Trevor Balderrama

Background: Anxiety disorders are disorders that are maladaptive coping mechanisms to stress that result in behaviors such as, “worry, social and performance fears, unexpected and/or triggered panic attacks, anticipatory anxiety, and avoidance behaviors.”¹ Anxiety disorders carry a heavy financial burden to society with the cost estimated to be around 4.6 workdays lost per month and more than 4 billion dollars in workplace costs worldwide.^1. The WHO estimates about 301 million people suffered from anxiety worldwide in 2019.² Benzodiazepines are effective in the treatment of acute panic attacks and episodes of severe anxiety but are known to have a very high risk of abuse which limits their efficacy in long-term treatment .³

Objective: To characterize the role of TMEM132D in panic disorder.

Search Methods: Using PubMed I began searching for general review articles that linked potential genes with various anxiety disorders.⁴  The TMEM132D gene referenced in a 2023 review article was found to be highly correlated with panic disorder and established the topic of this research. I further investigated primary research articles discussing TMEM132D  using MeSH keywords and search phrases such as, “TMEM132D”, “protein”, “function”, “anxiety”, “panic disorder”, “epigenetics”, and “polymorphisms” with articles ranging from 2018-2023.^4,5,6,7  Due to the limited understanding and research into the TMEM132D gene, further research had to be expanded to characterize its behavior with associated proteins like the WAVE-Regulatory Complex.⁷

Results: One 2022 study aimed to identify the correlation between TMEM132D levels experience of physical abuse in patients with panic disorder vs. those without panic disorder.⁵ The researchers performed the Hamilton Anxiety Scale (HAMA), the Panic Disorder Severity Scale (PDSS), and the Childhood Trauma Questionnaire (CTQ) to quantify the levels of anxiety, panic disorder, and childhood trauma in the participants.⁵ Analyzing that with Illumina DNA data from the participants they found individuals in the PD group were much more likely to have undermethylated regions of the TMEM132D promoter specifically in the CPG2 site with a p-value of 0.0064. They found those with a history of physical abuse were more likely to show decreased methylation of the CPG2 site with a p-value of 0.0464.⁵ This implies an increase in TMEM132D expression in the panic disorder group of this study. In a 2018 study, researchers found that mice with a polymorphism that had a greater affinity for RNA Polymerase II had greater expression of TMEM132D and exhibited more severe anxiety behaviors.⁶ Finally, in a 2023 study, researchers found that TMEM132D works in mammalian and C. elegans by inhibiting the WAVE Regulatory Complex and in turn hindering neuronal migration.⁷ Specifically, these researchers found that expression of TMEM132D is exclusively in the central nervous system and highly expressed in the anterior cingulate cortex, a brain region largely thought to be responsible for panic disorder.⁷ They found it plays a crucial role in preventing abnormal neuronal development, but this system gets disrupted in panic disorder.⁷

Conclusions: The exact role of the TMEM132D gene and protein in the manifestation of panic disorder is not entirely known.⁷ What is considered too high or too low TMEM132D has not been well studied. The field of molecular biology and genetics is still in its early stages.  The findings and discoveries of the TMEM132D gene support further study into its role in panic disorder to provide an example of what can be done with the discovery of the underlying mechanisms of life and biology.

Works Cited:

1. Szuhany KL, Simon NM. Anxiety Disorders: A Review. JAMA. 2022;328(24):2431-2445. doi:10.1001/jama.2022.22744
2. Anxiety disorders. Accessed February 20, 2024. https://www.who.int/news-room/fact-sheets/detail/anxiety-disorders
3. Garakani A, Murrough JW, Freire RC, et al. Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options. Front Psychiatry. 2020;11. Accessed February 12, 2024. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2020.595584
4. Koskinen MK, Hovatta I. Genetic insights into the neurobiology of anxiety. Trends Neurosci.2023;46(4):318-331. doi:10.1016/j.tins.2023.01.007
5. Yu Q, Wang C, Xu H, et al. The mediating role of transmembrane protein 132D methylation in predicting the occurrence of panic disorder in physical abuse. Front Psychiatry. 2022;13:972522. doi:3389/fpsyt.2022.972522
6. Naik R, Sotnikov S, Diepold R, et al. Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex. In: Vol 8. Springer Nature; 2018:1-18. Accessed March 4, 2024. https://search.ebscohost.com/login.aspx?direct=true&db=edsbl&AN=vdc.100105575258.0×000001&site=eds-live&scope=site&authtype=shib&custid=s8516548
7. Wang X, Jiang W, Luo S, et al. The C. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex. Mol Brain. 2021;14(1):54. doi:10.1186/s13041-021-00767-w