# PRDM12

## Overview
PRDM12 is a gene that encodes the PR/SET domain 12 protein, a transcription factor involved in the development and function of nociceptive sensory neurons, which are critical for pain perception. The PRDM12 protein is characterized by its PR domain and multiple zinc finger domains, which facilitate its role in DNA binding and protein interactions. Although it lacks intrinsic histone lysine methyltransferase activity, PRDM12 recruits the methyltransferase G9a to modify histone H3 at lysine 9, influencing gene expression during neurogenesis (Chen2015Transcriptional; Rienzo2021PRDM12). Mutations in the PRDM12 gene are linked to congenital insensitivity to pain (CIP) and other sensory neuropathies, underscoring its clinical significance in sensory neuron development and function (Yu2023Congenital; Rienzo2021PRDM12).

## Structure
The PRDM12 protein is composed of 367 amino acids and includes several key structural domains. It features a PR domain located between amino acids 86 and 203, which is associated with lysine methyltransferase activity, although PRDM12 itself lacks intrinsic histone lysine methyltransferase activity (Rienzo2021PRDM12). The protein also contains three C2H2-type zinc finger domains at positions 243-265, 271-293, and 299-323, which are involved in DNA binding and protein interactions (Rienzo2021PRDM12). Additionally, a C-terminal polyalanine tract is present from amino acids 344 to 359 (Rienzo2021PRDM12).

PRDM12 is primarily localized in the nucleus, exhibiting a diffuse, lace-like pattern (Rienzo2021PRDM12). It interacts with the H3K9 methyltransferase G9a to facilitate the dimethylation of H3K9me2, a repressive transcriptional mark, although the exact recruitment mechanism remains unclear (Rienzo2021PRDM12). The protein is predicted to be soluble with no transmembrane helices and is localized in the mitochondria and plasma membrane (Mehmood2020Structural).

Post-translational modifications of PRDM12 include predicted phosphorylation sites, which may influence its function (Mehmood2020Structural). The protein's structure and interactions are crucial for its role in pain perception and neurogenesis (Mehmood2020Structural).

## Function
PRDM12 is a transcription factor that plays a crucial role in the development and function of nociceptive sensory neurons, which are responsible for pain perception. It is involved in the regulation of gene expression through histone methylation, specifically by recruiting the methyltransferase G9a to dimethylate histone H3 at lysine 9 (H3K9me2), a critical epigenetic modification during neurogenesis (Chen2015Transcriptional). PRDM12 is expressed in developing and mature nociceptors, where it regulates the expression of the nerve growth factor receptor TrkA (Ntrk1), essential for the survival and differentiation of these neurons (Desiderio2019Prdm12).

In human cells, PRDM12 is active in the nucleus, where it modulates chromatin structure to control transcriptional activity. It cooperates with proneural factors like Ngn1 and Ngn2 to promote the nociceptor phenotype by maintaining the expression of nociceptive markers such as TRKA, while inhibiting the expression of Ntrk2 and Ntrk3 (Desiderio2019Prdm12; Rienzo2021PRDM12). This regulation is vital for the proper specification and differentiation of nociceptors, and mutations in PRDM12 can lead to congenital insensitivity to pain (CIP) (Nagy2015The; Desiderio2019Prdm12).

## Clinical Significance
Mutations in the PRDM12 gene are associated with congenital insensitivity to pain (CIP), a rare genetic disorder where individuals cannot perceive pain. This condition is characterized by a lack of pain perception, leading to self-mutilation behaviors, recurrent infections, and other complications. The mutations affect the development of nociceptors, which are responsible for pain perception, resulting in a severe loss of Aδ fibers in the sural nerves while other sensory modalities remain largely unaltered (Chen2015Transcriptional; Yu2023Congenital).

PRDM12 mutations have been linked to hereditary sensory and autonomic neuropathy type VIII (HSAN-VIII), also known as CIP3, which includes symptoms such as growth delays, anhidrosis, and oral and corneal ulcers (Yu2023Congenital). Specific mutations, such as missense, splice-site, frame-shift, and polyalanine-repeat mutations, impair the gene's histone-methylation capacity, affecting sensory neuron development (Rienzo2021PRDM12).

PRDM12 mutations are also associated with midface toddler excoriation syndrome (MiTES), characterized by severe midfacial lesions. The phenotypic spectrum of PRDM12 mutations is expanding, with reports of early-onset sensory polyneuropathy and other related conditions (Rienzo2021PRDM12). Genetic analysis is crucial for accurate diagnosis and prenatal testing, which can help reduce the incidence of these disorders (Yu2023Congenital).

## Interactions
PRDM12 interacts with various proteins and plays a significant role in neural development and pain perception. It is known to recruit the methyltransferase G9a (Ehmt2) to dimethylate histone H3 at lysine 9 (H3K9me2), a crucial modification for neurogenesis (Chen2015Transcriptional). PRDM12 also interacts with the nerve growth factor receptor TrkA, essential for the maturation and maintenance of nociceptive neurons (Desiderio2019Prdm12). In zebrafish, Prdm12b, a homolog of PRDM12, interacts with EHMT2/G9a and Bhlhe22 through its zinc-finger domain (Rienzo2021PRDM12).

PRDM12 is involved in the demarcation between pre-placodal ectoderm and neural crest regions through its interaction with Kdm4a, affecting H3K9 methylation levels on neural crest gene promoters (Rienzo2021PRDM12). It also interacts with proneural factors like Neurogenin1 (Ngn1) and Neurogenin2 (Ngn2) to promote nociceptive fate by initiating and maintaining TrkA expression (Desiderio2019Prdm12). These interactions highlight PRDM12's role in modulating chromatin structure and gene expression, crucial for sensory neuron development and function.


## References


[1. (Rienzo2021PRDM12) Monica Rienzo, Erika Di Zazzo, Amelia Casamassimi, Patrizia Gazzerro, Giovanni Perini, Maurizio Bifulco, and Ciro Abbondanza. Prdm12 in health and diseases. International Journal of Molecular Sciences, 22(21):12030, November 2021. URL: http://dx.doi.org/10.3390/ijms222112030, doi:10.3390/ijms222112030. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms222112030)

[2. (Nagy2015The) Vanja Nagy, Tiffany Cole, Claude Van Campenhout, Thang M Khoung, Calvin Leung, Simon Vermeiren, Maria Novatchkova, Daniel Wenzel, Domagoj Cikes, Anton A Polyansky, Ivona Kozieradzki, Arabella Meixner, Eric J Bellefroid, G Gregory Neely, and Josef M Penninger. The evolutionarily conserved transcription factor prdm12 controls sensory neuron development and pain perception. Cell Cycle, 14(12):1799–1808, June 2015. URL: http://dx.doi.org/10.1080/15384101.2015.1036209, doi:10.1080/15384101.2015.1036209. This article has 53 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/15384101.2015.1036209)

[3. (Yu2023Congenital) Hanrui Yu, Jie Wu, Jinju Cong, Mingxiong Chen, Yifei Huang, Jifeng Yu, and Liqiang Wang. Congenital insensitivity to pain associated with prdm12 mutation: two case reports and a literature review. Frontiers in Genetics, March 2023. URL: http://dx.doi.org/10.3389/fgene.2023.1139161, doi:10.3389/fgene.2023.1139161. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fgene.2023.1139161)

[4. (Mehmood2020Structural) Sarmad Mehmood, Rubina Dad, Arsalan Ahmad, Muhammad Ikram Ullah, Peter John, Amjad Ali, Christian A. Hubner, Aisha Mohyuddin, and Muhammad Jawad Hassan. Structural and functional annotation of pr/set domain (prdm) protein family: in-silico study elaborating role of prdm12 mutation in congenital insensitivity to pain. Computational Biology and Chemistry, 89:107382, December 2020. URL: http://dx.doi.org/10.1016/j.compbiolchem.2020.107382, doi:10.1016/j.compbiolchem.2020.107382. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.compbiolchem.2020.107382)

[5. (Chen2015Transcriptional) Ya-Chun Chen, Michaela Auer-Grumbach, Shinya Matsukawa, Manuela Zitzelsberger, Andreas C Themistocleous, Tim M Strom, Chrysanthi Samara, Adrian W Moore, Lily Ting-Yin Cho, Gareth T Young, Caecilia Weiss, Maria Schabhüttl, Rolf Stucka, Annina B Schmid, Yesim Parman, Luitgard Graul-Neumann, Wolfram Heinritz, Eberhard Passarge, Rosemarie M Watson, Jens Michael Hertz, Ute Moog, Manuela Baumgartner, Enza Maria Valente, Diego Pereira, Carlos M Restrepo, Istvan Katona, Marina Dusl, Claudia Stendel, Thomas Wieland, Fay Stafford, Frank Reimann, Katja von Au, Christian Finke, Patrick J Willems, Michael S Nahorski, Samiha S Shaikh, Ofélia P Carvalho, Adeline K Nicholas, Gulshan Karbani, Maeve A McAleer, Maria Roberta Cilio, John C McHugh, Sinead M Murphy, Alan D Irvine, Uffe Birk Jensen, Reinhard Windhager, Joachim Weis, Carsten Bergmann, Bernd Rautenstrauss, Jonathan Baets, Peter De Jonghe, Mary M Reilly, Regina Kropatsch, Ingo Kurth, Roman Chrast, Tatsuo Michiue, David L H Bennett, C Geoffrey Woods, and Jan Senderek. Transcriptional regulator prdm12 is essential for human pain perception. Nature Genetics, 47(7):803–808, May 2015. URL: http://dx.doi.org/10.1038/ng.3308, doi:10.1038/ng.3308. This article has 183 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ng.3308)

[6. (Desiderio2019Prdm12) Simon Desiderio, Simon Vermeiren, Claude Van Campenhout, Sadia Kricha, Elisa Malki, Sven Richts, Emily V. Fletcher, Thomas Vanwelden, Bela Z. Schmidt, Kristine A. Henningfeld, Tomas Pieler, C. Geoffrey Woods, Vanja Nagy, Catherine Verfaillie, and Eric J. Bellefroid. Prdm12 directs nociceptive sensory neuron development by regulating the expression of the ngf receptor trka. Cell Reports, 26(13):3522-3536.e5, March 2019. URL: http://dx.doi.org/10.1016/j.celrep.2019.02.097, doi:10.1016/j.celrep.2019.02.097. This article has 55 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.celrep.2019.02.097)