SLITRK1: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (→‎Function: task, replaced: PloS One → PLOS One using AWB)
 
m (1 revision imported)
 
(One intermediate revision by one other user not shown)
Line 1: Line 1:
{{Infobox protein|name=SLITRK1|AltNames=KIAA1910, LRRC12, UNQ233/PRO266|image=|width=|caption=|Symbol=SLITRK1|AltSymbols=|IUPHAR_id=|ATC_prefix=|ATC_suffix=|ATC_supplemental=|CAS_number=|CAS_supplemental=|DrugBank=|EntrezGene=114798|HGNCid=20297|OMIM=609678|PDB=4RCW|RefSeq=|UniProt=Q96PX8|EC_number=|Chromosome=13|Arm=q|Band=31.1|LocusSupplementaryData=}}
{{Infobox_gene}}
'''SLIT and NTRK-like protein 1''' is a [[protein]] that in humans is encoded by the ''SLITRK1'' [[gene]].<ref name="pmid14557068">{{cite journal | vauthors = Aruga J, Yokota N, Mikoshiba K | title = Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue | journal = Gene | volume = 315 | issue = | pages = 87–94 |date=Oct 2003 | pmid = 14557068 | pmc = | doi =10.1016/S0378-1119(03)00715-7  }}</ref><ref name="pmid12975309">{{cite journal | vauthors = Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A | title = The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment | journal = Genome Res | volume = 13 | issue = 10 | pages = 2265–70 |date=Oct 2003 | pmid = 12975309 | pmc = 403697 | doi = 10.1101/gr.1293003 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLITRK1 SLIT and NTRK-like family, member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=114798| accessdate = }}</ref>


'''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.<ref name=":0">{{Cite journal|last=Beaubien|first=François|last2=Raja|first2=Reesha|last3=Kennedy|first3=Timothy E.|last4=Fournier|first4=Alyson E.|last5=Cloutier|first5=Jean-François|date=2016-06-07|title=Slitrk1 is localized to excitatory synapses and promotes their development|journal=Scientific Reports|volume=6|pages=27343|doi=10.1038/srep27343|issn=2045-2322|pmc=4895136|pmid=27273464}}</ref><ref name=":1">{{Cite journal|last=Um|first=Ji Won|last2=Kim|first2=Kee Hun|last3=Park|first3=Beom Seok|last4=Choi|first4=Yeonsoo|last5=Kim|first5=Doyoun|last6=Kim|first6=Cha Yeon|last7=Kim|first7=Soo Jin|last8=Kim|first8=Minhye|last9=Ko|first9=Ji Seung|date=2014-11-14|title=Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion|journal=Nature Communications|volume=5|pages=5423|doi=10.1038/ncomms6423|issn=2041-1723|pmid=25394468}}</ref><ref name=":5">{{Cite journal|last=Chattopadhyay|first=Koushik|last2=Chatterjee|first2=Koushik|date=August 2012|title=The genetic factors influencing the development of trichotillomania|journal=Journal of Genetics|volume=91|issue=2|pages=259–262|issn=0973-7731|pmid=22942103}}</ref> Expression of the gene has been linked to early formation of excitatory synapses through binding with receptor tyrosine phosphatase PTP (LAR-RPTP).<ref name=":0" /><ref name=":1" /> Various studies over the years have linked mutations in the gene to conditions on the OCD spectrum, [[Tourette syndrome|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.   
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =  
| summary_text = 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).[supplied by OMIM]<ref name="entrez" />
}}


== Gene Information ==
==References==
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.<ref name=":8" /><ref name=":7" /> Mice contain an ortholog of the gene called Slitrk1.<ref name=":8">{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/114798|title=SLITRK1 SLIT and NTRK like family member 1 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2017-11-30}}</ref>
{{reflist}}


== Protein Structure ==
==Further reading==
SLITRK1 contains 2 horseshoe shaped leucine rich repeat domains ([[Leucine-rich repeat|LRRs]]) in its extracellular domain which are vital to its function.<ref name=":0" /> The LRRs have 6 modules each and are connected by a 70-90 amino acid loops.<ref name=":1" /> LRR1 is a more conserved sequence and is present as a dimer while LRR2 is a monomer and has a more variable sequence.<ref name=":1" /> 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.<ref name=":0" /><ref name=":1" /> Both LRR sequences are randomly positioned on the protein and contain variable linker regions.<ref name=":1" /> The protein also contains a short intracellular domain, but lacks a tyrosine phosphorylation motif which is present in other SLITRK genes.<ref name=":3">{{Cite journal|last=Karagiannidis|first=I.|last2=Rizzo|first2=R.|last3=Tarnok|first3=Z.|last4=Wolanczyk|first4=T.|last5=Hebebrand|first5=J.|last6=Nöthen|first6=M. M.|last7=Lehmkuhl|first7=G.|last8=Farkas|first8=L.|last9=Nagy|first9=P.|date=July 2012|title=Replication of association between a SLITRK1 haplotype and Tourette Syndrome in a large sample of families|journal=Molecular Psychiatry|volume=17|issue=7|pages=665–668|doi=10.1038/mp.2011.151|issn=1476-5578|pmid=22083730}}</ref>
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | vauthors=Nagase T, Kikuno R, Ohara O |title=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. |journal=DNA Res. |volume=8 |issue= 4 |pages= 179–87 |year= 2002 |pmid= 11572484 |doi=10.1093/dnares/8.4.179  }}
*{{cite journal  |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
*{{cite journal  | vauthors=Aruga J, Mikoshiba K |title=Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. |journal=Mol. Cell. Neurosci. |volume=24 |issue= 1 |pages= 117–29 |year= 2004 |pmid= 14550773 |doi=10.1016/S1044-7431(03)00129-5  }}
*{{cite journal  |vauthors=Dunham A, Matthews LH, Burton J, etal |title=The DNA sequence and analysis of human chromosome 13. |journal=Nature |volume=428 |issue= 6982 |pages= 522–8 |year= 2004 |pmid= 15057823 |doi= 10.1038/nature02379  | pmc=2665288 }}
*{{cite journal  |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 }}
*{{cite journal   |vauthors=Abelson JF, Kwan KY, O'Roak BJ, etal |title=Sequence variants in SLITRK1 are associated with Tourette's syndrome. |journal=Science |volume=310 |issue= 5746 |pages= 317–20 |year= 2005 |pmid= 16224024 |doi= 10.1126/science.1116502 }}
*{{cite journal  | author=Burton A |title=SLITRK1 trouble in Tourette's syndrome. |journal=Lancet Neurology |volume=4 |issue= 12 |pages= 801 |year= 2006 |pmid= 16323357 |doi=10.1016/S1474-4422(05)70242-8  }}
*{{cite journal  | vauthors=Wendland JR, Kruse MR, Murphy DL |title=Functional SLITRK1 var321, varCDfs and SLC6A4 G56A variants and susceptibility to obsessive-compulsive disorder. |journal=Mol. Psychiatry |volume=11 |issue= 9 |pages= 802–4 |year= 2006 |pmid= 16936762 |doi= 10.1038/sj.mp.4001848 }}
*{{cite journal  |vauthors=Zuchner S, Cuccaro ML, Tran-Viet KN, etal |title=SLITRK1 mutations in trichotillomania. |journal=Mol. Psychiatry |volume=11 |issue= 10 |pages= 887–9 |year= 2006 |pmid= 17003809 |doi= 10.1038/sj.mp.4001865 }}
}}
{{refend}}


== Function ==
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
SLITKR1 is highly expressed in the [[central nervous system]].<ref name=":0" /> It plays a critical part in regulating synapse formation between hippocampal neurons and in differentiation of synapses, helping in neuronal outgrowth.<ref name=":0" /><ref name=":1" /><ref name=":3" /><ref name=":6">{{Cite journal|last=Ozomaro|first=Uzoezi|last2=Cai|first2=Guiqing|last3=Kajiwara|first3=Yuji|last4=Yoon|first4=Seungtai|last5=Makarov|first5=Vladimir|last6=Delorme|first6=Richard|last7=Betancur|first7=Catalina|last8=Ruhrmann|first8=Stephan|last9=Falkai|first9=Peter|date=2013|title=Characterization of SLITRK1 variation in obsessive-compulsive disorder|journal=PLOS One|volume=8|issue=8|pages=e70376|doi=10.1371/journal.pone.0070376|issn=1932-6203|pmc=3749144|pmid=23990902}}</ref> It is expressed during embryonic stages and postnatally but expression decreases over time and is localized to the postsynaptic membrane.<ref name=":0" /><ref name=":1" />
{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


Overexpression of SLITKR1 promotes postsynaptic differentiation for excitatory and inhibitory synapses, but because of the localization only excitatory synapses are affected.<ref name=":0" /> Inhibition of SLITKR1 only reduces differentiation of excitatory synapses because of this.<ref name=":0" />


=== Interaction with LAR-RPTP ===
{{gene-13-stub}}
Since they lack tyrosine phosphorylation motifs, SLITKR1 binds to LAR-RPTP through its LRR1 region in order to differentiate synapses.<ref name=":0" /><ref name=":1" /> The LRR2 domain's function is not clearly understood yet but it is hypothesised that it is for dimerization to the cell surface.<ref name=":0" />
 
LAR-RPTP binds to the LRR1 region through its PTPδ Ig region, with 3 separate binding sites in a 1:1 binding ratio.<ref name=":1" /> Ig1 binds through electrostatic and hydrophobic interactions, Ig2 binds through ionic and hydrogen bonds, and Ig2 binds through hydrogen bonding.<ref name=":1" /> The unique properties on the concave surface are what determine which LAR-RPTP binds to it.<ref name=":1" /> 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.<ref name=":1" /> Point mutations in the LRR1 region impaired differentiation as well but not binding.<ref name=":1" />
 
== Clinical Significance ==
 
=== Tourette Syndrome ===
In 2005, medical researchers observed a de novo translocation on 13q in a patient with [[Tourette syndrome]] (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 non-coding variant (called var321 and varCDfs) in two patients with TS.<ref name=":2" />  These variants were not found in several thousand controls supporting an association of the variants with TS.<ref name=":2" /> It is hypothesized that this mutation in SLITRK1 may be a direct or indirect cause of Tourette syndrome in this small subset (1–2%) of Tourette's patients.
 
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.<ref>{{cite journal |vauthors=Deng H, Le WD, Xie WJ, Jankovic J |title=Examination of the SLITRK1 gene in Caucasian patients with Tourette syndrome |journal=Acta Neurol. Scand. |volume=114 |issue=6 |pages=400–2 |date=December 2006 |pmid=17083340 |doi=10.1111/j.1600-0404.2006.00706.x}}</ref> 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.<ref>{{Cite journal|last=Jia|first=Yifang|last2=Zhao|first2=Heyong|last3=Shi|first3=Donghong|last4=Peng|first4=Wen|last5=Xie|first5=Luwen|last6=Wang|first6=Wei|last7=Jiang|first7=Fuman|last8=Zhang|first8=Hongyun|last9=Wang|first9=Xietong|date=2014|title=Genetic effects of a 13q31.1 microdeletion detected by noninvasive prenatal testing (NIPT)|journal=International Journal of Clinical and Experimental Pathology|volume=7|issue=10|pages=7003–7011|issn=1936-2625|pmc=4230093|pmid=25400788}}</ref> 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.<ref name=":4">{{Cite journal|last=Inai|first=Aya|last2=Tochigi|first2=Mamoru|last3=Kuwabara|first3=Hitoshi|last4=Nishimura|first4=Fumichika|last5=Kato|first5=Kayoko|last6=Eriguchi|first6=Yosuke|last7=Shimada|first7=Takafumi|last8=Furukawa|first8=Masaomi|last9=Kawamura|first9=Yoshiya|date=December 2015|title=Analysis of SLITRK1 in Japanese patients with Tourette syndrome using a next-generation sequencer|journal=Psychiatric Genetics|volume=25|issue=6|pages=256–258|doi=10.1097/YPG.0000000000000104|issn=1473-5873|pmid=26317387}}</ref> 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 [[Single-nucleotide polymorphism|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.<ref name=":3" /> In a different study of 381 Caucasians with some form of [[Obsessive–compulsive disorder|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.<ref name=":6" /> The non-OCD patient did have compulsive nail biting, but these studies show that a genetic link between SLITRK1 and patients with tourette syndrome may exist they are more complex in nature than previously understood.<ref name=":6" />
 
The impact of the research findings to the population of Tourette Syndrome patients as a whole is unclear.  SLITRK1, while it may not be a major gene implicated in the cause of tourette syndrome, can help contribute to our understanding of tourettes.<ref>{{cite journal |vauthors=Grados MA, Walkup JT |title=A new gene for Tourette's syndrome: a window into causal mechanisms? |journal=Trends Genet. |volume=22 |issue=6 |pages=291–3 |date=June 2006 |pmid=16678301 |doi=10.1016/j.tig.2006.04.003}}</ref><ref name=":2">{{cite journal  |vauthors=Abelson JF, Kwan KY, O'Roak BJ, etal |title=Sequence variants in SLITRK1 are associated with Tourette's syndrome |journal=Science |volume=310 |issue=5746 |pages=317–20 |date=October 2005 |pmid=16224024 |doi=10.1126/science.1116502}}</ref> Rare variants in SLITRK1 may lead to tourettes, 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.<ref name=":3" /><ref name=":4" />
 
=== Trichotillomania ===
The SLITRK1 gene has also been implicated in a small percentage of cases of [[trichotillomania]], an impulse disorder where the patients compulsively pull their own hair.<ref name="Chamberlain">{{cite journal |vauthors=Chamberlain SR, Menzies L, Sahakian BJ, Fineberg NA |author3-link=Barbara Sahakian |title=Lifting the veil on trichotillomania |journal=Am J Psychiatry |volume=164 |issue=4 |pages=568–74 |date=April 2007 |pmid=17403968 |doi=10.1176/appi.ajp.164.4.568 |url=http://ajp.psychiatryonline.org/cgi/content/full/164/4/568}}</ref><ref name=":7">{{Cite journal|last=Zuchner|first=S.|last2=Cuccaro|first2=M. L.|last3=Tran-Viet|first3=K. N.|last4=Cope|first4=H.|last5=Krishnan|first5=R. R.|last6=Pericak-Vance|first6=M. A.|last7=Wright|first7=H. H.|last8=Ashley-Koch|first8=A.|date=October 2006|title=SLITRK1 mutations in trichotillomania|journal=Molecular Psychiatry|volume=11|issue=10|pages=887–889|doi=10.1038/sj.mp.4001865|issn=1359-4184|pmid=17003809}}</ref> 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.<ref name=":6" /><ref name=":7" />
 
A study was done where 44 families with individuals who had trichotillomania had their SLITRK1 gene sequenced. 2 new non-synonymous mutations were discovered about 9 base pairs apart from each other, in an area separate from the one the tourettes mutations were found.<ref name=":5" /><ref name=":7" /> These results were compared to a controls and none had the mutation, suggesting that these mutations, while rare were associated with trichotillomania.<ref name=":7" />
 
== See also ==
[[SLITRK2]]
 
[[Protein tyrosine phosphatase|Protein Tyrosine Phosphatase]]
 
== References ==
{{reflist|2}}
 
== External links ==
* [http://pharyngula.org/index/weblog/comments/tourettes_and_sltrk1/ Tourette's and SLITRK1]
 
[[Category:Etiology|Tourette syndrome]]
[[Category:Human genes]]
[[Category:Trichotillomania]]
[[Category:Tourette syndrome]]

Latest revision as of 11:36, 9 January 2019

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

SLIT and NTRK-like protein 1 is a protein that in humans is encoded by the SLITRK1 gene.[1][2][3]

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).[supplied by OMIM][3]

References

  1. ↑ Aruga J, Yokota N, Mikoshiba K (Oct 2003). "Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue". Gene. 315: 87–94. doi:10.1016/S0378-1119(03)00715-7. PMID 14557068.
  2. ↑ Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (Oct 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
  3. ↑ 3.0 3.1 "Entrez Gene: SLITRK1 SLIT and NTRK-like family, member 1".

Further reading



Retrieved from "https://www.wikidoc.org/index.php?title=SLITRK1&oldid=1518423"