nucleus of wildtype mice. The mean number of the knockout median raphe nucleus was lower than that of wildtype. Exp Paradigm: SERT; Tph2
Description: No significant differences were found in paired-pulse ratio between Slitrk2 knockout and wildtype mice in both perforant path-dentate gyrus granule cell synapses and mossy fiber-CA3 pyramidal cell synapses. The frequency facilitation of mossy fiber synaptic transmission was significantly increased at 1 Hz in Sltrk2 knockout mice. Exp Paradigm: Low-frequency stimulation (LFS): 0.2, 1, 2 Hz; mossy fiber-CA3 synapse
Description: Slitrk2 knockout mice had significantly lower magnitude of serotonin-induced potentiation compared wildtype mice at both concentrations (44% lower at 1 Micromolar, and 20% lower in 5 Micromolar).
Description: The serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was significantly higher in the hippocampus and amygdala, and serotonin (5-HT) levels tended to be higher in the hippocampus. Serotonin turnover as defined 5-HIAA/5-HT was increased in the Slitrk2 knockout amygdala.
Description: The dopamine metabolite homovanillic acid (HVA) was significantly increased in the hippocampus of Slitrk2 knockout mice, but there were no clear differences in the striatum and nucleus accumbens.
Description: Slitrk2 knockout mice showed significantly increased vestibulo-ocular response (VOR) gains at the frequency of 0.17 or 0.33 Hz. VOR phase was not difference in either Slitrk2 knockout or wildtype mice.
Cued or contextual fear conditioning: Memory of cue1
Decreased
Description: Slitrk2 knockout mice displayed lower freezing response from the cue in fear conditioning, but no changes in basal freezing percentage in the cued test compared to wildtype mice.
