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
Gene Name: SLIT and NTRK like family member 2
Aliases: A930040J07
Human Ortholog: SLITRK2
Rescue agent: Reinstatement of Slitrk2 Parent model: M_SLITRK2_3_CKO_HM_CA1
Summary Statistics:
# of Reports: 2
# of Models: 7
Rescue Type:
RESCUE-Genetic
Rescue Paradigm:
Adeno-associated viruses (AAVs) expressing Cre and wildtype Slitrk2 were stereotactically injected into the CA1 region of adult Slitrk2-floxed mice.
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: Co-expression of SLITRK2 WT, but not that of the SLITRK2 T312A variant, completely rescued the decreased integrated intensity of VGLUT1 and PSD-95 puncta in hippocampal CA1-specific Slitrk2-cKO mice.
Exp Paradigm: VGLUT1, PSD-95
Description: Hippocampal CA1-specific Slitrk2 cKO mice exhibited a significant reduction in the integrated intensity of VGLUT1 and PSD-95 puncta in the SO and SR layers. Exp Paradigm: VGLUT1, PSD-95
Description: CA1 region-specific Slitrk2-cKO mice exhibited impaired retention of spatial reference memory after 17 days compared to normal Slitrk2-cKO mice.
Description: CA1 region-specific Slitrk2-cKO mice exhibited impaired retention of spatial reference memory after 3 days compared to normal Slitrk2-cKO mice.
