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PRDM12 gene is normally switched on during the development of pain-sensing nerve cells. People with homozygous mutations of the PRDM12 gene experience congenital insensitivity to pain (CIP). PRMD12 is a part of a larger domain that mediate histone methyltransferases. Enzymes target gene promoters in order to control gene expression.

Gene Location & Expression

Protein Integration

Protein Function

PRDM12 codes for a protein which regulates the neurological path through which pain in perceived, known as PR domain zinc finger protein 12. As stated in Transcriptional regulator PRDM12 is essential for human pain perception, the “protein isoform is made up of 367 amino acids containing a PR domain (related to the SET methyltransferase domain), 3 zinc fingers, and a C-terminal polyalanine tract.” The protein plays a vital role in the regulation of histone H3-K9 dimethylation. PRDM12’s protein also directly affects the development of nerve-endings. The protein is synthesized at the same developmental point as the neurons which sense pain and the growth of the two is linked. The mutation of this gene results in a non-functioning protein, which in-turn causes a failure to develop the pain-sensing nerve endings and an organism without sensitivity to pain. This lack of pain-sensing nerve endings can cause severe harm to the individual, as they cannot sense when they are injured by something such as a hot stove-eye or broken bone. PRDM12’s protein has also been found to be a tumor suppressor for chronic myloid leukemia. The protein controls gene expression by modifying chromatin. PRDMs as a family tend to require enzyme help to modify histones, with some exceptions.  

Clinical Significance

There are a number of diseases and conditions that can result from mutations in the PRDM12 gene. Congenital insensitivity to pain (CIP) is a rare extreme phenotype characterized by an inability to perceive pain present from birth due to a lack of, or malfunction of, nociceptors. There are two common forms of CIP. First, loss-of-function mutation in the SCN9A renders nociceptors unable to respond to any noxious stimulus. Second, loss-of-function mutation in the NTRK1 leads to a failure of nociceptors to develop. Researchers identified 10 homozygous mutations on PRDM12 that appeared to be linked to the condition.They then studied nerve biopsies from some of the affected individuals and found that these patients had about half the usual number of pain-sensing nerve fibers in their legs, or lacked these nerves altogether. Past research has shown that PRDM12 is involved in the modification of chromatin, a molecule that attaches itself to chromosomes and acts as an epigenetic “switch” that can turn genes on and off, the researchers noted. Since chromatin plays an important role in the development of neurons, they theorized that mutated PRDM12 might block the normal development of nociceptors (pain-sensing neurons) and nerve fibers

History

Notes

1. ^ Chen, YC; Auer-Grumbach, M; Matsukawa, S; Zitzelsberger, M; Themistocleous, AC; Strom, TM; Samara, C; Moore, AW; Cho, LT; Young, GT; Weiss, C; Schabhüttl, M; Stucka, R; Schmid, AB; Parman, Y; Graul-Neumann, L; Heinritz, W; Passarge, E; Watson, RM; Hertz, JM; Moog, U; Baumgartner, M; Valente, EM; Pereira, D; Restrepo, CM; Katona, I; Dusl, M; Stendel, C; Wieland, T; Stafford, F; Reimann, F; von Au, K; Finke, C; Willems, PJ; Nahorski, MS; Shaikh, SS; Carvalho, OP; Nicholas, AK; Karbani, G; McAleer, MA; Cilio, MR; McHugh, JC; Murphy, SM; Irvine, AD; Jensen, UB; Windhager, R; Weis, J; Bergmann, C; Rautenstrauss, B; Baets, J; De Jonghe, P; Reilly, MM; Kropatsch, R; Kurth, I; Chrast, R; Michiue, T; Bennett, DL; Woods, CG; Senderek, J (July 2015). "Transcriptional regulator PRDM12 is essential for human pain perception". Nature Genetics. 47 (7): 803–8. doi:10.1038/ng.3308. PMID 26005867.
2. ^ Costandi, Mo. "Uncomfortably numb: The people who feel no pain". the guardian. the guardian. Retrieved 31 July 2015.
3. Hohenauer, Tobias; Moore, Adrian W. (2012-07-01). "The Prdm family: expanding roles in stem cells and development". Development. 139 (13): 2267–2282. doi:10.1242/dev.070110. ISSN 0950-1991. PMID 22669819.
4. EMBL-EBI, InterPro. "PR domain zinc finger protein 12 (Q9H4Q4) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2018-11-09.
5. "The requirement of histone modification by PRDM12 and Kdm4a for the development of pre-placodal ectoderm and neural crest in Xenopus". Developmental Biology. 399 (1): 164–176. 2015-03-01. doi:10.1016/j.ydbio.2014.12.028. ISSN 0012-1606.
6. Database, GeneCards Human Gene. "PRDM12 Gene - GeneCards | PRD12 Protein | PRD12 Antibody". www.genecards.org. Retrieved 2018-11-09.
7. ^ Hiscott, Rebecca. "Researchers Identify New Genetic Mutations Linked to Pain Insensitivity". Journals.lww.com. American Academy of Neurology. Retrieved 11/6/2018. {{cite web}}: Check date values in: |accessdate= (help)
8. Reid, A G; Nacheva, E P (2003-10-02). "A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion". Leukemia. 18 (1): 178–180. doi:10.1038/sj.leu.2403162. ISSN 0887-6924.
9. "Characterization of the PR domain of RIZ1 histone methyltransferase". Biochemical and Biophysical Research Communications. 333 (3): 925–934. 2005-08-05. doi:10.1016/j.bbrc.2005.05.190. ISSN 0006-291X.
10. ^ Zhang, Stella; Sharif, Saghira; Chen, Ya-Chun; Valente, Enza-Maria; Ahmed, Mushtaq; Sheridan, Eamonn; Bennett, Christopher; Woods, Geoffrey. "Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain". jmg.bmj.com. BMJ Publishing Group. Retrieved 11/6/2018. {{cite web}}: Check date values in: |accessdate= (help)

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