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Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases

Year 2024, Volume: 14 Issue: 4, 1041 - 1047, 29.12.2024
https://doi.org/10.33808/clinexphealthsci.1480334

Abstract

Objective: Suicide is important in forensic medicine. Studies conducted to determine the etiology of suicide have shown that genetic factors have a critical role along with neuroendocrine changes occurring in the brain. It has been shown that dysregulation in the glutamatergic signaling pathway plays an essential role. One of the glutamatergic genes that causes suicide is the leucine-rich repeating transmembrane protein4 (LRRTM4). In our study, unlike previous studies, we planned to investigate LRRTM4 gene expression levels at mRNA and protein levels by taking samples from the dorsolateral prefrontal cortex (DLPFC) of the brain from autopsy cases. It was aimed to determine whether there is a statistically significant difference in LRRTM4 gene expression levels between suicide and non-suicide cases.
Methods: The study group consisted of 38 suicides. The control group consisted of 30 non-suicidal cases. Samples were taken from the DLPFC in the brain from these cases at autopsy. In the tissue samples obtained LRRTM4 gene expressions were analyzed at the mRNA and protein level using quantitative PCR and western blot methods.
Results: LRRTM4 gene expression values of suicides and non-suicide cases were compared. It was found to be 1.6 times higher in the study group than in the control group.
Conclusion: It has been determined that there is a statistically significant positive relationship between suicide and the LRRTM4. Our findings will contribute positively to the pre-detection of risk factors in suicidal individuals and the medicolegal evaluation. Furthermore, our study will guide further research on the role of genetic factors in the etiology of suicide.

Ethical Statement

Helsinki Declaration rules were followed to conduct this study. The study was approved by Pamukkale University Medical School Ethics Committee (60116787-020/53631 09.09.2020).

Supporting Institution

This work was supported by Pamukkale University Scientific Research Projects Coordination Unit under project number 2021TIPF007.

Project Number

2021TIPF007

Thanks

The authors express their gratitude to the staff of the Medical Genetics Laboratory at İzmir Tınaztepe University and Ass. Prof. Hande ŞENOL for her statistical contributions.

References

  • Kew JNC, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005;179(1):4-29. DOI:10.1007/s00213-005-2200-z.
  • Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 2009;4(8):e6585. DOI:10.1371/journal.pone.0006585.
  • Sokolowski M, Ben-Efraim YJ, Wasserman J, Wasserman D. Glutamatergic GRIN2B and polyaminergic ODC1 genes in suicide attempts: associations and gene-environment interactions with childhood/adolescent physical assault. Mol Psychiatry 2013;18(9):985-92. DOI:10.1038/mp.2012.112.
  • Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M, Steele J, Schweizer B, Goes FS, Mondimore FM, Mackinnon DF; Bipolar Genome Study Consortium; Perlis RH, Lee PH, Huang J, Kelsoe JR, Shilling PD, Rietschel M, Nöthen M, Cichon S, Gurling H, Purcell S, Smoller JW, Craddock N, DePaulo JR, Schulze TG, McMahon FJ, Zandi PP, Potash JB. A genome-wide association study of attempted suicide. Mol Psychiatry 2012;17(4):433-44. DOI:10.1038/mp.2011.4.
  • Linhoff MW, Laurén J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, Airaksinen MS, Strittmatter SM, Craig AM. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 2009;61(5):734-49. DOI:10.1016/j.neuron.2009.01.017.
  • Laurén J, Airaksinen MS, Saarma M, Timmusk T. A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics. 2003;81(4):411-21. DOI:10.1016/s0888-7543(03)00030-2.
  • Siddiqui TJ, Tari PK, Connor SA, Zhang P, Dobie FA, She K, Kawabe H, Wang YT, Brose N, Craig AM. An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells. Neuron 2013;79(4):680-95. DOI:10.1016/j.neuron.2013.06.029.
  • Willour VL, Zandi PP, Badner JA, Steele J, Miao K, Lopez V, MacKinnon DF, Mondimore FM, Schweizer B, McInnis MG, Miller EB, Depaulo JR, Gershon ES, McMahon FJ, Potash JB. Attempted suicide in bipolar disorder pedigrees: Evidence for linkage to 2p12. Biol Psychiatry 2007;61(5):725-7. DOI:10.1016/j.biopsych.2006.05.014.
  • Butler AW, Breen G, Tozzi F, Craddock N, Gill M, Korszun A, Maier W, Middleton LT, Mors O, Owen MJ, Perry J, Preisig M, Rice JP, Rietschel M, Jones L, Farmer AE, Lewis CM, McGuffin P. A genomewide linkage study on suicidality in major depressive disorder confirms evidence for linkage to 2p12. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(8):1465-73. DOI:10.1002/ajmg.b.31127.
  • Zubenko GS, Maher BS, Hughes HB 3rd, Zubenko WN, Scott Stiffler J, Marazita ML. Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression. Am J Med Genet B Neuropsychiatr Genet. 2004;129B(1):47-54. DOI:10.1002/ajmg.b.30092.
  • Hesselbrock V, Dick D, Hesselbrock M, Foroud T, Schuckit M, Edenberg H, Bucholz K, Kramer J, Reich T, Goate A, Bierut L, Rice JP, Nurnberger JI. The search for genetic risk factors associated with suicidal behavior. Alcohol Clin Exp Res. 2004;28(5 Suppl):70S-76S. DOI:10.1097/01.alc.0000127416.92128.b0.
  • Sudol K, Mann JJ. Biomarkers of suicide attempt behavior: towards a biological model of risk. Curr Psychiatry Rep. 2017;19(6):31. DOI:10.1007/s11920-017-0781-y.
  • Gray AL, Hyde TM, Deep-Soboslay A, Kleinman JE, Sodhi MS. Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry 2015;20(9):1057-68. DOI:10.1038/mp.2015.91.
  • Martinez-Lozada Z, Guillem AM, Robinson MB. Transcriptional Regulation of Glutamate Transporters: From Extracellular Signals to Transcription Factors. Adv Pharmacol. 2016;76:103-45. DOI:10.1016/bs.apha.2016.01.004.
  • Reichman RD, Gaynor SC, Monson ET, Gaine ME, Parsons MG, Zandi PP, Potash JB, Willour VL. Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2020;183(2):128-139. DOI:10.1002/ajmg.b.32767.
  • Clinckemalie L, Spans L, Dubois V, Laurent M, Helsen C, Joniau S, Claessens F. Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element. Mol Endocrinol. 2013;27(12):2028-40. DOI:10.1210/me.2013-1098.
  • Moghanibashi M, Mohamadynejad P, Rasekhi M, Ghaderi A, Mohammadianpanah M. Polymorphism of estrogen response element in TFF1 gene promoter is associated with an increased susceptibility to gastric cancer. Gene. 2012;492(1):100-3. DOI:10.1016/j.gene.2011.10.048.
  • Zhao J, Verwer RWH, Gao SF, Qi XR, Lucassen PJ, Kessels HW, Swaab DF. Prefrontal alterations in GABAergic and glutamatergic gene expression in relation to depression and suicide. J Psychiatr Res. 2018;102:261-274. DOI:10.1016/j.jpsychires.2018.04.020.
  • Zhao J, Verwer RW, van Wamelen DJ, Qi XR, Gao SF, Lucassen PJ, Swaab DF. Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide. J Psychiatr Res. 2016;82:8-15. DOI:10.1016/j.jpsychires.2016.06.017.
Year 2024, Volume: 14 Issue: 4, 1041 - 1047, 29.12.2024
https://doi.org/10.33808/clinexphealthsci.1480334

Abstract

Project Number

2021TIPF007

References

  • Kew JNC, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005;179(1):4-29. DOI:10.1007/s00213-005-2200-z.
  • Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 2009;4(8):e6585. DOI:10.1371/journal.pone.0006585.
  • Sokolowski M, Ben-Efraim YJ, Wasserman J, Wasserman D. Glutamatergic GRIN2B and polyaminergic ODC1 genes in suicide attempts: associations and gene-environment interactions with childhood/adolescent physical assault. Mol Psychiatry 2013;18(9):985-92. DOI:10.1038/mp.2012.112.
  • Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M, Steele J, Schweizer B, Goes FS, Mondimore FM, Mackinnon DF; Bipolar Genome Study Consortium; Perlis RH, Lee PH, Huang J, Kelsoe JR, Shilling PD, Rietschel M, Nöthen M, Cichon S, Gurling H, Purcell S, Smoller JW, Craddock N, DePaulo JR, Schulze TG, McMahon FJ, Zandi PP, Potash JB. A genome-wide association study of attempted suicide. Mol Psychiatry 2012;17(4):433-44. DOI:10.1038/mp.2011.4.
  • Linhoff MW, Laurén J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, Airaksinen MS, Strittmatter SM, Craig AM. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 2009;61(5):734-49. DOI:10.1016/j.neuron.2009.01.017.
  • Laurén J, Airaksinen MS, Saarma M, Timmusk T. A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics. 2003;81(4):411-21. DOI:10.1016/s0888-7543(03)00030-2.
  • Siddiqui TJ, Tari PK, Connor SA, Zhang P, Dobie FA, She K, Kawabe H, Wang YT, Brose N, Craig AM. An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells. Neuron 2013;79(4):680-95. DOI:10.1016/j.neuron.2013.06.029.
  • Willour VL, Zandi PP, Badner JA, Steele J, Miao K, Lopez V, MacKinnon DF, Mondimore FM, Schweizer B, McInnis MG, Miller EB, Depaulo JR, Gershon ES, McMahon FJ, Potash JB. Attempted suicide in bipolar disorder pedigrees: Evidence for linkage to 2p12. Biol Psychiatry 2007;61(5):725-7. DOI:10.1016/j.biopsych.2006.05.014.
  • Butler AW, Breen G, Tozzi F, Craddock N, Gill M, Korszun A, Maier W, Middleton LT, Mors O, Owen MJ, Perry J, Preisig M, Rice JP, Rietschel M, Jones L, Farmer AE, Lewis CM, McGuffin P. A genomewide linkage study on suicidality in major depressive disorder confirms evidence for linkage to 2p12. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(8):1465-73. DOI:10.1002/ajmg.b.31127.
  • Zubenko GS, Maher BS, Hughes HB 3rd, Zubenko WN, Scott Stiffler J, Marazita ML. Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression. Am J Med Genet B Neuropsychiatr Genet. 2004;129B(1):47-54. DOI:10.1002/ajmg.b.30092.
  • Hesselbrock V, Dick D, Hesselbrock M, Foroud T, Schuckit M, Edenberg H, Bucholz K, Kramer J, Reich T, Goate A, Bierut L, Rice JP, Nurnberger JI. The search for genetic risk factors associated with suicidal behavior. Alcohol Clin Exp Res. 2004;28(5 Suppl):70S-76S. DOI:10.1097/01.alc.0000127416.92128.b0.
  • Sudol K, Mann JJ. Biomarkers of suicide attempt behavior: towards a biological model of risk. Curr Psychiatry Rep. 2017;19(6):31. DOI:10.1007/s11920-017-0781-y.
  • Gray AL, Hyde TM, Deep-Soboslay A, Kleinman JE, Sodhi MS. Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry 2015;20(9):1057-68. DOI:10.1038/mp.2015.91.
  • Martinez-Lozada Z, Guillem AM, Robinson MB. Transcriptional Regulation of Glutamate Transporters: From Extracellular Signals to Transcription Factors. Adv Pharmacol. 2016;76:103-45. DOI:10.1016/bs.apha.2016.01.004.
  • Reichman RD, Gaynor SC, Monson ET, Gaine ME, Parsons MG, Zandi PP, Potash JB, Willour VL. Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2020;183(2):128-139. DOI:10.1002/ajmg.b.32767.
  • Clinckemalie L, Spans L, Dubois V, Laurent M, Helsen C, Joniau S, Claessens F. Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element. Mol Endocrinol. 2013;27(12):2028-40. DOI:10.1210/me.2013-1098.
  • Moghanibashi M, Mohamadynejad P, Rasekhi M, Ghaderi A, Mohammadianpanah M. Polymorphism of estrogen response element in TFF1 gene promoter is associated with an increased susceptibility to gastric cancer. Gene. 2012;492(1):100-3. DOI:10.1016/j.gene.2011.10.048.
  • Zhao J, Verwer RWH, Gao SF, Qi XR, Lucassen PJ, Kessels HW, Swaab DF. Prefrontal alterations in GABAergic and glutamatergic gene expression in relation to depression and suicide. J Psychiatr Res. 2018;102:261-274. DOI:10.1016/j.jpsychires.2018.04.020.
  • Zhao J, Verwer RW, van Wamelen DJ, Qi XR, Gao SF, Lucassen PJ, Swaab DF. Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide. J Psychiatr Res. 2016;82:8-15. DOI:10.1016/j.jpsychires.2016.06.017.
There are 19 citations in total.

Details

Primary Language English
Subjects Forensic Medicine
Journal Section Articles
Authors

Hatice Kübra Ata Öztürk 0000-0002-4875-0826

Volkan Zeybek 0000-0002-8079-2671

Selcan Kesan 0000-0002-6762-9634

Kemalettin Acar 0000-0002-0200-4764

Project Number 2021TIPF007
Publication Date December 29, 2024
Submission Date May 8, 2024
Acceptance Date September 24, 2024
Published in Issue Year 2024 Volume: 14 Issue: 4

Cite

APA Ata Öztürk, H. K., Zeybek, V., Kesan, S., Acar, K. (2024). Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases. Clinical and Experimental Health Sciences, 14(4), 1041-1047. https://doi.org/10.33808/clinexphealthsci.1480334
AMA Ata Öztürk HK, Zeybek V, Kesan S, Acar K. Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases. Clinical and Experimental Health Sciences. December 2024;14(4):1041-1047. doi:10.33808/clinexphealthsci.1480334
Chicago Ata Öztürk, Hatice Kübra, Volkan Zeybek, Selcan Kesan, and Kemalettin Acar. “Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases”. Clinical and Experimental Health Sciences 14, no. 4 (December 2024): 1041-47. https://doi.org/10.33808/clinexphealthsci.1480334.
EndNote Ata Öztürk HK, Zeybek V, Kesan S, Acar K (December 1, 2024) Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases. Clinical and Experimental Health Sciences 14 4 1041–1047.
IEEE H. K. Ata Öztürk, V. Zeybek, S. Kesan, and K. Acar, “Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases”, Clinical and Experimental Health Sciences, vol. 14, no. 4, pp. 1041–1047, 2024, doi: 10.33808/clinexphealthsci.1480334.
ISNAD Ata Öztürk, Hatice Kübra et al. “Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases”. Clinical and Experimental Health Sciences 14/4 (December 2024), 1041-1047. https://doi.org/10.33808/clinexphealthsci.1480334.
JAMA Ata Öztürk HK, Zeybek V, Kesan S, Acar K. Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases. Clinical and Experimental Health Sciences. 2024;14:1041–1047.
MLA Ata Öztürk, Hatice Kübra et al. “Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases”. Clinical and Experimental Health Sciences, vol. 14, no. 4, 2024, pp. 1041-7, doi:10.33808/clinexphealthsci.1480334.
Vancouver Ata Öztürk HK, Zeybek V, Kesan S, Acar K. Determining Expression Profile of Leucine-Rich Repeating Transmembrane Protein4 (LRRTM4) In Suicide Cases. Clinical and Experimental Health Sciences. 2024;14(4):1041-7.

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