The  HUGO Gene Nomenclature Committee  (HGNC) maintains an official symbol and name for each human gene, as well as a list of synonyms and previous symbols and names. For example, for  AFF1  (AF4/FMR2 family, member 1), previous symbols and names are  MLLT2  ("myeloid/lymphoid or mixed-lineage leukemia (trithorax (Drosophila) homolog); translocated to, 2") and  PBM1  ("pre-B-cell monocytic leukemia partner 1"), and synonyms are  AF-4  and  AF4 . Authors of journal articles often use the latest official symbol and name, but just as often they use synonyms and previous symbols and names, which are well established by earlier use in the literature. AMA style is that "authors should use the most up-to-date term" [ 22 ]   and that "in any discussion of a gene, it is recommended that the approved gene symbol be mentioned at some point, preferably in the title and abstract if relevant." [ 22 ]  Because copyeditors are not expected or allowed to rewrite the gene and protein nomenclature throughout a manuscript (except by rare express instructions on particular assignments), the middle ground in manuscripts using synonyms or older symbols is that the copyeditor will add a mention of the current official symbol at least as a parenthetical gloss at the first mention of the gene or protein, and query for confirmation.


Some basic conventions, such as (1) that animal/human homolog (ortholog) pairs differ in  letter case  ( title case  and  all caps , respectively) and (2) that the symbol is italicized when referring to the gene but nonitalic when referring to the protein, are often not followed by contributors to medical journals. Many journals have the copyeditors restyle the casing and formatting to the extent feasible, although in complex genetics discussions only  subject-matter experts  (SMEs) can effortlessly parse them all. One example that illustrates the potential for ambiguity among non-SMEs is that some official gene names have the word "protein" within them, so the phrase "brain protein I3 ( BRI3 )" (referring to the gene) and "brain protein I3 (BRI3)" (referring to the protein) are both valid. The  AMA Manual  gives another example: both "the TH gene" and "the  TH  gene" can validly be parsed as correct ("the gene for tyrosine hydroxylase"), because the first mentions the alias (description) and the latter mentions the symbol. This seems confusing on the surface, although it is easier to understand when explained as follows: in this gene's case, as in many others, the alias (description) "happens to use the same letter string" that the symbol uses. (The matching of the letters is of course acronymic in origin and thus the phrase "happens to" implies more coincidence than is actually present; but phrasing it that way helps to make the explanation clearer.) There is no way for a non-SME to know this is the case for any particular letter string without looking up every gene from the manuscript in a database such as NCBI Gene, reviewing its symbol, name, and alias list, and doing some mental cross-referencing and double-checking (plus it helps to have biochemical knowledge). Most medical journals do not (in some cases cannot) pay for that level of  fact-checking  as part of their copyediting service level; therefore, it remains the author's responsibility. However, as pointed out earlier, many authors make little attempt to follow the letter case or italic guidelines; and regarding protein symbols, they often will not use the official symbol at all. For example, although the guidelines would call  p53  protein "TP53" in humans or "Trp53" in mice, most authors call it "p53" in both (and even refuse to call it "TP53" if edits or queries try to), not least because of the biologic principle that many proteins are essentially or exactly the same molecules regardless of mammalian species. Regarding the gene, authors are usually willing to call it by its human-specific symbol and capitalization,  TP53 , and may even do so without being prompted by a query. But the end result of all these factors is that the published literature often does not follow the nomenclature guidelines completely.


A  gene  is said to be polymorphic if more than one  allele  occupies that gene's  locus  within a population. [ 1 ]  In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to generally be considered polymorphic. [ 2 ]


Gene polymorphisms can occur in any region of the genome. The majority of polymorphisms are silent, meaning they do not alter the function or expression of a gene. [ 3 ]  Some polymorphisms are visible. For example, in dogs the E locus can have any of five different alleles, known as E, E m , E g , E h , and e. [ 4 ]  Varying combinations of these alleles contribute to the pigmentation and patterns seen in dog coats. [ 5 ]


A polymorphic variant of a gene can lead to the abnormal expression or to the production of an abnormal form of the protein; this abnormality may cause or be associated with disease.  For example, a polymorphic variant of the gene encoding the enzyme  CYP4A11 , in which  thymidine  replaces  cytosine  at the gene's nucleotide 8590 position encodes a CYP4A11 protein that substitutes phenylalanine with serine at the protein's amino acid position 434. [ 6 ]   This variant protein has reduced enzyme activity in metabolizing  arachidonic acid  to the blood pressure-regulating  eicosanoid ,  20-hydroxyeicosatetraenoic acid . A study has shown that humans bearing this variant in one or both of their CYP4A11 genes have an increased incidence of  hypertension , ischemic  stroke , and  coronary artery disease . [ 6 ]


Most notably, the genes coding for the  major histocompatibility complex  (MHC) are in fact the most polymorphic genes known. MHC molecules are involved in the immune system and interact with  T-cells . There are more than 32,000 different  alleles  of human MHC class I and II genes, and it has been estimated that there are 200 variants at the HLA-B HLA-DRB1 loci alone. [ 7 ]


Some polymorphism may be maintained by  balancing selection .


A rule of thumb that is sometimes used is to classify genetic variants that occur below 1% allele frequency as  mutations  rather than polymorphisms. [ 8 ]  However, since polymorphisms may occur at low allele frequency, this is not a reliable way to tell new mutations from polymorphisms. [ 9 ]   A mutation is a change to an inherited genetic sequence.


In the case of  silent  mutations there isn't a change in fitness, and the pressures responsible for  Hardy-Weinberg  equilibrium have no impact on the accumulation of  silent polymorphisms  over time . Most often, a polymorphism is  variation in a single nucleotide  (SNP), but also can be  insertion or deletion  of one or more nucleotides, changes in the  number of times  a short or  longer  sequence is repeated (both of these are common in parts of DNA that don't directly code for a protein, as are SNPs, but can have major effects on  gene expression ). [ 11 ] [ 12 ]  Polymorphisms which result in a change in fitness are the grist for the mill of  evolution by natural selection .  All genetic polymorphisms start out as a mutation, but only if they are germline and are not  lethal  can they spread into a population. Polymorphisms are classified based on what happens at the level of the individual mutation in the  DNA sequence  (or RNA sequence in the case of  RNA viruses ), and what effect the mutation has on the  phenotype  (i.e. silent or resulting in some change in function or change in fitness).  Polymorphisms are also classified based on whether the change is in the sequence of the  resulting  protein or in the regulation of the  expression  of the gene, which can occur at sites that are typically upstream and adjacent to the gene, but not always. [ 13 ] [ 11 ]


Polymorphisms can be identified in the laboratory using a variety of methods. Many methods employ  PCR  to amplify the sequence of a gene. Once amplified, polymorphisms and mutations in the sequence can be detected by  DNA sequencing , either directly or after screening for variation with a method such as  single strand conformation polymorphism analysis . [ 14 ]


A polymorphism can be any sequence difference. Examples include:


Many different human disease result from polymorphisms.  Polymorphisms also play significant role as risk factors for development of disease. [ 19 ]   Finally, polymorphisms in   drug metabolism , esp.  cytochrome p450   isoenzymes , proteins involved in drug transport (whether into the body, into protected areas of the body like the brain, or secreted out) as well as in specific  cell surface receptor  proteins alter the effect of various drugs. [ 13 ]   This is a rapidly evolving area of drug safety research. [ 20 ] [ 21 ]  Resources such as  HapMap ,  DbSNP , Ensembl ,  DNA Data Bank of Japan ,  DrugBank ,  Kyoto Encyclopedia of Genes and Genomes (KEGG) ,  GenBank , and other parts of the   International Nucleotide Sequence Database Collaboration  have become crucial in  Personalized medicine ,  bioinformatics , and  pharmacogenomics . [ 22 ]


Polymorphisms have been discovered in multiple XPD exons. XPD refers to " xeroderma pigmentosum  group D" and is involved in a  DNA repair  mechanism used during  DNA replication . XPD works by cutting and removing segments of DNA that have been damaged due to things such as cigarette smoking and inhalation of other environmental  carcinogens . [ 23 ]  Asp312Asn and Lys751Gln are the two common polymorphisms of XPD that result in a change in a single amino acid. [ 24 ]  This variation in Asn and Gln alleles has been related to individuals having a reduced DNA repair efficiency. [ 25 ]  Several studies have been conducted to see if this diminished capacity to repair DNA is related to an increased risk of lung cancer. These studies examined the XPD gene in lung cancer patients of varying age, gender, race, and  pack-years . The studies provided mixed results, from concluding individuals who are homozygous for the Asn allele or homozygous for the Gln allele had an increased risk of developing lung cancer, [ 26 ]  to finding no statistical significance between smokers who have either allele polymorphism and their  susceptibility to lung cancer . [ 27 ]  Research continues to be conducted to determine the relationship between XPD polymorphisms and lung cancer risk.


As a cornerstone of  Peronalized medicine   cancers ,  Sequence analysis  is becoming increasingly important to understand the specific mutations involved in the individual's cancer, such as needed to select specific molecular targets such as mutations in various receptors, but also understanding the polymorphisms they inherited which play important roles in diagnosis, prognosis, and treatment, such as treatment of  leukemia  with  6-mercaptopurine  where toxicity largely depends on polymorphisms in multiple different genes involved in its metabolism. [ 28 ]


Asthma is an inflammatory disease of the lungs and more than 100 loci have been identified as contributing to the development and severity of the condition. [ 29 ]   By using the traditional linkage analysis, these asthma correlated genes were able to be identified in small quantities using  genome-wide association studies  (GWAS). There have been a number of studies looking into various polymorphisms of asthma-associated genes and how those polymorphisms interact with the carrier's environment. One example is the gene CD14, which is known to have a polymorphism that is associated with increased amounts of CD14 protein as well as reduced levels of IgE serum. [ 30 ]  A study was conducted on 624 children looking at their IgE serum levels as it related to the polymorphism in CD14. The study found that IgE serum levels differed in children with the C allele in the CD14/-260 gene based on the type of allergens they regularly exposed to. [ 31 ]  Children who were in regular contact with house pets showed higher serum levels of IgE while children who were regularly exposed to stable animals showed lower serum levels of IgE. [ 31 ]  Continued research into gene-environment interactions may lead to more specialized treatment plans based on an individual's surroundings.


Gene redundancy  is the existence of multiple genes in the genome of an organism that perform the same function. Gene redundancy can result from  gene duplication . [ 1 ]  Such duplication events are responsible for many sets of  paralogous  genes. [ 1 ]  When an individual gene in such a set is disrupted by mutation or targeted  knockout , there can be little effect on  phenotype  as a result of gene redundancy, whereas the effect is large for the knockout of a gene with only one copy. [ 2 ]  Gene knockout is a method utilized in some studies aiming to characterize the maintenance and fitness effects functional overlap. [ 3 ]


Classical models of maintenance propose that duplicated genes may be conserved to various extents in genomes due to their ability to compensate for deleterious loss of function mutations. [ 4 ] [ 5 ]  These classical models do not take into account the potential impact of positive selection. Beyond these classical models, researchers continue to explore the mechanisms by which redundant genes are maintained and evolve. [ 6 ] [ 7 ] [ 8 ]  Gene redundancy has long been appreciated as a source of novel gene origination; [ 8 ]  that is, new genes may arise when selective pressure exists on the duplicate, while the original gene is maintained to perform the original function, as proposed by newer models [ 4 ] .


Gene redundancy most often results from  Gene duplication . [ 9 ]   Three of the more common mechanisms of gene duplication are  retroposition , unequal  crossing over , and non-homologous segmental duplication. Retroposition is when the mRNA transcript of a gene is reverse transcribed back into DNA and inserted into the genome at a different location. During unequal crossing over,  homologous  chromosomes exchange uneven portions of their DNA. This can lead to the transfer of one chromosome's gene to the other chromosome, leaving two of the same gene on one chromosome, and no copies of the gene on the other chromosome. Non-homologous duplications result from replication errors that shift the gene of interest into a new position. A tandem duplication then occurs, creating a chromosome with two copies of the same gene. Figure 1 provides a visualization of these three mechanisms. [ 10 ]  When a gene is duplicated within a genome, the two copies are initially functionally redundant. These redundant genes are considered paralogs as they accumulate changes over time, until they functionally diverge. [ 11 ]


Much research is centered around the question of  how redundant genes persist. [ 12 ]  Three models have arisen to attempt to explain preservation of redundant genes: adaptive radiation, divergence, and escape from adaptive conflict. Notably, retainment following a duplication event is influenced by type of duplication event and type of gene class. That is, some gene classes are better suited for redundancy following a small scale duplication or whole genome duplication event. [ 13 ]  Redundant genes are more likely to survive when they are involved in complex pathways and are the product of whole genome duplication or multifamily duplication. [ 13 ]


The currently accepted outcomes for single gene duplicates include: gene loss (non-functionalization), functional divergence, and conservation for increased genetic robustness. [ 11 ]  Otherwise, multigene families may undergo concerted evolution, or birth and death evolution. [ 11 ]   Concerted evolution is the idea that genes in a group, such as a gene family, evolve in parallel. [ 11 ]   The birth death evolution concept is that the gene family undergoes strong purifying selection. [ 11 ]


As the genome replicates over many generations, the redundant gene's function will most likely evolve due to  Genetic drift . Genetic drift influences genetic redundancy by either eliminating variants or fixing variants in the population. [ 12 ]  In the event that genetic drift maintains the variants, the gene may accumulate mutations that change the overall function. [ 14 ]  However, many redundant genes may diverge but retain original function by mechanisms such as subfunctionalization, which preserves original gene function albeit by complementary action of the duplicates. [ 13 ] [ 12 ]  The three mechanisms of functional divergence in genes are nonfunctionalization (or gene loss), neofunctionalization and subfunctionalization. [ 11 ]


During nonfunctionalization, or degeneration/gene loss, one copy of the duplicated gene acquires mutations that render it inactive or  silent . Non-functionalization is often the result of single gene duplications. [ 11 ]  At this time, the gene has no function and is called a  pseudogene . Pseudogenes can be lost over time due to genetic mutations. Neofunctionalization occurs when one copy of the gene accumulates mutations that give the gene a new, beneficial function that is different than the original function. Subfunctionalization occurs when both copies of the redundant gene acquire mutations. Each copy becomes only partially active; two of these partial copies then act as one normal copy of the original gene. Figure 2 to the right provides a visualization of this concept.


Transposable elements play various roles in functional differentiation. By enacting recombination, transposable elements can move redundant sequences in the genome. [ 15 ]  This change in sequence structure and location is a source of functional divergence. [ 15 ]  Transposable elements potentially impact gene expression, given that they contain a sizeable amount of micro-RNAs. [ 15 ]


The evolution and origin of redundant genes remain unknown, largely because evolution happens over such a long period of time. Theoretically, a gene can not be maintained without mutation unless it has a selective pressure acting on it. Gene redundancy, therefore, would allow both copies of the gene to accumulate mutations as long as the other was still able to perform its function. This means that all redundant genes should theoretically become a  pseudogene  and eventually be lost. Scientists have devised two hypotheses as to why redundant genes can remain in the genome: the backup hypothesis and the piggyback hypothesis. [ 16 ]


The backup hypothesis proposes that redundant genes remain in the genome as a sort of "back-up plan". If the original gene loses its function, the redundant gene is there to take over and keep the cell alive. The piggyback hypothesis states that two  paralogs  in the genome have some kind of non-overlapping function as well as the redundant function. In this case, the redundant part of the gene remains in the genome due to the proximity to the area that codes for the unique function. [ 17 ]  The reason redundant genes remain in the genome is an ongoing question and gene redundancy is being studied by researchers everywhere. There are many hypotheses in addition to the backup and piggyback models. For example, at the University of Michigan, a study provides the theory that redundant genes are maintained in the genome by reduced expression.


Researchers often use the history of redundant genes in the form of  gene families  to learn about the phylogeny of a species. It takes time for redundant genes to undergo functional diversification;  the degree of diversification between  orthologs  tells us how closely related the two genomes are. Gene duplication events can also be detected by looking at increases in gene duplicates.


A good example of using gene redundancy in evolutionary studies is the  Evolution of the KCS gene family in plants . This paper studies how one KCS gene evolved into an entire gene family via duplication events. The number of redundant genes in the species allows researchers to determine when duplication events took place and how closely related species are.


Currently, there are three ways to detect paralogs in a known genomic sequence: simple homology (FASTA), gene family evolution (TreeFam) and orthology (eggNOG v3). Researchers often construct phylogenies and utilize microarrays to compare the structures of genomes to identify redundancy. [ 18 ]  Methods like creating syntenic alignments and analysis of orthologous regions are used to compare multiple genomes. Single genomes can be scanned for redundant genes using exhaustive pairwise comparisons. [ 18 ]  Before performing more laborious analyses of redundant genes, researchers typically test for functionality by comparing  open reading frame  length and the rates between silent and non-silent mutations. [ 18 ]  Since the  Human Genome Project 's completion, researchers are able to annotate the human genome much more easily. Using online databases like the Genome Browser at UCSC, researchers can look for homology in the sequence of their gene of interest.


The mode of duplication by which redundancy occurs has been found to impact the classifications in breast cancer disposition genes. [ 19 ]  Gross duplications complicate clinical interpretation because it is difficult to discern if they occur in tandem. Recent methods, like DNA breakpoint assay, have been used to determine tandem status. [ 19 ]  In turn, these tandem gross duplications can be more accurately screened for pathogenic status. [ 19 ]  This research has important implications for evaluating risk of breast cancer. [ 19 ]


Researchers have also identified redundant genes that confer selective advantage on the organismal level. The partial ARM1 gene, a redundant gene resulting from a partial duplication, has been found to confer resistance to  Blumeria graminis , a mildew fungus. [ 20 ]  This gene exists in members of the  Triticeae  tribe, including  wheat ,  rye , and  barley . [ 20 ]


The Human Olfactory Receptor (OR) gene family contains 339 intact genes and 297 pseudogenes. These genes are found in different locations throughout the genome, but only about 13% are on different chromosomes or on distantly spaced loci. 172 subfamilies of OR genes have been found in humans, each at its own loci. Because the genes in each of these subfamilies are structurally and functionally similar, and in close proximity to each other, it is hypothesized that each evolved from single genes undergoing duplication events. The high number of subfamilies in humans explains why we are able to recognize so many odors.


Human OR genes have homologues in other mammals, such as mice, that demonstrate the evolution of Olfactory Receptor genes. One particular family that is involved in the initial event of odor perception has been found to be highly conserved throughout all of vertebrate evolution. [ 21 ]


Duplication events and redundant genes have often been thought to have a role in some human diseases. Large scale whole genome duplication events that occurred early in vertebrate evolution may be the reason that human monogenic disease genes often contain a high number of redundant genes. Chen et al. hypothesizes that the functionally redundant paralogs in human monogenic disease genes mask the effects of dominant deleterious mutations, thereby maintaining the disease gene in the human genome. [ 22 ]


Whole genome duplications may be a leading cause of retention of some tumor causing genes in the human genome. [ 23 ]  For example, Strout et al. [ 24 ]  have shown that tandem duplication events, likely via homologous recombination, are linked to  acute myeloid leukemia . The partial duplication of the  ALL1  ( MLL ) gene is a genetic defect has been found in patients with acute myeloid leukemia.


2MMZ ,  2WUL


Glutaredoxin 5 , also known as  GLRX5 , is a  protein  which in humans is encoded by the  GLRX5   gene  located on  chromosome 14 . [ 5 ]  This gene encodes a  mitochondrial  protein, which is evolutionarily  conserved . It is involved in the biogenesis of  iron- sulfur clusters , which are required for normal  iron homeostasis . Mutations in this gene are associated with autosomal recessive  pyridoxine-refractory   sideroblastic anemia . [ 6 ]


The GLRX5 gene contains 2  exons  and encodes for a protein that is 13 kDa in size. The protein is highly expressed in  erythroid cells . [ 7 ]   Crystal structure  of the GLRX5 protein reveals that the protein likely exists as a tetramer with two  Fe-S clusters  buried in the interior. [ 8 ]


GLRX5 is a  mitochondrial  protein is conserved evolutionarily and plays a role in the formation of  iron-sulfur clusters , which function to maintain  iron homeostasis  within the mitochondria and in the cell. GLRX5 is required for the steps in  haem synthesis  that involves mitochondrial enzymes, [ 9 ]  and is therefore involved in  hematopoiesis . GLRX5 activity is required for normal regulation of hemoglobin synthesis by the iron-sulfur protein  ACO1 . The function of GLRX5 is highly conserved evolutionarily. [ 10 ]


Mutations in the GLRX5 gene have been associated with  sideroblastic anemia , [ 11 ]  variant  glycine encephalopathy  (also known as non-ketotic hyperglycinemia,  NKH ). [ 12 ]  as well as pyridoxine-refractory, autosomal recessive anemia (PRARSA). [ 10 ]  Cells with mutations in GLRX5 activity show deficiency in Fe-S cluster synthesis, which is likely causative of the observed symptoms. [ 7 ]


NM_001280796 NM_001280797 NM_001280798 NM_013267 NM_138566


NM_001033264 NM_001285777 NM_001285779


NP_001267725 NP_001267726 NP_001267727 NP_037399


NP_001028436 NP_001272706 NP_001272708


Glutaminase 2 (liver, mitochondrial)  is a  protein  that in humans is encoded by the GLS2  gene . [ 5 ]


The GLS2 gene is on the 12th chromosome in humans, with its specific location being 12q13.3. It contains 19 exons. [ 5 ]


GLS2 is a part of the  glutaminase  family. The protein encoded by this gene is a mitochondrial phosphate-activated glutaminase that catalyzes the hydrolysis of glutamine to stoichiometric amounts of glutamate and ammonia. Originally thought to be liver-specific, this protein has been found in other tissues as well. Alternative splicing results in multiple transcript variants that encode different isoforms.


GLS2 has interesting molecular relationships with tumor progression and cancer. Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma. [ 6 ]  Additionally, silencing of GLS and overexpression of GLS2 genes cooperate in decreasing the proliferation and viability of  glioblastoma  cells. [ 7 ]


Within the science of  molecular biology  and  cell biology , for human  genetics , the GRIA2  gene  is located on  chromosome 4q 32-q33. The  gene product  is the  ionotropic  AMPA  glutamate receptor  2 ( also known as  Glur2  or GlurB). The  protein  belongs to a family of  ligand -activated  glutamate   receptors  that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole  propionate  (AMPA). Glutamate receptors function as the main excitatory  neurotransmitter  at many  synapses  in the  central nervous system .  L-glutamate , an excitatory neurotransmitter, binds to the Gria2 resulting in a conformational change. This leads to the opening of the channel converting the  chemical signal  to an  electrical impulse . AMPA receptors (AMPAR) are composed of four subunits, designated as GluR1 (GRIA1), GluR2 (GRIA2), GluR3 (GRIA3), and GluR4(GRIA4) which combine to form  tetramers . They are usually  heterotrimeric  but can be  homodimeric . [ 1 ]  Each AMPAR has four sites to which an  agonist  (such as L-glutamate) can bind, one for each subunit.[5]


Gria2 pre-mRNA undergoes a type of editing called adenosine-to-inosine (A-to-I) editing.  Adenosine   deaminases  acting on  RNA  (ADARs) are the  RNA editing   enzymes  responsible for A-to-I editing. ADARs deaminate adenosine bases to  inosine  bases in a site-specific manner in  double-stranded RNA  substrates (dsRNA). ADAR2 has been experimentally shown to be the specifically responsible [ 2 ]


The pre-mRNA of GRIA2 is modified at amino acid 607, found in the second transmembrane domain of the receptor subunit. This is called the Q/R site.


Editing occurs in 100% of transcripts in human brain. Editing levels are lower in other tissues. Deletion analysis determined that editing requires 5' portion of intron B. The predicted minimum fragment required for editing to occur contains inverted repeat structure separated by 120 nucleotides. The inverted repeat contains 3 double stranded elements of 22-23 base pairs with distortion after 15-17 base pairs with mismatched pairs in helical structure 1 and 3 and a bulge in helical structure 2. [ 3 ]


The genomically encoded GluR2 subunit has a Gln (CAG) at the editing site position. Editing of the pre-mRNA results in conversion to Arg (CGG) being encoded at this position. [ 4 ]


Editing alters Ca2+ permeability.


GluA2 RNA editing has recently been described to be dysregualted in Alzheimer's disease and the latest research has shown that modulating RNA editing can lead to functional benefits in an Alzheimer mouse model  [ 5 ]


Deficiency of vitamin B1 is correlated with alterations in editing of Glur2 pre-mRNA. [ 6 ]  Thiamine deficiency leads to mild impairment of oxidative metabolism and regional selective neuronal loss in the central nervous system. An increase in intracellular calcium has been experimentally observed in cultured cortical neurons as a result of lack of thiamine. Deficiency also inhibits editing of the Q/R site of Glur2 thereby increasing the level of unedited Glur2 resulting in increased calcium permeability of Glur2 containing channels.


Glutamate-rich protein 3 , also known as  Uncharacterized Protein C1orf173 , is a protein encoded by the  ERICH3  gene. [ 5 ]   ERICH3  was named “chromosome 1  open reading frame  173 ( C1orf173 )” based on its map location in the human genome.  It was subsequently renamed “E-rich 3” as a result of the high content of glutamate (E) in its encoded amino acid sequence. [ 6 ]   Single-nucleotide polymorphisms (SNPs)  in the  ERICH3  gene has been identified as one of the "top" signals in a  genome-wide association study  (GWAS) for plasma  serotonin  concentrations which were themselves associated with  selective serotonin reuptake inhibitor  (SSRI) response in  major depressive disorder  (MDD) patients. [ 7 ]   The same  ERICH3  SNP was later demonstrated that was significantly associated with SSRI treatment outcomes in three independent MDD trials, [ 6 ] [ 7 ]  including STAR*D, [ 8 ]  ISPC [ 9 ]  and PReDICT. [ 10 ]   ERICH3 is most highly expressed in a variety of regions of the human brain, including the nucleus accumbens (basal ganglia) and frontal cortex based on  the GTEx   RNA-seq  data.  The single-cell RNA-seq data for human brain samples revealed that ERICH3 is predominantly expressed in  neurons  rather than other  CNS  cell types. [ 6 ]   ERICH3 was found interacts with proteins function in  vesicle  biogenesis and may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response. [ 6 ]   ERICH3 protein was also found abundant in blood  platelets [ 11 ]  and  cilia [ 12 ]  based on the proteomic studies.  Its function in platelet was thought related to plasma serotonin storage [ 6 ]  because more than 99% of blood serotonin was stored in platelet [ 13 ]  and ERICH3 SNPs has been associated with plasma serotonin concentration in MDD patients. [ 7 ]   ERICH3 in primary cilia might regulates cilium formation and the localizations of ciliary transport. [ 14 ]


The  ERICH3  gene in humans is 105,628 bases and is encoded on the  minus strand  at position 31.1 on the short arm of  chromosome 1  from  base pair  75,033,795 bp to 75,139,422 bp from  pter . [ 15 ]   ERICH3 RNA was predominantly expressed in human brain and testis based on  the GTEx   RNA-seq  data.  The  Ensembl  human genome assembly annotated five ERICH3 RNA transcripts. The reference transcript consisted of fifteen exons, with exon 14 encoding half of the open reading frame. The reference ERICH3 transcript was expressed in brain, predominantly in neurons but not in testis. [ 6 ]   A "shorter" ERICH3 transcript consisted of seven exons, of which its first exon mapping to intron 6 of the reference ERICH3 transcript, was predominantly expressed in testis. In addition to ERICH3 vesicular function in antidepressant treatment response and cilium formation, expression of this gene has been linked to several forms of  cancer , such as breast cancer and  skin sarcomas . [ 16 ] [ 17 ]  C1orf173 is expressed in the brain, eye, lung, mammary gland, muscle,  pituitary gland , testis, trachea, and uterus. [ 18 ]


The C1orf173 protein in humans is 1,530 amino acids (aa) in length and  [ 19 ]  contains two  domains of unknown function , DUF4590 and DUF4543. Both DUF regions are currently uncharacterized though they are found in  eukaryotes  including humans. [ 20 ] [ 21 ]  There are currently three known  isoforms  of the C1orf173 protein in humans, Q5RHP9-1 ( canonical ), Q5RHP9-2 and Q5RHP9-3. Other animals tend to have a multitude of variant forms of this gene. [ 15 ]   The canonical ERICH3 protein, which was encoded from its reference RNA transcript, has been demonstrated is the predominant ERICH3 isoform in neurons by  Western blot  assays. [ 6 ]


C1orf173 is predicted to be a nuclear protein based on  PSORT II  analysis and the suggested protein interactions found between c1orf173 and other proteins such as TAF5L.
Analyzing the protein for isoelectric point using the Compute pI/Mw tool in  Expasy , it was found that C1orf173 is slightly acidic ranging from a  pH  of 4.6-5 for most orthologs. [ 22 ]  Further analysis using the NetPhos tool on Expasy found that there are a large number of phosphorylated serines, an intermediate number of phosphorylated  threonines  and a few phosphoylated  tyrosines . [ 23 ]


However, the experimental data clearly showed that ERICH3 proteins, including all three known isoforms, are localized in  cytoplasma  but not in  nucleus . [ 6 ]   The “canonical” ERICH3 protein was predicted to have a molecular weight (MW) of 168.5 kD, but a band at ~250 kD was observed by Western blot. [ 6 ]   This striking difference (>80kD) between predicted and observed MWs was unlikely to result from post-translational modification such as glycosylation or phosphorylation but from the high content of glutamate (E) in its amino acid sequence. [ 6 ]    Previous studies have reported that proteins with a high content of glutamate (E) and/or aspartate (D), amino acids with acidic side chains, can display higher apparent MW values during Western blot analysis than would be predicted. [ 24 ]


The C1orf173 protein has a secondary structure that is primarily alpha helices and random coils based on bioinformatical analysis. [ 25 ] [ 26 ] [ 27 ]  In humans the tertiary structure of C1orf173 has two components that resemble ubiquitin-like 2 activating enzyme e1b and alginase. [ 28 ] [ 29 ]


The C1orf173 protein has been predicted or experimentally observed to interact with the following proteins:


Graves disease, susceptibility to, X-linked  is a  protein  that in humans is encoded by the GRDX  gene .
 [ 2 ]


This article on a  gene  on the human  X chromosome  and/or its associated  protein  is a  stub . You can help Wikipedia by  expanding it .


NM_000837 NM_001009184


NP_000828 NP_001009184


Glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (glutamate binding)  is a  protein  in humans that is encoded by the GRINA  gene .
 [ 5 ]


2C3N ,  2C3Q ,  2C3T


NM_001293811 NM_001293812 NM_001293813 NM_001293814


NP_001280740 NP_001280741 NP_001280742 NP_001280743


Glutathione S-transferase theta-1  is an  enzyme  that in humans is encoded by the  GSTT1   gene . [ 2 ]


Glutathione S-transferase (GST) theta 1 (GSTT1) is a member of a superfamily of proteins that catalyze the conjugation of reduced  glutathione  to a variety of electrophilic and hydrophobic compounds. Human GSTs can be divided into five main classes: alpha, mu, pi, theta, and zeta. The theta class includes GSTT1 and GSTT2. The GSTT1 and GSTT2 share 55% amino acid sequence identity and both of them were claimed to have an important role in human carcinogenesis. The GSTT1 gene is located approximately 50kb away from the GSTT2 gene. The GSTT1 and GSTT2 genes have a similar structure, being composed of five exons with identical exon/intron boundaries. [ 3 ]


2D31 ,  2DYP ,  3SHV ,  3SQD ,  3SZM ,  1YDP ,  2AZM ,  3U3Z


H2A histone family member X  (usually abbreviated as  H2AX ) is a type of  histone  protein from the  H2A family  encoded by the  H2AFX  gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.


In humans and other  eukaryotes , the  DNA  is wrapped around  histone  octamers, consisting of  core histones  H2A,  H2B ,  H3  and  H4 , to form  chromatin . H2AX contributes to  nucleosome -formation, chromatin-remodeling and  DNA repair , and is also used  in vitro  as an assay for double-strand breaks in  dsDNA .


H2AX becomes phosphorylated on serine 139, then called γH2AX, as a reaction on  DNA double-strand breaks (DSB) . The kinases of the PI3-family ( Ataxia telangiectasia mutated ,  ATR  and DNA-PKcs) are responsible for this phosphorylation, especially ATM. The modification can happen accidentally during replication fork collapse or in the response to ionizing radiation but also during controlled physiological processes such as V(D)J recombination. γH2AX is a sensitive target for looking at DSBs in cells. The presence of γH2AX by itself, however, is not the evidence of the DSBs. [ 5 ]  The role of the phosphorylated form of the histone in DNA repair is under discussion but it is known that because of the modification the DNA becomes less condensed, potentially allowing space for the recruitment of proteins necessary during repair of DSBs.  Mutagenesis experiments have shown that the modification is necessary for the proper formation of ionizing radiation induced foci in response to double strand breaks, but is not required for the recruitment of proteins to the site of DSBs.


The  histone  variant H2AX constitutes about 2-25% of the H2A histones in mammalian chromatin. [ 6 ]   When a double-strand break occurs in DNA, a sequence of events occurs in which H2AX is altered.


Very early after a double-strand break, a specific protein that interacts with and affects the architecture of chromatin is phosphorylated and then released from the chromatin.  This protein,  heterochromatin protein 1  (HP1)-beta ( CBX1 ), is bound to  histone H3   methylated  on lysine 9 (H3K9me). Half-maximum release of HP1-beta from damaged DNA occurs within one second. [ 7 ]   A dynamic alteration in chromatin structure is triggered by HP1-beta release.  This alteration in chromatin structure promotes H2AX phosphorylation by  ATM ,  ATR  and  DNA-PK , [ 8 ]  allowing formation of γH2AX (H2AX phosphorylated on serine 139).  γH2AX can be detected as soon as 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurs in one minute. [ 6 ]   Chromatin with phosphorylated γH2AX extends to about a million base pairs on each side of a DNA double-strand break. [ 6 ]


MDC1  (mediator of DNA damage checkpoint protein 1) then binds to γH2AX and the γH2AX/MDC1 complex then orchestrates further interactions in double-strand break repair. [ 9 ]   The ubiquitin ligases RNF8 and  RNF168  bind to the γH2AX/MDC1 complex, ubiquitylating other chromatin components.  This allows the recruitment of BRCA1 and 53BP1 to the long, modified γH2AX/MDC1 chromatin. [ 9 ]   Other proteins that stably assemble on the extensive γH2AX-modified chromatin are the  MRN complex  (a  protein complex  consisting of  Mre11 ,  Rad50  and  Nbs1 ),  RAD51  and the  ATM kinase . [ 10 ] [ 11 ]   Further DNA repair components, such as RAD52 and RAD54, rapidly and reversibly interact with the core components stably associated with γH2AX-modified chromatin. [ 11 ]  The constitutive level of γH2AX expression in live cells, untreated by exogenous agents, likely represents DNA damage by endogenous oxidants generated during cellular respiration. [ 12 ]


The packaging of eukaryotic DNA into  chromatin  presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action.  To allow DNA repair, the chromatin must be  remodeled .


γH2AX, the phosphorylated form of H2AX, is involved in the steps leading to chromatin decondensation after DNA double-strand breaks.  γH2AX does not, itself, cause chromatin decondensation, but within 30 seconds of  ionizing radiation ,  RNF8  protein can be detected in association with γH2AX. [ 13 ]   RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with  CHD4 , [ 14 ]  a component of the nucleosome remodeling and deacetylase complex  NuRD .


An assay for γH2AX generally reflects the presence of double-strand breaks in DNA, though the assay may indicate other minor phenomena as well. [ 15 ]   On the one hand, overwhelming evidence supports a strong, quantitative correlation between γH2AX foci formation and DNA double-strand break induction following  ionizing radiation  exposure, based on absolute yields and distributions induced per unit dose. [ 15 ]   On the other hand, not only the formation of distinct γH2AX foci but also the induction of pan-nuclear γH2AX signals have been reported as a cellular reaction to various stressors other than ionizing radiation. [ 16 ]  The γH2AX signal is always stronger at DNA double-strand breaks than in undamaged chromatin. [ 16 ]  γH2AX in undamaged chromatin is thought to possibly be generated via direct phosphorylation of H2AX by activated kinases, most likely diffusing from DNA damage sites. In using γH2AX as a marker for double strand breaks, it is important to recognize that it is a down-stream proxy that can be useful for representing DNA damage repair. It does not represent double strand breaks themselves and this needs careful consideration when interpreting data from such assays. [ 17 ]


The γH2AX-assay has several disadvantages, therefore new assays have been created.  [ 18 ]


H2AX has been shown to  interact  with:


NM_001284413 NM_001284415 NM_001284416 NM_012260


NP_001271342 NP_001271344 NP_001271345 NP_036392


2-hydroxyacyl-CoA lyase 1  is a  protein  that in humans is encoded by the HACL1  gene .
 [ 5 ]


Probable E3 ubiquitin-protein ligase HERC3  is an  enzyme  that in humans is encoded by the  HERC3   gene . [ 1 ] [ 2 ]  The gene is a member of the HERC family of  ubiquitin ligases  and encodes a protein with a  HECT domain  and an  RCC1 -like domain (RLD). It binds  ubiquitin  and hPLIC-1/2 via its HECT domain. Alternatively spiced transcript variants encoding multiple isoforms have been observed, and mutations in this gene have been linked to colorectal and gastric carcinomas. The protein is localized in the cytosol and vesicular-like structures containing  β-COP ,  ARF , and  Rab5 . Since HERC3 can itself be ubiquitinated and degraded by the proteasome, it likely has roles in both vesicular traffic and ubiquitin-dependent processes. [ 3 ] [ 4 ] [ 5 ]


The  hisB  gene, found in the  enterobacteria  (such as  E. coli ), in  Campylobacter jejuni  and in  Xylella / Xanthomonas  encodes a protein involved in catalysis of two step in  histidine biosynthesis  (the sixth and eight step), namely the bifunctional  Imidazoleglycerol-phosphate dehydratase / histidinol-phosphatase . [ 1 ]


The former function ( EC   4.2.1.19 ), found at the  N-terminal , dehydrated  d -erythroimidazoleglycerolphosphate to imidazoleacetolphosphate, the latter function ( EC   3.1.3.15 ), found at the  C-terminal , dephosphorylates  l -histidinolphosphate producing histidinol. [ 2 ] [ 3 ] [ 4 ]


The firth step is catalysed instead by histadinolphosphate aminotransferase (encoded by  hisC ) [ 5 ]


The peptide is 40.5kDa and associates to form a hexamer (unless truncated) [ 6 ]


In E. coli hisB is found on the hisGDCBHAFI operon [ 7 ]


The phosphatase activity possess a substrate ambiguity and overexpression of hisB can rescue phosphoserine phosphatase (serB) knockouts. [ 8 ]


hisB-N


hisB-C


HIS3  from  Saccharomyces cerevisiae  is not a fused IGP dehydratase and hisidinol phosphatase, but an IGPD only (homologous to hisB-N). Whereas HIS2 is the HP (analogous to hisB-C, called hisJ in some prokaryotes).


HLA complex group 22  is a  protein  that in humans is encoded by the HCG22  gene .
 [ 2 ]


2Q6W ,  4H1L


HLA class II histocompatibility antigen, DRB3-1 beta chain  is a  protein  that in humans is encoded by the  HLA-DRB3   gene . [ 2 ]


The  protein  encoded by this gene belongs to the  HLA class II  beta chain  paralogues . The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), both anchored in the membrane. It plays a central role in the  immune system  by presenting peptides derived from extracellular proteins. Class II molecules are expressed in  antigen-presenting cells  (APC: B lymphocytes, dendritic cells, macrophages). [ 2 ]


The beta chain is approximately 26–28 kDa. It is encoded by 6  exons , exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular  domains , exon 4 encodes the  transmembrane  domain and exon 5 encodes the  cytoplasmic  tail. Within the DR molecule the beta chain contains all the  polymorphisms  specifying the peptide binding specificities. Typing for these polymorphisms is routinely done for  bone marrow  and  kidney transplantation . [ 2 ]


DRB1  is expressed at a level five times higher than its paralogues DRB3,  DRB4  and  DRB5 . DRB1 is present in all individuals. Allelic variants of DRB1 are linked with either none or one of the genes DRB3, DRB4 and DRB5. There are 4 related pseudogenes: DRB2, DRB6, DRB7, DRB8 and DRB9. [ 2 ]


Distal hereditary motor neuropathy, Jerash type  is a  protein  that in humans is encoded by the HMNJ  gene . [ 2 ]


This article on a  gene  on human  chromosome 9  is a  stub . You can help Wikipedia by  expanding it .


A  homeobox  is a  DNA sequence , around 180  base pairs  long, that regulates large-scale anatomical features in the early stages of embryonic development.  Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.


Homeoboxes are found within  genes  that are involved in the regulation of patterns of anatomical development ( morphogenesis ) in  animals ,  fungi ,  plants , and numerous single cell  eukaryotes . [ 2 ]  Homeobox genes encode  homeodomain   protein  products that are  transcription factors  sharing a characteristic  protein fold  structure that binds  DNA  to regulate expression of target genes. [ 3 ] [ 4 ] [ 2 ]   Homeodomain proteins regulate gene expression and cell differentiation during early embryonic development, thus mutations in homeobox genes can cause developmental disorders. [ 5 ]


Homeosis  is a term coined by  William Bateson  to describe the outright replacement of a discrete body part with another body part, e.g.  antennapedia —replacement of the antenna on the head of a fruit fly with legs. [ 6 ]  The "homeo-" prefix in the words "homeobox" and "homeodomain" stems from this  mutational phenotype , which is observed when some of these genes are mutated in  animals . The homeobox domain was first identified in a number of  Drosophila   homeotic  and segmentation proteins, but is now known to be well-conserved in many other animals, including  vertebrates . [ 3 ] [ 7 ] [ 8 ]


The existence of homeobox genes was first discovered in  Drosophila  by isolating the gene responsible for a homeotic transformation where legs grow from the head instead of the expected antennae. Walter Gehring identified a gene called  antennapedia  that caused this homeotic phenotype. [ 9 ]  Analysis of  antennapedia  revealed that this gene contained a 180 base pair sequence that encoded a DNA binding domain, which William McGinnis termed the "homeobox". [ 10 ]  The existence of additional  Drosophila  genes containing the  antennapedia  homeobox sequence was independently reported by Ernst Hafen,  Michael Levine ,  William McGinnis , and  Walter Jakob Gehring  of the  University of Basel  in  Switzerland  and  Matthew P. Scott  and Amy Weiner of  Indiana University  in  Bloomington  in 1984. [ 11 ] [ 12 ]  Isolation of homologous genes by  Edward de Robertis  and William McGinnis revealed that numerous genes from a variety of species contained the homeobox. [ 13 ] [ 14 ]  Subsequent  phylogenetic  studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all  bilaterian  animals.


The characteristic homeodomain  protein fold  consists of a 60- amino acid  long domain composed of three  alpha helices . The following shows the  consensus  homeodomain (~60 amino acid chain): [ 15 ]


Helix 2 and helix 3 form a so-called  helix-turn-helix  (HTH) structure, where the two alpha helices are connected by a short loop region. The  N-terminal  two helices of the homeodomain are  antiparallel  and the longer  C-terminal  helix is roughly perpendicular to the axes of the first two. It is this third helix that interacts directly with  DNA  via a number of hydrogen bonds and hydrophobic interactions, as well as indirect interactions via water molecules, which occur between specific  side chains  and the exposed  bases  within the  major groove  of the DNA. [ 7 ]


Homeodomain proteins are found in  eukaryotes . [ 2 ]  Through the HTH motif, they share limited sequence similarity and structural similarity to  prokaryotic transcription factors, [ 16 ]  such as  lambda phage  proteins that alter the expression of genes in  prokaryotes . The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g.,  cro  and  repressor proteins , homeodomain proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereochemical requirement for  glycine  in the turn which is needed to avoid  steric  interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, whereas for many of the homeotic and other DNA-binding proteins the requirement is relaxed.


Homeodomains can bind both specifically and nonspecifically to  B-DNA  with the C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in the minor groove. The recognition helix and the inter-helix loops are rich in  arginine  and  lysine  residues, which form  hydrogen bonds  to the DNA backbone.  Conserved   hydrophobic  residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-TAAT-3'; sequence-independent binding occurs with significantly lower affinity. The specificity of a single homeodomain protein is usually not enough to recognize specific target gene promoters, making cofactor binding an important mechanism for controlling binding sequence specificity and target gene expression. To achieve higher target specificity, homeodomain proteins form complexes with other transcription factors to recognize the  promoter region  of a specific target gene.


Homeodomain proteins function as  transcription factors  due to the DNA binding properties of the conserved HTH motif. Homeodomain proteins are considered to be master control genes, meaning that a single protein can regulate expression of many target genes. Homeodomain proteins direct the formation of the body axes and body structures during  early embryonic development . [ 17 ]  Many homeodomain proteins induce  cellular differentiation  by initiating the cascades of coregulated genes required to produce individual  tissues  and  organs . Other proteins in the family, such as  NANOG  are involved in maintaining  pluripotency  and preventing cell differentiation.


Hox genes  and their associated  microRNAs  are highly conserved developmental master regulators with tight tissue-specific, spatiotemporal control. These genes are known to be dysregulated in several cancers and are often controlled by DNA methylation. [ 18 ] [ 19 ]  The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory.  Drosophila  is known to use the  polycomb  and  trithorax  complexes to maintain the expression of Hox genes after the down-regulation of the pair-rule and gap genes that occurs during larval development.  Polycomb-group proteins  can silence the Hox genes by modulation of  chromatin  structure. [ 20 ]


Mutations to homeobox genes can produce easily visible  phenotypic  changes in body segment identity, such as the Antennapedia and Bithorax mutant phenotypes in  Drosophila . Duplication of homeobox genes can produce new body segments, and such duplications are likely to have been important in the  evolution  of segmented animals.


Phylogenetic analysis of homeobox gene sequences and homeodomain protein structures suggests that the last common ancestor of plants, fungi, and animals had at least two homeobox genes. [ 21 ]  Molecular evidence shows that some limited number of Hox genes have existed in the  Cnidaria  since before the earliest true  Bilatera , making these genes pre- Paleozoic . [ 22 ]  It is accepted that the three major animal ANTP-class clusters, Hox, ParaHox, and NK (MetaHox), are the result of segmental duplications. A first duplication created MetaHox and ProtoHox, the latter of which later duplicated into Hox and ParaHox. The clusters themselves were created by tandem duplications of a single ANTP-class homeobox gene. [ 23 ]  Gene duplication followed by  neofunctionalization  is responsible for the many homeobox genes found in eukaryotes. [ 24 ] [ 25 ]  Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans. [ 26 ]


Hox genes are the most commonly known subset of homeobox genes. They are essential  metazoan  genes that determine the identity of embryonic regions along the anterior-posterior axis. [ 27 ]   The first vertebrate Hox gene was isolated in  Xenopus  by  Edward De Robertis  and colleagues in 1984. [ 28 ]  The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to the order in which they are expressed in both time and space during development. This phenomenon is called colinearity.


Mutations in these  homeotic genes  cause displacement of body segments during embryonic development. This is called  ectopia . For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into a more posterior one. Famous examples are  Antennapedia  and  bithorax  in  Drosophila , which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively. [ 29 ]


In vertebrates, the four  paralog  clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along the  limb  axis. [ 30 ] [ 31 ]  Specific members of the Hox family have been implicated in vascular remodeling,  angiogenesis , and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM. [ 32 ]  HoxA5 is implicated in atherosclerosis. [ 33 ] [ 34 ]  HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively. [ 35 ] [ 36 ] [ 37 ] [ 38 ]  HoxA3 induces  endothelial  cell (EC) migration by upregulating MMP14 and uPAR. Conversely, HoxD10 and HoxA5 have the opposite effect of suppressing EC migration and angiogenesis, and stabilizing adherens junctions by upregulating TIMP1/downregulating uPAR and MMP14, and by upregulating Tsp2/downregulating VEGFR2, Efna1, Hif1alpha and COX-2, respectively. [ 39 ] [ 40 ]  HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN. [ 41 ]  Suppression of HoxA5 has been shown to attenuate  hemangioma  growth. [ 42 ]  HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines. [ 42 ]  HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs. [ 43 ] [ 44 ]


LIM genes (named after the initial letters of the names of three proteins where the characteristic domain was first identified) encode two 60 amino acid cysteine and histidine-rich LIM domains and a homeodomain. The LIM domains function in protein-protein interactions and can bind zinc molecules. LIM domain proteins are found in both the cytosol and the nucleus. They function in cytoskeletal remodeling, at focal adhesion sites, as scaffolds for protein complexes, and as transcription factors. [ 45 ]


Most Pax genes contain a homeobox and a paired domain that also binds DNA to increase binding specificity, though some Pax genes have lost all or part of the homeobox sequence. [ 46 ]  Pax genes function in embryo  segmentation ,  nervous system  development, generation of the  frontal eye fields ,  skeletal  development, and formation of face structures.  Pax 6  is a master regulator of eye development, such that the gene is necessary for development of the optic vesicle and subsequent eye structures. [ 47 ]


Proteins containing a POU region consist of a homeodomain and a separate,  structurally homologous  POU domain that contains two  helix-turn-helix  motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with  consensus sequence  5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. The POU domain itself has significant structural similarity with repressors expressed in  bacteriophages , particularly  lambda phage .


As in animals, the plant homeobox genes code for the typical 60 amino acid long DNA-binding homeodomain or in case of the TALE (three amino acid loop extension) homeobox genes for an atypical homeodomain consisting of 63 amino acids. According to their conserved intron–exon structure and to unique codomain architectures they have been grouped into 14 distinct classes: HD-ZIP I to IV, BEL, KNOX, PLINC, WOX, PHD, DDT, NDX, LD, SAWADEE and PINTOX. [ 24 ]  Conservation of codomains suggests a common eukaryotic ancestry for TALE [ 48 ]  and non-TALE homeodomain proteins. [ 49 ]


The Hox genes in humans are organized in four chromosomal clusters:


ParaHox  genes are analogously found in four areas. They include  CDX1 ,  CDX2 ,  CDX4 ;  GSX1 ,  GSX2 ; and  PDX1 . Other genes considered Hox-like include  EVX1 ,  EVX2 ;  GBX1 ,  GBX2 ;  MEOX1 ,  MEOX2 ; and  MNX1 . The NK-like (NKL) genes, some of which are considered "MetaHox", are grouped with Hox-like genes into a large ANTP-like group. [ 50 ] [ 51 ]


Humans have a  "distal-less homeobox" family :  DLX1 ,  DLX2 ,  DLX3 ,  DLX4 ,  DLX5 , and  DLX6 . Dlx genes are involved in the development of the nervous system and of limbs. [ 52 ]  They are considered a subset of the NK-like genes. [ 50 ]


Human TALE (Three Amino acid Loop Extension) homeobox genes for an "atypical" homeodomain consist of 63 rather than 60 amino acids:
 IRX1 ,  IRX2 ,  IRX3 ,  IRX4 ,  IRX5 ,  IRX6 ;  MEIS1 ,  MEIS2 ,  MEIS3 ;  MKX ;  PBX1 ,  PBX2 ,  PBX3 ,  PBX4 ;  PKNOX1 ,  PKNOX2 ;  TGIF1 ,  TGIF2 ,  TGIF2LX ,  TGIF2LY . [ 50 ]


In addition, humans have the following homeobox genes and proteins: [ 50 ]


Homeotic genes  are genes which regulate the development of anatomical structures in various organisms such as echinoderms, [ 1 ]  insects, mammals, and plants. Homeotic genes often encode  transcription factor  proteins, and these proteins affect development by regulating downstream gene networks involved in body patterning. [ 2 ]


Mutations  in homeotic genes cause displaced body parts ( homeosis ), such as antennae growing at the posterior of the fly instead of at the head. [ 3 ]   Mutations that lead to development of ectopic structures are usually lethal. [ 4 ]


There are several subsets of homeotic genes. They include many of the  Hox  and  ParaHox  genes that are important for  segmentation . [ 5 ]  Hox genes are found in bilateral animals, including  Drosophila  (in which they were first discovered) and humans. Hox genes are a subset of the  homeobox  genes. The Hox genes are often  conserved  across species, so some of the Hox genes of  Drosophila  are homologous to those in humans. In general, Hox genes play a role of regulating expression of genes as well as aiding in development and assignment of specific structures during embryonic growth. This can range from segmentation in  Drosophila  to  central nervous system  (CNS) development in vertebrates. [ 6 ]  Both Hox and ParaHox are grouped as HOX-Like (HOXL) genes, a subset of the ANTP class (named after the  Drosophila  gene,  Antennapedia ). [ 7 ]


They also include the  MADS-box -containing genes involved in the  ABC model of flower development . [ 8 ]  Besides flower-producing plants, the MADS-box motif is also present in other organisms such as insects, yeasts, and mammals. They have various functions depending on the organism including flower development, proto-oncogene transcription, and gene regulation in specific cells (such as muscle cells). [ 9 ]


Despite the terms being commonly interchanged, not all homeotic genes are Hox genes; the MADS-box genes are homeotic but not Hox genes. Thus, the Hox genes are a subset of homeotic genes.


One of the most commonly studied  model organisms  in regards to homeotic genes is the fruit fly  Drosophila melanogaster . Its homeotic Hox genes occur in either the Antennapedia complex (ANT-C) or the Bithorax complex (BX-C) discovered by  Edward B. Lewis . [ 10 ]  Each of the complexes focuses on a different area of development. The  antennapedia  complex consists of five genes, including  proboscipedia , and is involved in the development of the front of the embryo, forming the segments of the head and thorax. [ 11 ]  The bithorax complex consists of three main genes and is involved in the development of the back of the embryo, namely the abdomen and the posterior segments of the thorax. [ 12 ]


During development (starting at the  blastoderm  stage of the embryo), these genes are constantly expressed to assign structures and roles to the different segments of the fly's body. [ 13 ]  For  Drosophila , these genes can be analyzed using the  Flybase  database.


Much research has been done on homeotic genes in different organisms, ranging from basic understanding of how the molecules work to mutations to how homeotic genes affect the human body. Changing the expression levels of homeotic genes can negatively impact the organism. For example, in one study, a pathogenic phytoplasma caused homeotic genes in a flowering plant to either be significantly upregulated or downregulated. This led to severe phenotypic changes including dwarfing, defects in the pistils, hypopigmentation, and the development of leaf-like structures on most floral organs. [ 14 ]  In another study, it was found that the homeotic gene  Cdx2  acts as a  tumor suppressor . In normal expression levels, the gene prevents tumorgenesis and colorectal cancer when exposed to  carcinogens ; however, when  Cdx2  was not well expressed, carcinogens caused tumor development. [ 15 ]  These studies, along with many others, show the importance of homeotic genes even after development.


Homeotic selector genes  confer  segment  identity in  Drosophila . They encode  homeodomain  proteins which interact with  Hox  and other  homeotic genes  to initiate segment-specific gene regulation. Homeodomain proteins are transcription factors that share a DNA-binding domain called the homeodomain. [ 1 ]  Changes in the expression and function of homeotic genes are responsible for the changes in the morphology of the limbs of arthropods as well as in the axial skeletons of vertebrates. [ 2 ] [ 3 ]  Mutations in homeotic selector genes do not lead to elimination of a segment or pattern, but instead cause the segment to develop incorrectly.


The homeotic selector genes were discovered through the genetic analysis of  Drosophila  over 80 years ago  [ citation needed ] . Unusual disturbances were found in the organization of the adult fly, resulting in misplaced limbs, such as legs developing where antennae usually develop or an extra pair of wings developing where halteres should be. This discovery provided a glimpse to understanding how each segment acquires its individual identity. [ 2 ]


The first homeotic gene cluster, the bithorax complex, was discovered by  Edward B. Lewis  in 1978. Similar mutations in the complex were found to cluster together, leading Lewis to propose that these homeotic genes arose through a duplication mechanism which would conserve the clusters through evolution. [ 4 ]
The independent discoveries of the  homeobox  in the 1983 by  Walter Gehring's  laboratory at the University of Basel, Switzerland, and Thomas Kaufman's laboratory at Indiana University confirmed Lewis's theory. [ 5 ]


Collinearity is found between the order of the genes on the chromosome and the order in which the genes are expressed along the anteroposterior axis of the embryo. For example, the lab gene is found in the 3' position in the Antennapedia complex, and is expressed in the most anterior head region of the embryo. At the same time, the Abd-B gene is located at the 5' position of the Bithorax complex, and expressed in the most posterior region of the embryo. This suggests that the genes may be activated through a graded process, in which the action is gradually spread along the chromosome. Although the significance of colinearity is still not understood, it is thought to have an important role, due to its conservation in arthropods, and vertebrates including humans. [ 6 ]


Homeotic selector genes encode regulatory  DNA-binding proteins  which are all related through a highly conserved DNA binding sequences called the  homeobox  (from which the "Hox Complex" name is derived from). Although each all of the DNA-binding complexes are conserved, each para-segment still has an individual identity. The proteins do not bind directly to the DNA, rather, they interact with other regulatory proteins which are already bound to DNA-binding complexes. Different interactions determine which DNA binding sites are recognized and subsequently activated or repressed. Homeotic selector proteins combine in different combinations with regulatory proteins to give each parasegment its identity.
 [ 2 ]


Certain signals set up the spatial pattern of expression of the Hox complex early in development. The Hox complex acts like a stamp, giving cells in each segment a long term positional value. The cell memory of a given positional value depends on two inputs, the first being the ability of many Hox proteins to autoactivate their own transcription, and the second derived from two large groups of transcriptional regulators: The  Polycomb group  and the  Trithorax group . A defect in either of these regulators results in a  pattern which is initially correct but is not maintained at later embryonic stages.
The Polycomb and Trithorax regulators act in opposite ways. The Trithorax group maintains Hox transcription after transcription is already activated. The Polycomb group forms stable complexes that bind to the chromatin of Hox genes, and keep it in a repressed state at sites where Hox genes are not active. [ 2 ]


Homologs of the Homeotic selector gene are found in a variety of species, varying from  cnidarians  to  nematodes , to mammals. These genes are grouped similarly to the Hox complex found in insects. The mouse has four complexes, HoxA, HoxB, HoxC, and HoxD, each on different chromosomes. Individual genes in each complex correspond to specific members of the Drosophila genome. The mammalian Hox genes can function in  Drosophila  as partial replacements for the Drosophila Hox genes. Each of the four mammalian Hox complexes has a rough counterpart in the insect complex.


The theory behind this evolutionary conservation stems from the belief that some common ancestor of worms, flies, and vertebrates had a single primordial homeotic selector gene, an ancestral Hox complex, that went through repeated duplication to form a series of tandem genes. In  Drosophila , this ancestral Hox complex split into two separate complexes: Antennapedia and Bithorax. In mammals, the whole complex repeatedly duplicated resulting in four Hox complexes. This theory has some faults, including that some individual genes have been duplicated while others have been lost. [ 6 ]


Changes in homeotic gene expression contributes to the diversity. The  Drosophila  genome holds its eight homeotic genes in two complexes. The  Invertebrate  genome contains 8-10 of is homeotic genes in only one complex, while  Vertebrates  have duplicated the Hox complex and have four clusters. Changes in the expression and functionality of individual genes result in various morphology as seen in  arthropods . The diversity found between the five groups of arthropods is a result of their modular architecture. The arthropods are composed of a series of repeating body segments that can be modified in a limitless number of ways. While some segments may carry antenna, others can be modified to carry wings. [ 6 ]   Crustaceans  have different morphology within the group due to different patterns of Ubx expression in  isopods  and  brachiopods . Similar to brachiopods, isopods have swimming limbs on the second through eighth thoracic segments, however the limbs on the first thoracic segment are smaller than the others, and are used as feeding limbs. The different pattern of Ubx expression correlates with these modifications, possibly a result of an acquired mutation that allows the Ubx enhancers to no longer mediate expression in the first thoracic segment. [ 6 ]


Brachiopods : Src expression is limited to the head region in brachipods and helps in the development of feeding appendages. Ubx is expressed in the thorax where it controls the development of swimming limbs. [ 2 ]


Isopods : Src expression is detected in both the head and the first thoracic segment (T1) in isopods and as a result, the swimming limb in T1 is transformed into a feeding appendage (the maxillipped). The posterior expansion of Src is possible by the loss of Ubx expression in T1 because Ubx normally represses Src expression. [ 2 ]


Every insect has six legs, one pair found on each of the three thoracic segments while other  arthropods  have a variable number of limbs. This change in morphology is due to functional changes in the Ubx regulatory protein. Ubx and abd-A repress the expression of Distal-less, Dll, a gene responsible for the development of limbs. In the Drosophila embryo, Ubx is expressed at high levels in the  metathorax  and anterior abdominal segments; abd-A is expressed in the posterior abdominal segments. In combination, these two genes do not allow Dll to function in the first seven abdominal segments. However, Ubx is expressed in the metathorax and does not interfere with the Dll expression because Dll is activated before Ubx is expressed. [ 6 ]


In crustaceans, there are high levels of both Ubx and DII in all 11 thoracic segments. The expression of DII promotes the development of swimming limbs. The Ubx protein does not repress DII in crustaceans because Ubx is functionally different in insects and crustaceans. [ 6 ]


In  molecular biology ,  housekeeping genes  are typically  constitutive genes  that are required for the maintenance of basic cellular function, and are  expressed  in all cells of an organism under normal and patho-physiological conditions. [ 1 ] [ 2 ] [ 3 ] [ 4 ]   Although some housekeeping genes are expressed at relatively constant rates in most non-pathological situations, the expression of other housekeeping genes may vary depending on experimental conditions. [ 1 ] [ 5 ]


The origin of the term "housekeeping gene" remains obscure.  Literature from 1976 used the term to describe specifically  tRNA  and  rRNA . [ 6 ]  For experimental purposes, the expression of one or multiple housekeeping genes is used as a reference point for the analysis of expression levels of other genes. The key criterion for the use of a housekeeping gene in this manner is that the chosen housekeeping gene is uniformly expressed with low variance under both control and experimental conditions. Validation of housekeeping genes should be performed before their use in gene expression experiments such as  RT-PCR . Recently a web-based database of  human  and  mouse  housekeeping genes and reference genes/transcripts, named  Housekeeping and Reference Transcript Atlas  (HRT Atlas), was developed to offer updated list of  housekeeping genes and reliable candidate reference genes/transcripts for RT-qPCR data normalization. [ 1 ]  This database can be accessed at  http://www.housekeeping.unicamp.br .


Housekeeping genes account for majority of the active genes in the genome, and their expression is obviously vital to survival. The housekeeping gene expression levels are fine-tuned to meet the metabolic requirements in various tissues. Biochemical studies on  transcription  initiation of the housekeeping gene promoters have been difficult, partly due to the less-characterized  promoter  motifs and transcription initiation process.


Human housekeeping gene promoters are generally depleted of  TATA -box, have high GC content and high incidence of  CpG Islands . [ 7 ]  In Drosophila, where  promoter  specific CpG Islands are absent, housekeeping gene promoters contain DNA elements like DRE, E-box or DPE. [ 8 ]  Transcription start sites of housekeeping genes can span over a region of around 100 bp whereas transcription start sites of developmentally regulated genes are usually focused in a narrow region. [ 9 ] [ 10 ] [ 11 ]  Little is known about how the dispersed transcription initiation of housekeeping gene is established. There are  transcription factors  that are specifically enriched on and regulate housekeeping gene promoters. [ 12 ] [ 13 ]  Furthermore, housekeeping promoters are regulated by housekeeping  enhancers  but not developmentally regulated enhancers. [ 14 ]


The following is a partial list of "housekeeping genes." For a more complete and updated list, see  HRT Atlas database  compiled by Bidossessi W. Hounkpe et al. [ 1 ]  The database was constructed by mining more than 12000 human and mouse RNA-seq datasets. [ 1 ]


There is significant overlap in function with regards to some of these proteins.  In particular, the Rho-related genes are important in nuclear trafficking (i.e.: mitosis) as well as with mobility along the cytoskeleton in general.  These genes of particular interest in cancer research.


(Note that COX1, COX2, and COX3 are mitochondrially encoded)


[ 2 ] [ 17 ]
 [ 18 ]


A specialized form of cell signaling


Although this page is devoted to genes that should be ubiquitously expressed, this section is for genes whose current name reflects their relative upregulation in testes


Hypertrichosis 1 (universalis, congenital)  is a  protein  that  is encoded by the HTC1  gene  in humans.
 [ 2 ]


Insulin-dependent (type I)  diabetes mellitus    (IDDM) is a genetic heterogenous  autoimmune disorder , which is triggered by genetic predisposition and environmental factors. [ 1 ]  The prevalence of insulin-dependent (type I)  diabetes mellitus  (IDDM) among children and young adult from Europe is approximately 0.4%. [ 2 ]  Insulin-dependent (type I)  diabetes mellitus  (IDDM) is characterized by acute onset and insulin deficiency. [ 2 ] [ 3 ]  Patients with  insulin-dependent (type I) diabetes mellitus (IDDM) are found with gradual loss of the  pancreatic islet beta  cells and therefore not able to produce  insulin . [ 2 ] [ 3 ]  As a result, they usually need exogenous insulin to maintain their life. [ 2 ] [ 3 ]


Genome-wide linkage analysis  could be used for identification in susceptibility genes of insulin-dependent (type I)  diabetes mellitus  (IDDM). [ 4 ]  This analysis verifies that eighteen different genome regions are predisposed to insulin-dependent (type I)  diabetes mellitus (IDDM). There are 18 different symbols of genome region, which is labeled from  IDDM1  to IDDM18. [ 3 ]  The MHC HLA gene (IDDM1) and the insulin gene INS (IDDM2) are the major genetic candidates in the development of insulin-dependent (type I)  diabetes mellitus (IDDM), which are located on the chromosome 6p21.3 and chromosome 11p15 respectively. [ 1 ] [ 4 ]  IDDM3, IDDM4, IDDM5 IDDM7 reside in  chromosome 15q26, chromosome 11q13, chromosome 6q25 and 2q31 respectively. [ 5 ] IDDM11  (insulin-dependent diabetes mellitus 11) is one of the susceptibility genes for IDDM which locates on chromosome 14q24.3-q31. [ 2 ] [ 6 ]  This loci is identified by linkage to D14S67 marker via a sibling-pair linkage analysis [ 2 ] [ 6 ]  Based on the previous study, the biological behavior of IDDM11is different to HLA region genes so that IDDM11 is less predisposing to HLA. [ 5 ]  Moreover, IDDM11 has more involvement on the families that are less predisposing to HLA, while IDDM11 has less involvement on the families that are more predisposing to HLA. [ 5 ]


The rest of susceptibility genes locus in insulin-dependent (type I) diabetes mellitus (IDDM)are shown in table 1. [ 3 ]


Table 1 The locus for susceptibility genes for IDDM.


Most regions of IDDM loci are 1 to 40  cM , which are corresponded to 1 to 40 Mb . Each region of IDDM consists several genes. [ 2 ]


The etiological mutations of all IDDM loci have not been found. [ 2 ]


SEL1L gene  (sel-1 suppressor of Lin-12-like Caenorhabdits elegans) is a negative regulator of the   Notch signaling pathway  that is responsible for  pancreatic endocrine cell development. [ 2 ] [ 7 ]  SEL1L gene is located on chromosome 14q24.3-31. [ 2 ] [ 7 ]  The locus of  SEL1L is near to D14S67 marker used for identification of IDDM 11 so that SEL1L gene can serve as a candidate gene for IDDM11. [ 2 ] [ 7 ]  However, the present researchers are object to this thesis. The present researchers use LD ( Linkage disequilibrium ) analyses and TDT ( transmission disequilibrium test ) to analyze the SEL1L gene among Danish and Sardinian families. [ 2 ]  The research result indicates that the SEL1L gene is not supposed to a candidate gene for IDDM11. [ 2 ]  In addition, other candidate genes for IDDM11 could be tested and identified by using  single nucleotide polymorphism  (SNP) technology. The following table shows some candidate genes for IDDM11. [ 2 ]


subfamily K, member 2)


kinase, delta)


Table 2 Candidate genes for IDDM11.


IGF like family member 3  is a  protein  that in humans is encoded by the IGFL3  gene .
 [ 5 ]


IGFL3 belongs to the insulin-like growth factor (IGF; see MIM 147440) family of signaling molecules that play critical roles in cellular energy metabolism and in growth and development, especially prenatal growth (Emtage et al., 2006 [PubMed 16890402]).


Immunoglobulin lambda joining 3  is a  protein  that in humans is encoded by the IGLJ3  gene . [ 2 ]


NM_017563 NM_001318864


NM_027265 NM_134437


NP_001305793 NP_060033


Interleukin 17 receptor D  (also known as Sef) is a  protein  that in humans is encoded by the IL17RD  gene . [ 5 ]


This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. Alternate splicing generates multiple transcript variants encoding distinct isoforms. IL-17RD has been described to limit fibroblast growth factor receptor ( FGFR ) signaling and to be a part of the  IL-17 receptor signaling complex .


IL-17RD was initially discovered during a large-scale  in situ  hybridization screen for genes regulating zebrafish embryogenesis. It was identified as a part of a synexpression group (genes with similar spatio-temporal expression) with negative regulators of fibroblast growth factor ( FGF ) and termed Sef (similar expression to FGF genes). The name was later changed to IL-17RD due to its sequence similarity to other IL-17 receptors. It was further determined that IL-17RD co-immunoprecipitates with FGF receptor (FGFR) and inhibits FGF signaling at the level of signal transduction and not by interfering with the ligand or its binding to FGFR. [ 6 ] [ 7 ]


IL-17RD is a  type I transmembrane protein  containing extracellular Ig-like domain followed by a fibronectin type III domain, a short transmembrane domain of ~20 amino acids, and an intracellular SEFIR domain  which was identified in IL-17 receptors and some soluble factors involved in IL-17 signaling. [ 8 ]  The SEFIR domain contains a region with sequence similarity to the TIR domain, which is characteristic of Toll-like receptors (TLRs), receptors of the interleukin 1 family, and adaptor proteins involved in the signaling pathways of these receptors. The regions within SEFIR that can be found in the TIR domain include box 1 and box 2. [ 9 ]


IL-17RD (Sef) was identified as part of a group of genes involved in FGF signaling in zebrafish and  Xenopus laevis  embryo. Injection of 1-cell stage embryo with  sef  mRNA lead to ventralization of the embryo, a similar effect observed after injection with XFD (a dominant negative of FGF receptor), suggesting its function as a negative regulator of FGF receptor signaling. Co-immunoprecipitation assay revealed that the intracellular part, but not the SEFIR domain, is critical for IL-17RD association with FGFR. [ 6 ]  One of the pathways activated by stimulation of FGFR is Ras/MAPK (the rest being PI3/AKT and PLCγ). Injection of embryos with high amounts of Ras, Raf or MEK causes cell cycle arrest, which can be rescued by co-injection of IL-17RD, further supporting the role of IL-17RD in negative regulation of FGFR signaling. Moreover, IL-17RD appears to regulate FGF signaling at the level of downstream signaling, not the receptor, since overexpression of FGF or FGFR does not cause cell cycle arrest. [ 7 ]  Taken together IL-17RD seems to negatively regulate FGFR signaling by limiting MAPK signaling via its intracellular domain.


The IL-17 receptor family belongs to a group of structurally similar receptors with a distinctive SEFIR (Sef and IL-17R) domain. [ 9 ]  The founding member, IL-17RA, along with IL-17RC serve as a receptor complex for IL-17. IL-17 is a proinflammatory cytokine mainly produced by Th17 subset of T cells and plays an important role in extracellular pathogen elimination as well as several autoinflammatory diseases (such as psoriasis or rheumatoid arthritis). [ 10 ]  IL-17RD has been reported to associate and co-localize with IL-17RA, mediate IL-17 signaling, and interact with TRAF6 (an IL-17 downstream molecule). Moreover, deletion of IL-17RD intracellular domain has a dominant negative effect and suppresses IL-17 signaling. In contrast, deletion of extracellular domain had no effect on IL-17 signaling. [ 11 ]  However, full-body IL-17RD knockout mice do not present with any apparent phenotype. [ 12 ]  This might be accounted for by the presence of IL-17RC which to an extent substitutes IL-17RD. It is important to note, however, that IL-17RC or IL-17RD deletion fails to protect against imiquimod-induced psoriasis. [ 13 ]


Since the SEFIR domain contains a TIR domain, the possible role of IL-17RD in TLR signaling was investigated. One study discovered that IL-17RD interacts with TIR adaptor proteins (such as MyD88, Mal, and TRIF) following TLR stimulation. Additionally, this interaction was abolished in IL-17RD which lacks the SEFIR domain. The study concluded that IL-17RD targets TLR-induced pro-inflammatory pathways and inhibits signaling upstream of NF-κB and IRF3. [ 14 ]


One study reported that TNF induces IL-17RD expression, which then serves as a feedback loop inhibiting the activation of TNF-activated NF-κB. [ 15 ]  Another study focusing on renal cells describes IL-17RD to associate with TNFR2, but not TNFR1, to augment NF-κB activation. [ 16 ]  The contrasting results suggest different roles of IL-17RD in various tissues.


The  Imd pathway  is a broadly-conserved  NF-κB  immune signalling pathway of insects and some arthropods [ 1 ]  that regulates a potent antibacterial defence response. The pathway is named after the discovery of a mutation causing severe immune deficiency (the gene was named  "Imd"  for "immune deficiency"). The Imd pathway was first discovered in 1995 using  Drosophila  fruit flies by  Bruno Lemaitre  and colleagues, who also later discovered that the  Drosophila   Toll  gene regulated defence against Gram-positive bacteria and fungi. [ 2 ] [ 3 ]  Together the Toll and Imd pathways have formed a paradigm of insect immune signalling; as of September 2, 2019, these two landmark discovery papers have been cited collectively over 5000 times since publication on Google Scholar. [ 4 ] [ 5 ]


The Imd pathway responds to signals produced by  Gram-negative bacteria .  Peptidoglycan  recognition proteins (PGRPs) sense  DAP-type peptidoglycan , which activates the Imd signalling cascade. This culminates in the translocation of the  NF-κB  transcription factor Relish, leading to production of antimicrobial peptides and other effectors. [ 6 ]  Insects lacking Imd signalling either naturally or by genetic manipulation are extremely susceptible to infection by a wide variety of pathogens and especially bacteria.


The Imd pathway bears a number of similarities to mammalian  TNFR  signalling, though many of the intracellular regulatory proteins of Imd signalling also bear homology to different signalling cascades of human  Toll-like receptors . [ 6 ]


The following genes are analogous or homologous between  Drosophila melanogaster  (in bold) and human  TNFR1  signalling: [ 7 ] [ 8 ]


While the exact  epistasis  of Imd pathway signalling components is continually scrutinized, the mechanistic order of many key components of the pathway is well-established. The following sections discuss Imd signalling as it is found in  Drosophila melanogaster ,  where it is exceptionally well-characterized. [ 6 ]  Imd signalling is activated by a series of steps from recognition of a bacterial substance ( e.g.  peptidoglycan) to the transmission of that signal leading to activation of the NF-κB  transcription factor  Relish. [ 7 ]  Activated Relish then forms  dimers  that move into the nucleus and bind to  DNA  leading to the transcription of  antimicrobial peptides  and other effectors.


The sensing of bacterial signals is performed by peptidoglycan recognition protein LC (PGRP-LC), a transmembrane protein with an intracellular domain. Binding of bacterial peptidoglycan leads to dimerization of PGRP-LC which generates the conformation needed to bind and activate the Imd protein. However alternate  isoforms  of PGRP-LC can also be expressed with different functions: PGRP-LCx recognizes polymeric peptidoglycan, while PGRP-LCa does not bind peptidoglycan directly but acts alongside PGRP-LCx to bind monomeric peptidoglycan fragments (called  tracheal cytotoxin  or "TCT"). Another PGRP (PGRP-LE) also acts intracellularly to bind TCT that has crossed the cell membrane or is derived from an intracellular infection. PGRP-LA promotes the activation of Imd signalling in epithelial cells, but the mechanism is still unknown. [ 6 ] [ 7 ]


Other PGRPs can inhibit the activation of Imd signalling by binding bacterial signals or inhibiting host signalling proteins: PGRP-LF is a transmembrane PGRP that lacks an intracellular domain and does not bind peptidoglycan. Instead PGRP-LF forms dimers with PGRP-LC preventing PGRP-LC dimerization and consequently activation of Imd signalling. A number of secreted PGRPs have amidase activity that downregulate the Imd pathway by digesting peptidoglycan into short, non-immunogenic fragments. These include PGRP-LB, PGRP-SC1A, PGRP-SC1B, and PGRP-SC2. Additionally, PGRP-LB is the major regulator in the gut. [ 9 ]


The principle intracellular signalling protein is Imd, a death domain-containing protein that binds with FADD and Dredd to form a complex. Dredd is activated following  ubiquitination  by the Iap2 complex (involving Iap2, UEV1a, bend, and eff), which allows Dredd to cleave the 30 residue N-terminus of Imd, allowing it to also be ubiquitinated by Iap2. [ 7 ]  Following this, the Tak1/TAB2 complex binds to the activated form of Imd and subsequently activates the IKKγ/Ird5 complex through phosphorylation. This IKKγ complex activates Relish by phosphorylation, leading to cleavage of Relish and thereby producing both N-terminal and C-terminal Relish fragments. The N-terminal Relish fragments dimerize leading to their translocation into the nucleus where these dimers bind to Relish-family NF-κB binding sites. Binding of Relish promotes the  transcription  of effectors such as  antimicrobial peptides . [ 6 ] [ 7 ]


While Relish is integral for transcription of Imd pathway effectors, there is additional cooperation with other pathways such as  Toll  and  JNK . The TAK1/TAB2 complex is key to propagating intracellular signalling of not only the Imd pathway, but also the JNK pathway. As a result, mutants for JNK signalling have severely reduced expression of Imd pathway antimicrobial peptides. [ 10 ]


Imd signalling regulates a number of effector peptides and proteins that are produced en masse following immune challenge. [ 11 ]  This includes many of the major  antimicrobial peptide  genes of  Drosophila , particularly:  Diptericin ,  Attacin ,  Drosocin ,  Cecropin , and  Defensin . [ 12 ]  The Imd pathway regulates hundreds of genes after infection, however the antimicrobial peptides play one of the most essential roles of Imd signalling in defence. Flies lacking multiple antimicrobial peptide genes succumb to infections by a broad suite of Gram-negative bacteria. [ 13 ] [ 14 ]  Classical thinking suggested that antimicrobial peptides worked as a generalist cocktail in defence, where each peptide provided a small and somewhat redundant contribution. [ 15 ] [ 6 ]  However Hanson and colleagues found that single antimicrobial peptide genes displayed an unexpectedly high degree of specificity for defence against specific microbes. [ 13 ]  The fly  Diptericin A  gene is essential for defence against the bacterium  Providencia rettgeri  (also suggested by an earlier evolutionary study [ 16 ] ). A second specificity is encoded by  Diptericin B , which defends flies against  Acetobacter  bacteria of the fly microbiome. [ 17 ]  A third specificity is encoded by the gene  Drosocin . Flies lacking  Drosocin  are highly susceptible to  Enterobacter cloacae  infection. [ 13 ] [ 14 ] [ 18 ]  The Drosocin gene itself encodes two peptides (named Drosocin and Buletin), wherein it is specifically the Drosocin peptide that is responsible for defence against  E. cloacae , while the Buletin peptide instead mediates a specific defence against another bacterium,  Providencia burhodogranariea . [ 18 ]  These works accompany others on antimicrobial peptides and effectors regulated by the  Drosophila   Toll  pathway, which also display a specific importance in defence against certain fungi or bacteria. [ 19 ] [ 20 ] [ 21 ]


This work on  Drosophila  immune antimicrobial peptides and effectors has greatly revised the former view that such peptides are generalist molecules. The modern interpretation is now that specific molecules might provide a somewhat redundant layer of defence, but also single peptides can have critical importance, individually, against relevant microbes. [ 22 ] [ 23 ] [ 24 ] [ 25 ]


The Imd pathway appears to have evolved in the last common ancestor of centipedes and insects. [ 1 ]  However certain lineages of insects have since lost core components of Imd signalling. The first-discovered and most famous example is the pea aphid  Acyrthosiphon pisum . It is thought that plant-feeding aphids have lost Imd signalling as they bear a number of bacterial  endosymbionts , including both nutritional symbionts that would be disrupted by aberrant expression of antimicrobial peptides, and defensive symbionts that cover for some of the immune deficiency caused by loss of Imd signalling. [ 26 ]  It has also been suggested that antimicrobial peptides, the downstream components of Imd signalling, may be detrimental to fitness and lost by insects with exclusively plant-feeding ecologies. [ 27 ]


While the Toll and Imd signalling pathways of  Drosophila  are commonly depicted as independent for explanatory purposes, the underlying complexity of Imd signalling involves a number of likely mechanisms wherein Imd signalling interacts with other signalling pathways including  Toll  and  JNK . [ 6 ]  While the paradigm of Toll and Imd as largely independent provides a useful context for the study of immune signalling, the universality of this paradigm as it applies to other insects has been questioned. In  Plautia stali   stinkbugs , suppression of either Toll or Imd genes simultaneously leads to reduced activity of classic Toll and Imd effectors from both pathways. [ 28 ]


Immediate early genes  ( IEGs ) are  genes  which are activated transiently and rapidly in response to a wide variety of cellular stimuli.  They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized. IEGs are distinct from "late response" genes, which can only be activated later, following the synthesis of early response gene products. Thus IEGs have been called the "gateway to the genomic response". The term can describe viral regulatory proteins that are synthesized following viral infection of a host cell, or cellular proteins that are made immediately following stimulation of a resting cell by extracellular signals.


In their role as "gateways to genomic response", many IEG products are natural  transcription factors  or other  DNA-binding proteins . However, other important classes of IEG products include  secreted proteins ,  cytoskeletal proteins , and  receptor subunits . Neuronal IEGs are used prevalently as a marker to track brain activities in the context of memory formation and development of psychiatric disorders. [ 1 ]  IEGs are also of interest as a therapeutic target for treatment of  human cytomegalovirus . [ 2 ]


The earliest identified and best characterized  IEGs include  c-fos ,  c-myc  and  c-jun , genes that were found to be homologous to  retroviral   oncogenes .  Thus IEGs are well known as early regulators of cell growth and differentiation signals.  However, other findings suggest roles for IEGs in many other cellular processes. [ 3 ]   Arc/Arg3.1 ,  Zif268  and Homer are IEGs that regulate synaptic strength in neurons. [ 4 ]


Expression of IEGs occurs in response to internal and external cell signals, occurring rapidly without the need to synthesize new  transcription factors . [ 5 ]  The genetic sequences of IEGs are generally shorter in length (~19kb) and exhibit an enrichment of specific transcription factor binding sites, offering redundancy in transcription initiation. [ 6 ]  Translation of IEG mRNA into proteins occurs regardless of protein synthesis inhibitors which disrupts the process of protein production. [ 7 ]  Rapid expression of IEGs is also attributed to the accessibility of its promotor sequence through histone acetylation that is consistent pre- and post-expression. [ 6 ]  Downregulation of mRNA transcription occurs through redundant targeting of the  3' UTR  region by  microRNAs , resulting in translational repression and degradation. The expression of IEG protein is often transient due to rapid mRNA downregulation and increased  proteolysis  of translated products. [ 6 ]


Activation of gene transcription is a complex system of  signal cascades  and recruitment of necessary components such as  RNA polymerase  and  transcription factors . IEGs are often the first responders to regulatory signals with many reaching peak expression within 30 minutes after stimuli compared to 2–4 hours in the case of delayed primary response gene. [ 8 ]  There are many signaling pathways leading to the activation of IEGs, many of which ( MAPK/ERK ,  PI3K , etc.) are studied in the context of cancer. [ 6 ]  As such, many IEGs function as transcription factors regulating expression of downstream genes or are proto- oncogenes  associated with altered cell growth. [ 8 ]


Expression of IEGs is involved in neuronal activity and specifically memory formation, neuropsychiatric diseases, and behavioral activities. [ 9 ]  Immediate early genes present in the brain are associated with a range of functions such as modifying synaptic functions through transient and rapid activation growth factors or the expression of cellular proteins. [ 10 ]  These changes are theorized to be the means in which memory is stored in the brain as outline in the concept of memory trace or  engram . In the context of neuropsychiatric diseases, up-regulation of certain IEGs related to the formation of fear-related memories contribute to the development of a variety of disease such as  schizophrenia ,  Panic disorder ,  Post-traumatic stress disorder [ 11 ]


Some IEGs such as  ZNF268  and  Arc  have been implicated in  learning  and  memory  and  long-term potentiation . [ 12 ] [ 13 ]


A wide range of neuronal stimulation have been shown to induce IEG expression ranging from sensory and behavioral to drug-induced convulsions. [ 9 ]  As such, IEGs are utilized as a marker to understand  neuronal ensembles  associated with formations of certain memories such as fear, commonly attributed to the development of psychiatric disorders. [ 11 ]  For example, neurons expression  Arc  in the hippocampus show phenotypic and behavioral differences in response to stimuli such as altered  dendritic spine  morphology or spontaneous firing rate. [ 9 ]  This association suggests the expression of certain IEGs in response to a stimulus results in expansion of the related neuronal circuit by incorporating the activated neuron assembles. Other IEGs effect different neural properties with  knock out  of  Arc  showing adverse affects on the formation of long-term memory. [ 9 ]  These findings offer insight into the molecular mechanism and functional changes brought about by IEG expression, expanding the theory of memory trace.