PRDM12

Last updated
PRDM12
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PRDM12 , PFM9, HSAN8, PR domain 12, PR/SET domain 12
External IDs OMIM: 616458 MGI: 2685844 HomoloGene: 10999 GeneCards: PRDM12
Orthologs
SpeciesHumanMouse
Entrez

59335

381359

Ensembl

ENSG00000130711

ENSMUSG00000079466

UniProt

Q9H4Q4

A2AJ77

RefSeq (mRNA)

NM_021619

NM_001123362

RefSeq (protein)

NP_067632

NP_001116834

Location (UCSC) Chr 9: 130.66 – 130.68 Mb Chr 2: 31.53 – 31.55 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

PR domain zinc finger protein 12 is a protein that in humans is encoded by the PRDM12 gene. This 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). [5] [6] PRMD12 is a part of a larger domain that mediate histone methyltransferases. Enzymes target gene promoters in order to control gene expression. [7]

Contents

Structure

The human 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. [5]

Function

PRDM12 influences the development of nerve cells that assist in perception and sensation of pain, which is an important evolutionary advantage. In humans, mutations in the PRDM12 gene can cause loss of pain perception brought on by defects in the development of sensory neurons. [8] It also has a range of interactions with and affects on various proteins. In vertebrates, PRDM12 directly represses the DBX1 and NK X6 genes. This is thought to be accomplished by utilizing G9a, a strong H3K9 methyltransferase. The indicated result of PRDM12's cross-repressive interaction with the DBX1 and NKX6 genes is that the PRDM12 partially acts as a promoter of V1 interneurons (which are essential to the locomotion of vertebrates). [9] It is a member of the group of PR- domain-containing zinc-finger familyfingers, "which appear to function as negative regulators of oncogenesis and include the tumor-associated genes MDS1-EVI1, RIZ, BLIMP1, MEL1 and PFM1. PRDM12 therefore represents an attractive candidate tumour suppressor gene within the der(9) [derivative chromosome 9] CDR [commonly deleted region]." [10] Several members of the PRDM family are found to be acting as a tumor suppressor or a factor driving oncogenic processes in human diseases, specifically and most notably in solid cancers and hematological malignancies. It is hoped that further study may reveal target genes of PRDM proteins so a greater understanding of the functions of the PRDM family can be achieved. [11] In Xenopus embryos, PRDM12 expression "was partially co-localized with the lateral expression regions" of the SIX1, PAX3, ISLET1, and PAX6 genes, but not those of the FOXD3 and SIX3 genes. In cases where BMP4 was overexpressed, embryos showed an increase in PRDM12 expression. Data indicated that the regulation of PRDM12 expression in Xenopus embryos was controlled by BMP and Wnt signaling. [12]

PRDM12 codes for a protein which regulates the neurological path through which pain in perceived, known as PR domain zinc finger protein 12. [13] The protein plays a vital role in the regulation of histone H3-K9 dimethylation. [12] [14] 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. [6] 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. [15] 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. [6] PRDM12’s protein has also been found to be a tumor suppressor for chronic myloid leukemia. [10] The protein controls gene expression by modifying chromatin. [15] PRDMs as a family tend to require enzyme help to modify histones, with some exceptions. [16]  

Clinical significance

In humans, mutations in the PRDM12 gene can cause loss of pain perception brought on by defects in the development of sensory neurons. [8] There are a number of diseases and conditions that can result from mutations in the PRDM12 gene.

Congenital insensitivity to pain (CIP) is a characterized by an inability to feel pain. [17] This is a rare condition that is present at birth due to a lack of, or malfunction of, nociceptors. [17] There are three different genes that can be mutated to cause CIP. First, a mutation in the SCN9A makes it impossible for nociceptors to respond to harmful stimuli because it causes the gene to lose its function. [17] Second, a mutation in the NTRK1 causes a loss of function for the gene and leads to a failure in nociceptor development. [17] Finally, researchers have identified 10 homozygous mutations on PRDM12 that appeared to be linked to this condition. [15] Past research has shown that PRDM12 is involved in the modification of chromatin. [15] Chromatin can turn genes off and on by attaching itself to chromosomes and acting as an epigenetic switch. [15] Chromatin play a huge role in neuron development, so researcher hypothesized that mutations in the PRDM12 gene prevent nociceptors and nerve fibers from developing normally.  [15] They then studied the nerve biopsies of patients with this condition and found that the patients affected by this condition are lacking pain sensing never fibers in their legs, or only have half the amount they should have. [15]

Another condition caused by mutations in the PRDM12 gene is hereditary sensory and autonomic neuropathy type VIII.[ citation needed ] HSAN VIII is a very rare autosomal recessive inherited disorder that also begins at birth and is characterized by an inability to feel pain and an inability to sweat (anhidrosis).[ citation needed ] Anhidrosis can cause frequent episodes of high body temperature of high fever.[ citation needed ] Other signs of this condition can include early loss of teeth, server soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary, and mandibular osteomyelitis. [18] Abnormal functioning of the sensory nerves is what causes the sensory loss in patients with this condition.[ citation needed ]  

A third condition that may be caused by a mutation in the PRDM12 gene is Midface toddler excoriation syndrome (MiTES). [19] MiTES is an newly discovered condition that has recently been reported in three children who were unrelated. [19] Persistent scratching around the nose and eyes from the first year of life results in deep, scarring wounds in the patients with this condition. [19] Doctors say because of these wounds, it is easy to mistake this condition with child abuse. [19] Researchers found that four out of the five patients with MiTES have the same autosomal recessive mutations in the PRDM12 gene that causes HSAN VIII. [19]

Members of the PRDM family have all been connected to over-expression, epigentic splicing, deletion, or mutations in various types of cancer. [20] PRDM12 in particular has been found to play a role in Chronic myeloid leukaemia, which is a clonal stem cell disorder. [21] Researchers mapped the microdeletions and identified a minimal common deleted region. [21] Within this common deleted region was the PRDM12 gene. [21] Because the PRDM family appears to includes tumor suppressor genes and functions as negative regulators of oncogenesis, PDRM12 represents an ideal candidate tumor suppressor gene for chronic myeloid leukaemia. [21]

Related Research Articles

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Congenital insensitivity to pain (CIP), also known as congenital analgesia, is one or more extraordinarily rare conditions in which a person cannot feel physical pain. The conditions described here are separate from the HSAN group of disorders, which have more specific signs and cause. Because feeling physical pain is vital for survival, CIP is an extremely dangerous condition. It is common for people with the condition to die in childhood due to injuries or illnesses going unnoticed. Burn injuries are among the more common injuries.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

Na<sub>v</sub>1.7 Protein-coding gene in the species Homo sapiens

Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at dorsal root ganglion (DRG) and trigeminal ganglion and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.

<span class="mw-page-title-main">CREB-binding protein</span> Nuclear protein that binds to CREB

CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">DNA (cytosine-5)-methyltransferase 3A</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.

<span class="mw-page-title-main">EGR2</span> Protein-coding gene in the species Homo sapiens

Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 is a transcription regulatory factor, containing three zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells. It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development. It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish. In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development. When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects. These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex.

<span class="mw-page-title-main">KMT2A</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.

<span class="mw-page-title-main">PRDM2</span> Protein-coding gene in the species Homo sapiens

PR domain zinc finger protein 2 is a protein that in humans is encoded by the PRDM2 gene.

<span class="mw-page-title-main">SETDB1</span> Enzyme-coding gene in humans

Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.

<span class="mw-page-title-main">EHMT2</span> Protein-coding gene in the species Homo sapiens

Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the EHMT2 gene. G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 and lysine residue 27.

<span class="mw-page-title-main">KMT2C</span> Protein-coding gene in the species Homo sapiens

Lysine N-methyltransferase 2C (KMT2C) also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) is an enzyme that in humans is encoded by the KMT2C gene.

<span class="mw-page-title-main">JADE1</span> Protein-coding gene in the species Homo sapiens

JADE1 is a protein that in humans is encoded by the JADE1 gene.

<span class="mw-page-title-main">KMT2D</span> Protein-coding gene in humans

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.

Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN) is a condition used to describe any of the types of this disease which inhibit sensation.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

<span class="mw-page-title-main">Brpf1</span> Protein-coding gene in the species Mus musculus

Peregrin also known as bromodomain and PHD finger-containing protein 1 is a protein that in humans is encoded by the BRPF1 gene located on 3p26-p25. Peregrin is a multivalent chromatin regulator that recognizes different epigenetic marks and activates three histone acetyltransferases. BRPF1 contains two PHD fingers, one bromodomain and one chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000130711 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000079466 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, et al. (July 2015). "Transcriptional regulator PRDM12 is essential for human pain perception" (PDF). Nature Genetics. 47 (7): 803–8. doi:10.1038/ng.3308. hdl:2262/75983. PMC   7212047 . PMID   26005867.
  6. 1 2 3 Costandi M (25 May 2015). "Uncomfortably numb: The people who feel no pain". The Guardian. Retrieved 31 July 2015.
  7. ↑ Hohenauer T, Moore AW (July 2012). "The Prdm family: expanding roles in stem cells and development". Development. 139 (13): 2267–82. doi: 10.1242/dev.070110 . PMID   22669819.
  8. 1 2 Elhennawy K, Reda S, Finke C, Graul-Neumann L, Jost-Brinkmann PG, Bartzela T (August 2017). "Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature". Journal of Medical Case Reports. 11 (1): 233. doi: 10.1186/s13256-017-1387-z . PMC   5556355 . PMID   28807049.
  9. ↑ Thélie A, Desiderio S, Hanotel J, Quigley I, Van Driessche B, Rodari A, et al. (October 2015). "Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus". Development. 142 (19): 3416–28. doi:10.1242/dev.121871. PMC   4631751 . PMID   26443638.
  10. 1 2 Reid AG, Nacheva EP (January 2004). "A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion". Leukemia. 18 (1): 178–80. doi:10.1038/sj.leu.2403162. PMID   14523459.
  11. ↑ Fog CK, Galli GG, Lund AH (January 2012). "PRDM proteins: important players in differentiation and disease". BioEssays. 34 (1): 50–60. doi:10.1002/bies.201100107. PMID   22028065.
  12. 1 2 Matsukawa S, Miwata K, Asashima M, Michiue T (March 2015). "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. doi: 10.1016/j.ydbio.2014.12.028 . PMID   25576027.
  13. ↑ EMBL-EBI, InterPro. "PR domain zinc finger protein 12 (Q9H4Q4) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2018-11-09.
  14. ↑ "PRDM12 Gene". GeneCards Human Gene Database.
  15. 1 2 3 4 5 6 7 Hiscott R (28 May 2015). "Researchers Identify New Genetic Mutations Linked to Pain Insensitivity". Neurology Today. American Academy of Neurology. Retrieved 6 November 2018.
  16. ↑ Derunes C, Briknarová K, Geng L, Li S, Gessner CR, Hewitt K, et al. (August 2005). "Characterization of the PR domain of RIZ1 histone methyltransferase". Biochemical and Biophysical Research Communications. 333 (3): 925–34. doi:10.1016/j.bbrc.2005.05.190. PMID   15964548.
  17. 1 2 3 4 Zhang S, Malik Sharif S, Chen YC, Valente EM, Ahmed M, Sheridan E, Bennett C, Woods G (August 2016). "Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain". Journal of Medical Genetics. 53 (8): 533–5. doi:10.1136/jmedgenet-2015-103646. PMC   4975812 . PMID   26975306.
  18. ↑ Elhennawy K, Reda S, Finke C, Graul-Neumann L, Jost-Brinkmann PG, Bartzela T (August 2017). "Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature". Journal of Medical Case Reports. 11 (1): 233. doi: 10.1186/s13256-017-1387-z . PMC   5556355 . PMID   28807049.
  19. 1 2 3 4 5 Moss C, Srinivas SM, Sarveswaran N, Nahorski M, Gowda VK, Browne FM, Woods G (November 2018). "Midface toddler excoriation syndrome (MiTES) can be caused by autosomal recessive biallelic mutations in a gene for congenital insensitivity to pain, PRDM12". The British Journal of Dermatology. 179 (5): 1135–1140. doi: 10.1111/bjd.16893 . PMID   29949203.
  20. ↑ Mzoughi S, Tan YX, Low D, Guccione E (February 2016). "The role of PRDMs in cancer: one family, two sides". Current Opinion in Genetics & Development. 36: 83–91. doi:10.1016/j.gde.2016.03.009. PMID   27153352.
  21. 1 2 3 4 Reid AG, Nacheva EP (January 2004). "A potential role for PRDM12 in the pathogenesis of chronic myeloid leukaemia with derivative chromosome 9 deletion". Leukemia. 18 (1): 178–80. doi:10.1038/sj.leu.2403162. PMID   14523459.
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