# ZNF804A

## Overview
ZNF804A is a gene that encodes the zinc finger protein 804A, which is characterized by a C2H2-type zinc-finger domain, a motif commonly associated with DNA binding and transcription regulation. Unlike typical zinc-finger proteins, ZNF804A contains only a single C2H2 motif, suggesting a unique functional role (Deans2017Psychosis). The protein is largely unstructured except for this domain and is involved in various cellular processes, including protein translation, pre-mRNA processing, and synaptic function (Chapman2018Convergent; Zhou2017Interactome). ZNF804A is predominantly localized in the nucleus but also found in neuronal soma and dendrites, indicating its involvement in neurodevelopmental processes such as neuronal migration and synapse formation (Deans2017Psychosis). The gene has been implicated in psychiatric disorders, including schizophrenia and bipolar disorder, with specific variants linked to altered expression and neurodevelopmental disruptions (Chang2017The; Girgenti2012ZNF804a).

## Structure
ZNF804A is a protein encoded by the ZNF804A gene, characterized by the presence of a C2H2-type zinc-finger domain, which is a common motif associated with DNA binding and transcription regulation (Deans2017Psychosis; Klockmeier2021Schizophrenia). This zinc-finger domain is well-conserved and located in the N-terminal region of the protein (Klockmeier2021Schizophrenia). Unlike classical zinc-finger proteins, ZNF804A contains only a single C2H2 motif, suggesting it may not function as a typical zinc-finger protein (Deans2017Psychosis).

The protein is largely unstructured, except for the zinc-finger domain, and contains two central nuclear localization signals (Klockmeier2021Schizophrenia). ZNF804A is present in both nuclear and extranuclear compartments, indicating its role in various cellular functions beyond transcription regulation (Deans2017Psychosis; Klockmeier2021Schizophrenia). The protein's distribution changes during neural differentiation, which may reflect alterations in isoform expression or function (Deans2017Psychosis).

ZNF804A has several splice variants, including the E3/E4 isoform, which lacks the C2H2 domain and is expressed at reduced levels in schizophrenia patients (Deans2017Psychosis). This suggests that different isoforms may have distinct roles in cellular processes.

## Function
ZNF804A is a gene that encodes a protein involved in several critical molecular processes in healthy human cells, particularly in the brain. It plays a significant role in protein translation and is a component of the protein translational machinery. ZNF804A interacts with ribosomal proteins and is involved in ribosomal assembly and function, influencing translation efficiency and nascent protein synthesis (Zhou2017Interactome). The protein is also implicated in pre-mRNA processing and gene expression regulation. It interacts with splicing factors and RNA-binding proteins, suggesting a role in alternative splicing and RNA binding (Chapman2018Convergent).

In terms of cellular localization, ZNF804A is predominantly found in the nucleus but also localizes to the soma and dendrites in neurons, where it co-localizes with synaptic markers, indicating its involvement in synaptic function (Deans2017Psychosis). The protein is active in processes such as neuronal migration, neurite outgrowth, and synapse formation, which are essential for neurodevelopment and proper neuronal connectivity (Deans2017Psychosis; Zhou2017Interactome). These functions highlight ZNF804A's importance in maintaining normal cellular and organismal outcomes, particularly in the context of brain development and function.

## Clinical Significance
The ZNF804A gene has been implicated in several psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders. Variants in ZNF804A, particularly the SNP rs1344706, have been associated with an increased risk of schizophrenia and bipolar disorder. This SNP is linked to altered expression levels of ZNF804A, which may contribute to the pathogenesis of these conditions by affecting neurodevelopmental processes such as neuronal migration and synaptic development (Chang2017The; Girgenti2012ZNF804a).

Alterations in ZNF804A expression have been observed in patients with schizophrenia, where reduced expression is associated with the risk allele of rs1344706. This reduction in expression is thought to lead to aberrant neurite growth and decreased dendritic spine density, which are characteristic of schizophrenia (Chang2017The). The gene's interactions with proteins involved in cell adhesion and neurite outgrowth, such as LGALS1 and RPSA, further highlight its role in neurodevelopmental processes that, when disrupted, may contribute to psychiatric disorders (Zhou2017Interactome; Dong2021Schizophrenia).

Copy number variations in ZNF804A have also been identified in individuals with psychiatric disorders, suggesting that both genetic and expression-level alterations of ZNF804A are clinically significant (Donohoe2010The; Dong2021Schizophrenia).

## Interactions
ZNF804A is involved in various protein-protein interactions that are significant for its role in neural development and psychiatric disorders. A near genome-wide yeast two-hybrid screen identified 18 high-confidence interactors of ZNF804A, with many involved in RNA binding, circadian rhythm, and immune system regulation. Notably, STAT2 was identified as a key interactor, binding to the N-terminal region of ZNF804A, which influences interferon-mediated gene transcription (Klockmeier2021Schizophrenia). This interaction is significant in the context of schizophrenia, as STAT2 is associated with the disease (Klockmeier2021Schizophrenia).

ZNF804A also interacts with NT5C2, forming a protein complex in synaptic regions of cortical neurons. This interaction is crucial for synaptic function and is implicated in schizophrenia risk. The bidirectional interaction between ZNF804A and NT5C2 suggests a regulatory network that influences local protein translation at synapses (Aabdien2021Schizophrenia).

In addition, ZNF804A is involved in the regulation of neurite formation and synaptic localization, interacting with proteins such as NLGN4, which is associated with synapse density. Knockdown experiments have shown that reduced ZNF804A expression leads to decreased neurite length, highlighting its role in synaptic development (Deans2017Psychosis).


## References


[1. (Deans2017Psychosis) P.J. Michael Deans, Pooja Raval, Katherine J. Sellers, Nicholas J.F. Gatford, Sanjay Halai, Rodrigo R.R. Duarte, Carole Shum, Katherine Warre-Cornish, Victoria E. Kaplun, Graham Cocks, Matthew Hill, Nicholas J. Bray, Jack Price, and Deepak P. Srivastava. Psychosis risk candidate znf804a localizes to synapses and regulates neurite formation and dendritic spine structure. Biological Psychiatry, 82(1):49–61, July 2017. URL: http://dx.doi.org/10.1016/j.biopsych.2016.08.038, doi:10.1016/j.biopsych.2016.08.038. This article has 97 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.biopsych.2016.08.038)

[2. (Klockmeier2021Schizophrenia) Konrad Klockmeier, Eduardo Silva Ramos, Tamás Raskó, Adrián Martí Pastor, and Erich E. Wanker. Schizophrenia risk candidate protein znf804a interacts with stat2 and influences interferon-mediated gene transcription in mammalian cells. Journal of Molecular Biology, 433(19):167184, September 2021. URL: http://dx.doi.org/10.1016/j.jmb.2021.167184, doi:10.1016/j.jmb.2021.167184. This article has 5 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2021.167184)

[3. (Chapman2018Convergent) Ria M Chapman, Caroline L Tinsley, Matthew J Hill, Marc P Forrest, Katherine E Tansey, Antonio F Pardiñas, Elliott Rees, A Michelle Doyle, Lawrence S Wilkinson, Michael J Owen, Michael C O’Donovan, and Derek J Blake. Convergent evidence that znf804a is a regulator of pre-messenger rna processing and gene expression. Schizophrenia Bulletin, 45(6):1267–1278, December 2018. URL: http://dx.doi.org/10.1093/schbul/sby183, doi:10.1093/schbul/sby183. This article has 21 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/schbul/sby183)

[4. (Chang2017The) H Chang, X Xiao, and M Li. The schizophrenia risk gene znf804a: clinical associations, biological mechanisms and neuronal functions. Molecular Psychiatry, 22(7):944–953, March 2017. URL: http://dx.doi.org/10.1038/mp.2017.19, doi:10.1038/mp.2017.19. This article has 68 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/mp.2017.19)

5. (Aabdien2021Schizophrenia) Schizophrenia Risk Proteins ZNF804A and NT5C2 Interact at Synapses. This article has 0 citations.

[6. (Girgenti2012ZNF804a) Matthew J. Girgenti, Joseph J. LoTurco, and Brady J. Maher. Znf804a regulates expression of the schizophrenia-associated genes prss16, comt, pde4b, and drd2. PLoS ONE, 7(2):e32404, February 2012. URL: http://dx.doi.org/10.1371/journal.pone.0032404, doi:10.1371/journal.pone.0032404. This article has 78 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0032404)

[7. (Zhou2017Interactome) Y Zhou, F Dong, T A Lanz, V Reinhart, M Li, L Liu, J Zou, H S Xi, and Y Mao. Interactome analysis reveals znf804a, a schizophrenia risk gene, as a novel component of protein translational machinery critical for embryonic neurodevelopment. Molecular Psychiatry, 23(4):952–962, September 2017. URL: http://dx.doi.org/10.1038/mp.2017.166, doi:10.1038/mp.2017.166. This article has 35 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/mp.2017.166)

[8. (Donohoe2010The) G. Donohoe, D. W. Morris, and A. Corvin. The psychosis susceptibility gene znf804a: associations, functions, and phenotypes. Schizophrenia Bulletin, 36(5):904–909, August 2010. URL: http://dx.doi.org/10.1093/schbul/sbq080, doi:10.1093/schbul/sbq080. This article has 47 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/schbul/sbq080)

[9. (Dong2021Schizophrenia) Fengping Dong, Joseph Mao, Miranda Chen, Joy Yoon, and Yingwei Mao. Schizophrenia risk znf804a interacts with its associated proteins to modulate dendritic morphology and synaptic development. Molecular Brain, January 2021. URL: http://dx.doi.org/10.1186/s13041-021-00729-2, doi:10.1186/s13041-021-00729-2. This article has 18 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13041-021-00729-2)