SLITRK1

SLITRK1 ("SLIT and NTRK-like family, member 1") is a human gene that codes for a transmembrane and signalling protein that is part of the SLITRK gene family, which is responsible for synapse regulation and presynaptic differentiation in the brain.^[5][6][7] Expression of the gene has been linked to early formation of excitatory synapses through binding with receptor tyrosine phosphatase PTP (LAR-RPTP).^[5][6] Various studies over the years have linked mutations in the gene to conditions on the OCD spectrum, Tourette syndrome and trichotillomania, however the mutations in the genome itself vary greatly between individuals, with most mutations observed being hard to find in repeat studies.

SLITRK1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4RCA, 4RCW
Identifiers
Aliases	SLITRK1, LRRC12, TTM, SLIT and NTRK like family member 1, slitrk1
External IDs	OMIM: 609678 MGI: 2679446 HomoloGene: 14174 GeneCards: SLITRK1
Gene location (Human) Chr. Chromosome 13 (human)^[1] Band 13q31.1 Start 83,877,205 bp^[1] End 83,882,474 bp^[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)^[2] Band 14|14 E3 Start 109,146,232 bp^[2] End 109,151,590 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Brodmann area 46 prefrontal cortex Brodmann area 23 endothelial cell superior frontal gyrus entorhinal cortex postcentral gyrus middle temporal gyrus Brodmann area 9 hippocampus proper Top expressed in primary motor cortex piriform cortex cingulate gyrus ventromedial nucleus subiculum superior colliculus lateral hypothalamus paraventricular nucleus of hypothalamus lateral geniculate nucleus prefrontal cortex More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding Cellular component integral component of membrane membrane synapse extracellular region cell junction plasma membrane glutamatergic synapse GABA-ergic synapse integral component of postsynaptic density membrane Biological process adult behavior nervous system development multicellular organism growth homeostatic process positive regulation of synapse assembly synapse assembly positive regulation of axonogenesis axonogenesis regulation of synapse organization synaptic membrane adhesion regulation of presynapse assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 114798 76965 Ensembl ENSG00000178235 ENSMUSG00000075478 UniProt Q96PX8 Q810C1 RefSeq (mRNA) NM_052910 NM_001281503 NM_199065 RefSeq (protein) NP_001268432 NP_443142 NP_951020 Location (UCSC) Chr 13: 83.88 – 83.88 Mb Chr 14: 109.15 – 109.15 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Members of the SLITRK family, such as SLITRK1, are integral membrane proteins with 2 N-terminal leucine-rich repeat (LRR) domains similar to those of SLIT proteins (see SLIT1; MIM 603742). Most SLITRKs, but not SLITRK1, also have C-terminal regions that share homology with neurotrophin receptors (see NTRK1; MIM 191315). SLITRKs are expressed predominantly in neural tissues and have neurite-modulating activity (Aruga et al., 2003).^[8]

Gene

The gene for SLITRK1 is located on chromosome 13q31.1. The gene is expressed only in the brain of humans. The mRNA can differ from alternative splicing, and contains domains for the extracellular matrix as well as for the LRRs.^[9] Mice contain an ortholog of the gene called Slitrk1.^[8]

Protein structure

SLITRK1 contains 2 horseshoe shaped leucine rich repeat domains (LRRs) in its extracellular domain which are vital to its function.^[5] The LRRs have 6 modules each and are connected by a 70-90 amino acid loops.^[6] LRR1 is a more conserved sequence and is present as a dimer while LRR2 is a monomer and has a more variable sequence.^[6] The conserved sequence of LRR1 contains critical binding pockets and specific charged residues that are important for it to carry out its function of binding to LAR-RPTPs on the N-terminus.^[5][6] Both LRR sequences are randomly positioned on the protein and contain variable linker regions.^[6] The protein also contains a short intracellular domain, but lacks a tyrosine phosphorylation motif which is present in other SLITRK genes.^[10]

Function

SLITKR1 is highly expressed in the central nervous system.^[5] It plays a critical part in regulating synapse formation between hippocampal neurons and in differentiation of synapses, helping in neuronal outgrowth.^{[5][6][10][11]} It is expressed during embryonic stages and postnatally but expression decreases over time and is localized to the postsynaptic membrane.^[5][6]

Overexpression of SLITKR1 promotes postsynaptic differentiation for excitatory and inhibitory synapses, but because of the localization only excitatory synapses are affected.^[5] Inhibition of SLITKR1 only reduces differentiation of excitatory synapses because of this.^[5]

Interaction with LAR-RPTP

Since they lack tyrosine phosphorylation motifs, SLITKR1 binds to LAR-RPTP through its LRR1 region in order to differentiate synapses.^[5][6] The LRR2 domain's function is not clearly understood yet but it is hypothesised that it is for dimerization to the cell surface.^[5]

LAR-RPTP binds to the LRR1 region through its PTPδ Ig region, with 3 separate binding sites in a 1:1 binding ratio.^[6] Ig1 binds through electrostatic and hydrophobic interactions, Ig2 binds through ionic and hydrogen bonds, and Ig2 binds through hydrogen bonding.^[6] The unique properties on the concave surface are what determine which LAR-RPTP binds to it.^[6] If the proper LAR-RPTP is not bound to the LRR1 then synapse formation cannot occur, but bonding can still occur. Once they are bound properly, the complex is sufficient for synapse differentiation.^[6] Point mutations in the LRR1 region impaired differentiation as well but not binding.^[6]

Clinical significance

Tourette syndrome

The SLITRK1 gene "is not a major risk gene for the majority of individuals" with Tourette syndrome (TS), according to a 2009 review,^[12] although its study can help contribute to our understanding of TS.^[13][14] Rare variants in SLITRK1 may lead to TS, and mutations in non-coding regions of SLITRK1 may also play a part, but further research needs to be done before any conclusions can be drawn.^[10][15]

In 2005, medical researchers observed a de novo translocation on 13q in a patient with TS which broke the patient's chromosome near the SLITRK1 genome. In screening of additional patients, the authors observed a frameshift mutation in SLITRK1 in a patient with TS and the same rare ncRNA target variant (called var321 and varCDfs; target of miR-24-1) in two patients with TS.^[14] These variants were not found in several thousand controls supporting an association of the variants with TS.^[14][16]

A subsequent examination of the region of the SLITRK1 gene found the mutation in none of 82 patients with Tourette syndrome. The authors concluded that tests to detect variant(s) in the gene probably would have little diagnostic utility.^[17] An experiment in the effects of a microdeletion in chromosome 13q31.1 was done in a fetus, the mother had passed the microdeletion to the child and both did not have tourettes or any other OCD symptoms, showing that it may not be a direct cause of tourettes.^[18] Further attempts to replicate the study were done in multiple studies. In a Japanese study, next-gen sequencing was used to screen 92 TS patients and 361 healthy controls, none of TS patients were found to have mutations at either variant or any new mutations in the gene.^[15] In a European study it was found that the 2 original variations were not found in any of the 222 trios that were studied. However, tests were also done on SNPs in the groups and 3 were found to have variations. Two of the three variations were found to be associated with the formation of Tourette syndrome.^[10] In a different study of 381 Caucasians with some form of OCD with 356 non-OCD control patients, 3 genetic changes were found after genetic screening. Of the 3, 2 were identified only once each and the third was found in 4 OCD patients but also in a non-OCD patient.^[11] The non-OCD patient did have compulsive nail biting, but these studies show that a genetic link between SLITRK1 and patients with TS may exist they are more complex in nature than previously understood.^[11]

Trichotillomania

The SLITRK1 gene has also been implicated in a small percentage of cases of trichotillomania, an impulse disorder in which individuals compulsively pull their own hair.^[19][9] In one of the previously mentioned studies the mother of the child who had a de novo translocation on 13q had trichotillomania; this would suggest that there could be a genetic link between SLITRK1 and trichotillomania as well.^[11][9]

A study was done in which 44 families with individuals who had trichotillomania had their SLITRK1 gene sequenced. Two new non-synonymous mutations were discovered about 9 base pairs apart from each other, in an area separate from the one where the Tourette mutations were found.^[7][9] These results were compared to a control and none had the mutation, suggesting that these mutations, while rare, were associated with trichotillomania.^[9]

See also

• SLITRK2
• Protein tyrosine phosphatase

References

1. GRCh38: Ensembl release 89: ENSG00000178235 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000075478 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Beaubien F, Raja R, Kennedy TE, Fournier AE, Cloutier JF (June 2016). "Slitrk1 is localized to excitatory synapses and promotes their development". Scientific Reports. 6: 27343. Bibcode:2016NatSR...627343B. doi:10.1038/srep27343. PMC 4895136. PMID 27273464.
6. Um JW, Kim KH, Park BS, Choi Y, Kim D, Kim CY, Kim SJ, Kim M, Ko JS, Lee SG, Choii G, Nam J, Heo WD, Kim E, Lee JO, Ko J, Kim HM (November 2014). "Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion". Nature Communications. 5: 5423. Bibcode:2014NatCo...5.5423U. doi:10.1038/ncomms6423. PMID 25394468.
7. Chattopadhyay K, Chatterjee K (August 2012). "The genetic factors influencing the development of trichotillomania". Journal of Genetics. 91 (2): 259–62. doi:10.1007/s12041-011-0094-6. PMID 22942103. S2CID 18450060.
8. "Entrez Gene: SLITRK1 SLIT and NTRK-like family, member 1".
9. Zuchner S, Cuccaro ML, Tran-Viet KN, Cope H, Krishnan RR, Pericak-Vance MA, Wright HH, Ashley-Koch A (October 2006). "SLITRK1 mutations in trichotillomania". Molecular Psychiatry. 11 (10): 887–9. doi:10.1038/sj.mp.4001865. PMID 17003809. S2CID 28209408.
10. Karagiannidis I, Rizzo R, Tarnok Z, Wolanczyk T, Hebebrand J, Nöthen MM, Lehmkuhl G, Farkas L, Nagy P, Barta C, Szymanska U, Panteloglou G, Miranda DM, Feng Y, Sandor P, Barr C, Paschou P (July 2012). "Replication of association between a SLITRK1 haplotype and Tourette Syndrome in a large sample of families". Molecular Psychiatry. 17 (7): 665–8. doi:10.1038/mp.2011.151. PMID 22083730.
11. Ozomaro U, Cai G, Kajiwara Y, Yoon S, Makarov V, Delorme R, Betancur C, Ruhrmann S, Falkai P, Grabe HJ, Maier W, Wagner M, Lennertz L, Moessner R, Murphy DL, Buxbaum JD, Züchner S, Grice DE (2013). "Characterization of SLITRK1 variation in obsessive-compulsive disorder". PLOS ONE. 8 (8): e70376. Bibcode:2013PLoSO...870376O. doi:10.1371/journal.pone.0070376. PMC 3749144. PMID 23990902.
12. O'Rourke JA, Scharf JM, Yu D, Pauls DL (2009). "The genetics of Tourette syndrome: a review". J Psychosom Res. 67 (6): 533–45. doi:10.1016/j.jpsychores.2009.06.006. PMC 2778609. PMID 19913658.
13. Grados MA, Walkup JT (June 2006). "A new gene for Tourette's syndrome: a window into causal mechanisms?". Trends in Genetics. 22 (6): 291–3. doi:10.1016/j.tig.2006.04.003. PMID 16678301.
14. Abelson JF, Kwan KY, O'Roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M, Davis NR, Ercan-Sencicek AG, Guez DH, Spertus JA, Leckman JF, Dure LS, Kurlan R, Singer HS, Gilbert DL, Farhi A, Louvi A, Lifton RP, Sestan N, State MW (October 2005). "Sequence variants in SLITRK1 are associated with Tourette's syndrome". Science. 310 (5746): 317–20. Bibcode:2005Sci...310..317A. doi:10.1126/science.1116502. PMID 16224024. S2CID 30102870.
15. Inai A, Tochigi M, Kuwabara H, Nishimura F, Kato K, Eriguchi Y, Shimada T, Furukawa M, Kawamura Y, Sasaki T, Kakiuchi C, Kasai K, Kano Y (December 2015). "Analysis of SLITRK1 in Japanese patients with Tourette syndrome using a next-generation sequencer". Psychiatric Genetics. 25 (6): 256–8. doi:10.1097/YPG.0000000000000104. PMID 26317387. S2CID 36831784.
16. Larsen, K; Momeni, J; Farajzadeh, L; Bendixen, C (2014). "Porcine SLITRK1: Molecular cloning and characterization". FEBS Open Bio. 4: 872–8. doi:10.1016/j.fob.2014.10.001. PMC 4215120. PMID 25379384.
17. Deng H, Le WD, Xie WJ, Jankovic J (December 2006). "Examination of the SLITRK1 gene in Caucasian patients with Tourette syndrome". Acta Neurologica Scandinavica. 114 (6): 400–2. doi:10.1111/j.1600-0404.2006.00706.x. PMID 17083340. S2CID 40043299.
18. Jia Y, Zhao H, Shi D, Peng W, Xie L, Wang W, Jiang F, Zhang H, Wang X (2014). "Genetic effects of a 13q31.1 microdeletion detected by noninvasive prenatal testing (NIPT)". International Journal of Clinical and Experimental Pathology. 7 (10): 7003–11. PMC 4230093. PMID 25400788.
19. Chamberlain SR, Menzies L, Sahakian BJ, Fineberg NA (April 2007). "Lifting the veil on trichotillomania". The American Journal of Psychiatry. 164 (4): 568–74. doi:10.1176/appi.ajp.164.4.568. PMID 17403968.

Further reading

• Nagase T, Kikuno R, Ohara O (2002). "Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins". DNA Res. 8 (4): 179–87. doi:10.1093/dnares/8.4.179. PMID 11572484.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Aruga J, Mikoshiba K (2004). "Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth". Mol. Cell. Neurosci. 24 (1): 117–29. doi:10.1016/S1044-7431(03)00129-5. PMID 14550773. S2CID 25473221.
• Dunham A, Matthews LH, Burton J, et al. (2004). "The DNA sequence and analysis of human chromosome 13". Nature. 428 (6982): 522–8. Bibcode:2004Natur.428..522D. doi:10.1038/nature02379. PMC 2665288. PMID 15057823.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Abelson JF, Kwan KY, O'Roak BJ, et al. (2005). "Sequence variants in SLITRK1 are associated with Tourette's syndrome". Science. 310 (5746): 317–20. Bibcode:2005Sci...310..317A. doi:10.1126/science.1116502. PMID 16224024. S2CID 30102870.
• Burton A (2006). "SLITRK1 trouble in Tourette's syndrome". Lancet Neurology. 4 (12): 801. doi:10.1016/S1474-4422(05)70242-8. PMID 16323357. S2CID 39118365.
• Wendland JR, Kruse MR, Murphy DL (2006). "Functional SLITRK1 var321, varCDfs and SLC6A4 G56A variants and susceptibility to obsessive-compulsive disorder". Mol. Psychiatry. 11 (9): 802–4. doi:10.1038/sj.mp.4001848. PMID 16936762.
• Zuchner S, Cuccaro ML, Tran-Viet KN, et al. (2006). "SLITRK1 mutations in trichotillomania". Mol. Psychiatry. 11 (10): 887–9. doi:10.1038/sj.mp.4001865. PMID 17003809. S2CID 28209408.