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


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


Proline rich 35  is a  protein  that in humans is encoded by the PRR35  gene .
 [ 3 ]


Pseudo-response regulator  ( PRR ) refers to a group of genes that regulate the  circadian oscillator  in plants. There are four primary PRR proteins (PRR9, PRR7, PRR5 and  TOC1 /PRR1) that perform the majority of interactions with other proteins within the circadian oscillator, and another (PRR3) that has limited function. These genes are all paralogs of each other, and all repress the transcription of Circadian Clock Associated 1 ( CCA1 ) and  Late Elongated Hypocotyl  (LHY) at various times throughout the day. The expression of PRR9, PRR7, PRR5 and  TOC1 /PRR1 peak around morning, mid-day, afternoon and evening, respectively. As a group, these genes are one part of the three-part  repressilator  system that governs the biological clock in plants.


Multiple labs identified the PRR genes as parts of the circadian clock in the 1990s. In 2000, Akinori Matsushika, Seiya Makino, Masaya Kojima, and Takeshi Mizuno were the first to understand PRR genes as pseudo-response repressor genes rather than as  response regulator (ARR) genes . [ 1 ] [ 2 ]  The factor that distinguishes PRR from ARR genes is the lack of a phospho-accepting  aspartate  site that characterizes ARR proteins. Though their research that discovered PRR genes was primarily hailed during the early 2000s as informing the scientific community about the function of  TOC1  (named APRR1 by the Mizuno lab), an additional pseudo-response regulator in the  Arabidopsis thaliana  biological clock, [ 3 ]  the information about PRR genes that Matsushika and his team found deepened scientific understanding of circadian clocks in plants and led other researchers to hypothesize about the purpose of the PRR genes. [ 1 ]  Though current research has identified TOC1, PRR3, PRR5, PRR7, and PRR9 as of importance to the  A. thaliana  circadian clock mechanism, Matsushika et al. first categorized PRR genes into two subgroups (APRR1 and APRR2, the A stands for Arabidopsis) due to two differing amino acid structures. [ 4 ]  The  negative feedback loops  including  PRR  genes, proposed by Mizuno, were incorporated into a complex  repressilator  circuit by  Andrew Millar ’s lab in 2012. [ 5 ]  The conception of the plant biological clock as made up of interacting negative feedback loops is unique in comparison to mammal and fungal circadian clocks which contain autoregulatory negative feedback loops with positive and negative elements [ 6 ]  (see "Transcriptional and non-transcriptional control on the  Circadian clock  page).


PRR3, PRR5, PRR7 and PRR9 participate in the repressilator of a negative autoregulatory feedback loop that synchronizes to environmental inputs. The repressilator has a morning, evening, and night loop that are regulated in part by the pseudo-response regulator proteins' interactions with CCA1 and LHY. CCA1 and LHY exhibit peak binding to PRR9, PRR7, and PRR5 in the morning, evening, and night, respectively. [ 7 ]


When  phosphorylated  by an unknown  kinase , PRR5 and PRR3 proteins demonstrate increased binding to TIMING OF CAB2 EXPRESSION 1 (  TOC1 ). This interaction stabilizes both TOC1 and PRR5 and prevents their degradation by the  F-box protein  ZEITLUPE (ZTL). [ 7 ]  Through this mechanism, PRR5 is indirectly activated by light, as ZTL is inhibited by light. Additionally, PRR5 contributes to the transcriptional repression of the genes encoding the single MYB transcription factors CCA1 and LHY. [ 7 ]


Two single MYB transcription factors, CCA1 and LHY, activate expression of  PRR7  and  PRR9 . In turn, PRR7 and PRR9 repress  CCA1  and  LHY  through the binding of their promoters. This interaction forms the morning loop of the  repressilator  of the biological clock in  A. thaliana . [ 7 ]  Chromatin  immunoprecipitation  demonstrates that LUX binds to the  PRR9  promoter to repress it. Additionally, ELF3 has been shown to activate  PRR9  and repress  CCA1  and  LHY . [ 7 ]  PRR9 is also activated by alternative  RNA splicing . When  PRMT5  (a  methylation  factor) is prevented from methylating intron 2 of PRR9, a  frameshift  resulting in premature truncation occurs. [ 7 ]


PRR7 and PRR9 also play a role in the  entrainment  of  A. thaliana  to a temperature cycle. Double-mutant plants with inactivated  PRR7  and  PRR9  exhibit extreme period lengthening at high temperatures but show no change in period at low temperatures. However, the inactivation of  CCA1  and  LHY  in the  PRR7/PRR9  loss-of-function mutants shows no change in period at high temperatures—this suggests that  PRR7  and  PRR9  are acting by overcompensation. [ 7 ]


In  A. thaliana , the main feedback loop is proposed to involve a transcriptional regulation between several proteins. The three main components of this loop are  TOC1  (also known as PRR1), CCA1 and LHY. [ 8 ]  Each individual component peaks in transcriptions at different times of day. [ 9 ]  PRR 9, 7 and 5 each significantly reduce the transcription levels of CCA1 and LHY. [ 9 ]  In the opposite manner, PRR 9 and 7 slightly increase the transcription levels of TOC1. [ 9 ]  The Constans (CO) is also indirectly regulated by the PRR proteins as well by setting up the molecular mechanism to dictate the  photosensitive  period in the afternoon. [ 10 ]  PRRs are also known to stabilize CO at certain times of day to mediate its accumulation. [ 11 ]  This results in the regulation of early flowering in shorter  photoperiods , making light sensitivity and control of flowering time important functions of the PRR class. [ 10 ]


PPR3, PRR5, PRR7, and PRR9 are all paralogs of each other. They have similar structure, and all repress the transcription of CCA1 and LHY. Additionally, they are all characterized by their lack of a phospho-accepting aspartate site. These genes are also paralogs to TOC1, which is alternatively called PRR1. [ 7 ]


Several pseudo-response regulators have been found in  Selaginella,  but their function has not yet been explored. [ 12 ]


As PRR is a family of genes, several rounds mutant screening have been performed to identify each possible phenotype.


In regards to rhythmicity of the clock in a  free running  setting PRR9 and PRR5 are associated with longer and shorter periods respectively. [ 9 ]  For each gene, the double mutant with PRR7 exacerbates observed trends in rhythmicity. [ 9 ]  The triple mutant renders the plant arrhythmic. [ 9 ]


In terms of flowering time in long day conditions, all mutants made the observed flowering late, with PRR7 significantly more late in comparison to the other mutants. [ 9 ]  All double mutants with PRR7 saw much later flowering time than the PRR5/PRR9 mutant. [ 9 ]


With regard to light sensitivity, particularly in red light which is associated with hypocotyl lengthening, all PRR mutants were observed to be hypo-sensitive with PRR9 showing to be less sensitive. [ 9 ]  All the double mutants were equal in hyposensitivity as the PRR5 or PRR7 mutants; the triple mutant is extremely hypo-sensitive. [ 9 ]


Recent research has showed that expression of clock genes show tissue-specificity. [ 13 ]  Learning about how, when, and why specific tissues show certain peaks in clock genes like PRR can reveal more about the subtle nuances of each gene within the repressilator.


Few investigations into the circadian oscillator mechanisms in species other than  A. thaliana  have taken place; learning which genes are responsible for clock functions in other species will give more insight into the similarities and differences in clocks across plant species. [ 14 ]


The mechanistic details of each step in the plant biological clock repressilator system have yet to be fully understood. An understanding of these will give knowledge of clock function and, across species, increase understanding of the ecological and evolutionary functions of circadian oscillators. [ 7 ]


Additionally, identifying direct targets of PRR5, PRR7 and PRR9 that are not CCA1 and LHY will provide information about the molecular links from the PRRs to output genes like the flowering pathway and metabolism in mitochondria, which are CCA1-independent. [ 9 ]


R2d2  is a mouse genomic locus that is sometimes a  selfish region .


R2d2 is short for "Responder to meiotic drive 2", It was discovered by  UNC School of Medicine  researchers to display  transmission bias .
 [ 1 ]


R2d2 is a stretch of DNA on mouse chromosome 2 that contains multiple copies of the  Cwc22  gene. When seven or more copies of that latter gene are present,  R2d2  becomes selfish.


In one lab breeding population, in a  selective sweep ,  R2d2  increased from being in 50 percent of the lab mice's chromosomes to 85 percent in 10 generations. By 15 generations, it reached  fixation .


In female mice,  R2d2  somehow displaces the chromosome that doesn't contain it and it is preferentially incorporated into eggs. It has spread in the wild to several parts of the world. [ 2 ]


Retinoic acid early transcript 1L (RAET1L)  is a cell surface  glycoprotein  encoded by  RAET1L  gene located on the chromosome 6. [ 1 ]  RAET1L is related to MHC class I molecules, but its gene maps outside the MHC locus. [ 1 ]  RAET1L is composed of the α1α2 domain and is linked to the cell membrane by the  GPI anchor . [ 1 ] [ 2 ]  It functions as a  stress-induced  ligand for  NKG2D  receptor. [ 2 ]  Its expression is, for example, triggered in course of  HCMV  infection, but  HCMV  alters its function. [ 2 ]  HCMV-encoded UL16 glycoprotein retains ULBP6 inside the cells, preventing it from reaching the cell surface and being exposed to cells of the immune system. [ 2 ]


The  RARA gene , also known as  NR1B1 , is a protein coding gene located on  chromosome 17
that provides the instructions required to make transcription factor  Retinoic Acid Receptor Alpha  (or RARα). [ 1 ]


The RARα protein interacts with Vitamin A-derived retinoic acid to control the transcription of genes required for many processes involved in early embryonic development including neural differentiation,  organogenesis ,  cardiogenesis , and  limb development . [ 2 ] [ 3 ] [ 4 ]  It also plays an important role in the development of the  immune system  by inducing  T-regulatory cells , promoting tolerance, and controlling the differentiation of immature immune cells in the bone marrow called  promyelocytes  into mature white blood cells. [ 5 ]


RARA’s role in the developing immune system leaves it subject to possible defects, the most common of which is a condition known as  Acute Promyeloid Leukemia  (APL) caused by a somatic mutation described by the fusion of RARA and the PML gene located on chromosome 15. [ 1 ]  This fusion results in the formation of the protein complex PML-RARα Under normal circumstances, PML produces a tumor suppressing protein that works by inhibiting uncontrolled rapid cell growth. When the two proteins fuse together, their normal functions are hindered, resulting in the accumulation of promyelocytes in the bone marrow unable to differentiate past this immature phase. [ 1 ]  This fusion makes up for the cause of 98% of APL cases, with some other rare mutations and fusions making up the other 2%. [ 6 ]  Current treatment approaches include all-trans-retinoic acid (ATRA) which works by targeting and degrading the PML-RARα protein complex, in addition to chemotherapy and platelet transfusions. [ 7 ]


RNA-binding motif, single-stranded-interacting protein 3  is a  protein  that in humans is encoded by the  RBMS3   gene . [ 1 ]


Rck-2  is a  gene  that plays a major role in clock control of  translation . Rck-2 protein is a  kinase  and is rhythmically activated through  phosphorylation  events based on the periodicity of the clock. Rck-2 activation is directly associated with the phosphorylation of  eEF-2 , which is an elongation factor that plays a major role in translation. [ 1 ]  Phosphorylation of eEF-2 has an inhibitory effect on the activity of translation. Rck-2 is largely studied in  Neurospora crassa  but has significant homology to humans. [ 2 ]  Knockout strains have been produced in the model organism  N. crassa  but there are no human pathologies associated with its deletion. While the basic mechanisms of circadian transcriptional control are known, little is understood about how the clock controls  mRNA  translation, which makes the characterization of pathways responsible for translational control all the more important.


This article discusses the specific topic of reference genes. For a more general list of housekeeping genes see  housekeeping genes


Reference genes  are  expressed  in all cells of an organism under normal and patho-physiological conditions. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Although some  housekeeping genes  (such as  LDHA , [ 5 ]   NONO , [ 5 ]   PGK1 [ 5 ]  and  PPIH , [ 5 ] )  are expressed at relatively constant levels in most non-pathological situations, other housekeeping genes may vary depending on experimental conditions. [ 6 ]
Although the terms "housekeeping gene" and "reference gene" are used somewhat interchangeably, caution must be used in selecting genes for reference purposes. Suitable reference genes must be stably expressed in the specific experimental condition or tissue of interest. [ 1 ]  Recently a web-based database of  human  and  mouse  cell specific reference genes/transcripts, named  Housekeeping and Reference Transcript Atlas  (HRT Atlas), was developed to offer reliable reference genes/transcripts for RT-qPCR data normalization. [ 1 ]


This is a list of  housekeeping genes  and transcripts  stably expressed across 52 human tissues and cell types that may be used for reference purposes after empirical validation: [ 1 ]


HRT Atlas  allows searching of a complete list of reliable candidate reference genes and transcripts for RT-qPCR normalization in more than 120  human  and  mouse  tissues or cell types. The database also offers some empirically validated primers and predicted modifiers (disease and small molecules) of the expression of these reference genes.


The following represent genes that should probably  not be used  for reference purposes:  GUSB , [ 5 ]   RPLP0 , [ 5 ]   TFRC , [ 5 ]   GAPDH ,  HSP90 , and  β-actin .  Although they were once considered as "housekeeping genes," recent data suggests that they are not as reliable as once thought. [ 1 ] [ 2 ]


Reprimo-like  ( RPRML ) is a vertebrate gene located at human chromosome 17q21.32. It is a member of the  Reprimo   gene family  which consists of two human-related protein-coding and  intronless  genes:  Reprimo  ( RPRM ) and  RPRML . [ 1 ]  Although poorly characterized, this lineage has been implicated in important developmental and cancer processes. [ 2 ]


RPRML  is normally expressed during the embryonic development of zebrafish. [ 3 ]  Knocking down  RPRML  in this model, increases caspase-3 activity in the hemogenic endothelium, hindering the formation of hematopoietic precursor/stem cells and impairing definitive hematopoiesis. [ 4 ]


In humans, RPRML protein expression has been reported in the cytoplasm of glandular and foveolar epithelial cells of the stomach. [ 5 ]  Analyses of multiple gastric tumors show its expression is significantly downregulated when compared to normal adjacent tissues. This loss of expression is associated with a reduction of the apoptotic marker cleaved caspase-3 and with a worse prognosis of patients with advanced stages of the disease. [ 5 ]   RPRML  overexpression in  gastric cancer  cell lines inhibits cell cycle progression at the  G2/M phase , reduces cell proliferation, clonogenic capacity, and anchorage-independent growth. [ 5 ]  Hence, it has been proposed as a novel  tumor suppressor gene . In colorectal cancer cells,  RPRML  is a target of Wnt/β- catenin  signaling pathway. [ 6 ]  Further research is warranted to fully elucidate its biological function.


Similar to its homolog  RPRM , the silencing of  RPRML  in gastric cancer is mediated by  DNA methylation . Circulating methylated  RPRML  DNA in plasma samples has been successfully explored as a non-invasive  biomarker  for gastric cancer diagnosis. [ 5 ]


NM_001289661 NM_001289662 NM_026054


NP_001276590 NP_001276591 NP_080330


Retroelement silencing factor 1  is a  protein  that in humans is encoded by the  RESF1   gene . RESF1 is broadly expressed in the  lymph nodes ,  ovaries ,  appendix  and  spleen . [ 5 ]   RESF1 shows characteristics of being a  minor histocompatibility antigen , as well as tumor suppressor capabilities. [ 6 ] [ 7 ]  The high expression in the lymph nodes and spleen indicate function in the  immune system .


RESF1 is a protein coding gene found on Chromosome 12 and maps to 12p11.21. [ 8 ]  Alternative names for this gene include Gonad Expressed Transcript (GET), UTA2-1 and C12orf35. [ 5 ]  RESF1 has 7 exons, 3 of which occur before the  start codon . [ 5 ]


A study of normal human tissue  expression profiling  shows that RESF1 is highly expressed in the thymus, spleen, bone marrow and liver. [ 9 ]  This is interesting as it relates to common organs associated with the  Immune system .


Gene tissue expression patterns found through the  National Center for Biotechnology Information  UniGene EST Profile showed that there was also high expression of RESF1 in the  lymph nodes ,  uterus ,  mouth ,  thyroid ,  larynx  and  blood . [ 10 ]


An evaluation of RESF1 expression in health states was performed using NCBI Unigene’s EST Profile. [ 11 ]  Although RESF1 is highly expressed in uterine tumors, it is also highly expressed in the uterus, suggesting that it is unlikely the gene is associated closely with uterine cancer. However, RESF1 may be related to adrenal tumors, as there was lower expression of this gene within normal kidney tissue.


Transcription factor binding sites within the promoter of RESF1 included mainly transcription factors that were associated with bone marrow cells, antibody- producing cells, and blood cells. [ 12 ]  This supports the association of RESF1 with the functioning immune system.


RESF1 is 1747 amino acids in length and has one domain of unknown function, DUF4617. [ 13 ]  The  Molecular Weight  of RESF1 is 194.9 kdal. [ 14 ]  The basal isoelectric point is 8.95. [ 15 ]  A localization prediction suggests that RESF1 is likely a nuclear protein. [ 15 ]


The secondary structure of RESF1 consists of mainly random coil structures (approximately 59.2%), few alpha helices (24% of residues) and fewer extended strands (15.8% of residues). [ 16 ]


A predicted 3-D structure was created using Swiss model work space, shown above. [ 17 ]


RESF1 interacts with NANOG,  MDM2 ,  EXOC1  and  CALML3 . These interactions further suggest RESF1 is a  nuclear protein , and that it may be associated with  tumor-suppressor proteins  and immune system proteins. [ 18 ]


EXOC1  was involved in a schizophrenia study, relating a schizophrenia risk gene (DISC1) to a network of protein-protein interactions. [ 19 ]  This study used a two-hybrid assay as evidence to the protein interaction between RESF1 and EXOC1. EXOC1 functions as a response to microbial infections, which reduces viral RNA synthesis and protein translation. [ 20 ]


NANOG was predicted to interact with RESF1 based on an affinity capture-MS, which linked NANOG to proteins involved with the cell cycle. This study used affinity purification combined with high accuracy mass spectrometry to find specific protein interactions. [ 21 ]  NANOG was also found to be an essential transcription factor in embryonic stem cells, specifically involved in gene expression to affect cell fate. [ 22 ]


MDM2  is a gene that interacts with others to affect the cell cycle and apoptosis, and is located in tissues common to RESF1, such as the uterus and lymph node. [ 23 ]  MDM2 was found to interact with RESF1 through the use of a phage display library. This interaction further suggests that RESF1 is a nuclear protein, as MDM2 and its splice variants contain nuclear localization signals for nucleoplasmic distribution. [ 24 ]


CALML3  was found to interact with RESF1 based on affinity capture-MS assay, similar to how NANOG was found to interact with RESF1. [ 25 ]  A study on CALML3 expression in epidermal development showed that CALML3 was useful marker for development, and loss of CALML3 expression correlated with malignant phenotypes. [ 26 ]


The closest orthologs to RESF1 are primates, however, conserved sequences can be found in whales, bears, snakes, birds, turtles, and frogs. Orthologs of RESF1 diverged as long ago as 353 million years ago ( Xenopus laevis ), while the closest evolutionary ortholog is  Papio anubis , which diverged approximately 28.1 million years ago.


An unrooted phylogenetic tree of RESF1 was created of 20 orthologs and the human RESF1 gene.


A graph shown below of the molecular evolution of RESF1 shows that it evolved relatively quickly compared to both  cytochrome C , a slowly evolving protein, and  fibrinogen alpha , which evolved more quickly than cytochrome C. The comparison shows that RESF1 is fairly quickly diverging, which suggests that it could be a gene that changes quickly in response to its environment, such as the introduction of a  pathogen .


1WIE ,  2CSI ,  2CSP ,  2CSQ


NM_001351230 NM_001351231 NM_001351232 NM_001351233


NM_001081388 NM_001310733 NM_001378900


NP_001338159 NP_001338160 NP_001338161 NP_001338162


NP_001074857 NP_001297662 NP_001365829


RIMS binding protein 2  is a  protein  that in humans is encoded by the RIMBP2  gene .
 [ 5 ]  This protein plays a significant role in synaptic transmission and is involved in the regulation of voltage-gated calcium channels, which are crucial for neurotransmitter release at synapses. [ 6 ] [ 7 ]


RIMBP2 is primarily located in the presynaptic active zones of neurons, where it contributes to the organization and maintenance of synaptic structures. It is essential for the proper functioning of synaptic vesicles and calcium-dependent processes that facilitate communication between neurons. [ 8 ] [ 9 ]


Research has indicated that mutations or dysregulation of RIMBP2 may be associated with various neurological disorders, such as Pitt-Hopkins syndrome. [ 6 ] [ 10 ]


Uncharacterized LOC100287225  is a  protein  that in humans is encoded by the RP11-267C16.1  gene .
 [ 3 ]


This article on a  gene  on human  chromosome 18  is a  stub . You can help Wikipedia by  expanding it .


RTL1  (retrotransposon like 1) is a  retrotransposon  derived protein coding gene. [ 5 ]  It is also known as PEG11 and is a paternally expressed imprinted gene, part of  genomic imprinting . RTL1 plays an important role in the maintenance of fetal capillaries and is expressed in high quantities during late stage of fetal development. [ 5 ]  The expression of this gene is important for the development of the  placenta , the fetus-maternal interface. Because the placenta is the first organ to form during the development of an embryo, problems in its establishment and biological role lead to complications during gestation. [ 6 ]  This organ maintains the fetus throughout the pregnancy and is therefore sensitive to disruptions. Studies in mice suggest that disruption of the RTL1 concentration, whether increasing or decreasing the amount of this protein coding gene, can lead to serious errors in the conservation of placental fetal capillaries. RTL1  knockout mice  have shown obstruction in fetal development along with late fetal/neonatal death. [ 7 ]  Studies from sheep homologs suggest that high expression levels of RTL1 can lead to skeletal  muscle hypertrophy  This is due to over-expression patterns in the paternal allele specific gene. [ 8 ]


Sca-1  stands for " Stem cells   antigen -1" (official gene symbol: Ly6a). It consist of 18-kDa mouse  glycosyl   phosphatidylinositol -anchored  cell  surface  protein  (GPI-AP) of the  LY6   gene family . [ 1 ]  It is the common  biological marker  used to identify hematopoietic stem cell (HSC) along with other markers.


This  cell biology  article is a  stub . You can help Wikipedia by  expanding it .


Succinate dehydrogenase complex assembly factor 2 , formerly known as  SDH5  and also known as  SDH assembly factor 2  or  SDHAF2  is a  protein  that in humans is encoded by the SDHAF2  gene . This gene encodes a  mitochondrial  protein needed for the flavination of a  succinate dehydrogenase complex  subunit required for activity of the complex.  Mutations  in this gene are associated with   pheochromocytoma  and  paraganglioma . [ 5 ]


SDHAF2  is located on the  q arm  of  chromosome 11  in position 12.2 and spans 16,642 base pairs. [ 5 ]  The  SDHAF2  gene produces a 6.7 kDa protein composed of 65 amino acids. [ 6 ] [ 7 ]  This highly conserved protein is a cofactor of  flavin adenine dinucleotide  (FAD). [ 8 ]  The structure represents a five-helix bundle with a region of well-defined conserved surface residues. This conserved region includes a negatively charged periphery and a positively charged surface, and a patch that is  hydrophobic . The region is located in  α-helices  I, II, and the connecting band. [ 9 ]


The  SDHAF2  gene encodes a mitochondrial  protein  associated with the  succinate dehydrogenase (SDH) complex (mitochondrial complex II)  in the  mitochondrial respiratory chain , which plays essential roles in both the electron transport chain and the  Krebs (tricarboxylic acid) cycle . SDHAF2 is integral in the proper function of the SDH complex, mainly in SDH-dependent respiration, and interacts with the catalytic subunit of the complex. SDHAF2 participates in the flavination of  SDH1  (SDHA), another subunit of the SDH complex. It does so by incorporating the  flavin adenine dinucleotide  (FAD) cofactor into  SDHA . Such flavination is required for a fully functional SDH complex. Knockdown of SDHAF2 leads to the loss-of-function of the SDH complex, a decrease in the enzyme complex stability, and a substantial reduction in all subunits. SDHAF2 was also found to function as a  tumor suppressor . [ 10 ] [ 11 ] [ 12 ] [ 13 ]


SDHAF2  is a  tumor suppressor gene . Constitutional  mutations  in this gene cause  hereditary   paraganglioma , a neuroendocrine tumor formerly known to be linked to SDH subunit mutations.  paraganglioma  is a neural crest tumor usually derived from the  chemoreceptor  tissue of a  paraganglion , and may develop at various body sites, including the head, neck,  thorax  and  abdomen . Most commonly, they are located in the head and neck region, specifically at the  carotid bifurcation , the  jugular foramen , the  vagus nerve , and in the  middle ear . [ 14 ]  Phenotypes include excessive  catecholamine  induced  hypertension , dysfunction of major blood vessels and  cranial nerves , significant  morbidity ,  sweating , and  palpitations . In cases of extra-adrenal localization, the tumor may turn  metastatic  and aggressive. Loss of  SDH complex  function has been known to be responsible for  paraganglioma . [ 12 ] [ 11 ] [ 10 ]  Mutations in this gene are found in the  DNA  of only a small fraction of patients with the disease. [ 11 ]


SDHAF2 interacts with  SDHA  within the SDH catalytic dimer. In addition to  SDHA , SDHAF2 has 17  protein–protein interactions , including interactions with proteins such as  IMMT ,  SUCLG2 ,  UBINEDDSUMO1 ,  SSX2IP , and others. [ 15 ]


Set1  is a gene that codes for Histone-lysine N-methyltransferase and H3 lysine-4 specific proteins ( H3K ). [ 1 ]  Set1 proteins can also be referred to as  COMPASS  proteins. [ 1 ]  The first H3K4 methylase,  Saccharomyces cerevisiae  Set1/COMPASS, is highly conserved across a multitude of phylogenies. [ 2 ]  The  histone methylation  facilitated by Set1 is required for cell growth and transcription silencing through the repression of  RNA polymerase II . [ 3 ]  The Set1C, COMPASS Complex, also aids in transcription elongation regulation and the maintenance of telomere length. [ 1 ]


NM_001080420 NM_001372044


SH3 and multiple ankyrin repeat domains 3  (Shank3), also known as  proline-rich synapse-associated protein 2  (ProSAP2), is a  protein  that in humans is encoded by the  SHANK3   gene  on  chromosome 22 . [ 5 ]   Additional isoforms have been described for this gene but they have not yet been experimentally verified.


This gene is one of the 3-member Shank gene family (Shank1-3). The gene encodes a protein that contains 5 interaction domains or motifs including the  ankyrin repeats domain  (ANK), a src 3 domain ( SH3 ), a proline-rich domain, a  PDZ  domain and a  sterile α motif domain  (SAM). [ 6 ]  Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect  neurotransmitter  receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in  synapse  formation and  dendritic spine  maturation. [ 7 ]


Mutations in this gene are associated with  autism spectrum disorder . [ 8 ]  This gene is often missing in patients with  22q13.3 deletion syndrome  ( Phelan–McDermid syndrome ), [ 9 ]  although not in all cases. [ 10 ]


SHANK3 has been shown to  interact  with  ARHGEF7 . [ 11 ]


Mouse models of SHANK3 include N-terminal knock-outs [ 12 ] [ 13 ]  and a PDZ domain knock-out [ 14 ]  all of which also show social interaction deficits and variable other phenotypes. Most of these mice are homozygous knock-outs whereas all the human SHANK3 mutations have been heterozygous.


In an inducible knockout, restoration of SHANK3 expression in adult mice promoted dendritic spine growth and recovered normal grooming behaviour and voluntary social interaction. [ 15 ]  However, the reduced locomotion, anxiety and  rotarod  deficits remained. Germline restoration of the gene's expression rescued all measured phenotypes. Experiments on different developmental windows suggested that early intervention was more effective in restoring behavioural traits.


A rat model of SHANK3 was developed using  zinc finger nucleases  targeting exon 6 of the ankyrin (ANK) repeat domain. The deletion (-68bp) resulted in reduction of the full length SHANK3a protein. [ 16 ]  It is unclear if the expression of other isoforms (b and c) of SHANK3 is affected in this rodent model. The shank3 mutant rats have deficits in long-term social recognition memory but not short-term social recognition memory as well as deficits in attention. [ 16 ]  These are symptons of impaired  synaptic plasticity . In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein. [ 17 ]


Ski/Dach domain-containing protein 1  is a  protein  that in humans is encoded by the SKIDA1  gene . [ 5 ]  It is also known as C10orf140 and DLN-1. It has  orthologs  in  vertebrates . It has two  domains : the Ski/Sno/Dac domain and a  domain of unknown function , DUF4854. It is associated with multiple types of cancer, like  leukemia ,  ovarian cancer , and  colon cancer . [ 6 ] [ 7 ]  It's predicted to be a nuclear protein. [ 8 ]  It may interact with  PRC2 . [ 9 ] [ 10 ]


SKIDA1 has orthologs in vertebrate species. The species least related to humans with a SKIDA1 ortholog is the  lancelet   Branchiostoma belcheri . The  clades   amphibia  and  chondrichthyes  have at least two species with SKIDA1, but SKIDA1 is not found throughout the clades. No orthologs have been found in  lungfish  or  invertebrate  species. [ 11 ]


SKIDA1 shares the Ski/Sno/Dac domain with  Ski oncogene  (Ski),  Ski-like protein  (Sno), and  dachshund  (Dac). [ 12 ]  It shares DUF4584 with Elongin BC Polycomb Repressive Complex 2 associated Protein (EPOP). [ 5 ]


In humans, SKIDA1 is located on the reverse strand of  chromosome 10  at locus 10p12.31. It contains five  exons . [ 5 ]


There is not a consensus on whether humans have one or two SKIDA1  isoforms . NCBI Gene claims there is one, while UniProt claims there are two. [ 13 ] [ 14 ]  It's possible isoform 2 is recorded in NCBI Gene as DLN-1 (accession BAE93016.1). Isoform 1 is 908 amino acids long, while isoform 2 is 827 amino acids long; isoform 2 is missing amino acids 240-318 from isoform 1. [ 14 ]  Isoform 1 is predicted to weigh 98 kDa and have an  isoelectric point  of 8.7, while isoform 2 is predicted to weigh 90 kDa and have an isoelectric point of 7.6. [ 15 ]


Other mammalian species also have multiple isoforms of SKIDA1, including  carnivorans ,  rodents , and  primates . The number of isoforms each species has varies:  cheetahs  have five recorded isoforms,  chimpanzees  have three recorded, and  brown rats  have two recorded. [ 16 ]


Human SKIDA1 contains two poly-alanine regions, one poly-histidine region, and one poly-glutamic acid region. [ 5 ]  It's unknown if they have any function. The poly-alanine and poly-histidine regions are not highly conserved among  orthologs ; for example, while they are found in the  house mouse  ortholog, they are not found in the  western lowland gorilla  ortholog. [ 17 ] [ 18 ]  The poly-glutamic acid region shows more conservation, and is found abbreviated in species as distantly related from humans as the  tire track eel . [ 19 ]


SKIDA1 contains two  domains : Ski/Sno/Dac and DUF4854. The Ski/Sno/Dac domain is at the  N-terminus  end of the protein. The Ski/Sno/Dac domain is also found in the proteins Ski, Ski-like protein, and dachshund. [ 12 ]  It is potentially a DNA-binding domain. [ 20 ]


The other domain, DUF4854, is also found in EPOP, near its  C-terminus . However, the DUF4584 found in EPOP is roughly a fifth the size of that in SKIDA1. The C-termini of SKIDA1 (amino acids 844-908) and EPOP (amino acids 313-379) have 52% identity. The C-terminus of EPOP binds to the  SUZ12  subunit of  Polycomb Repressive Complex 2  (PRC2), suggesting that of SKIDA1 may as well. [ 9 ]


In humans, there are five predicted potential  promoters . Two align with the second half of the mRNA transcript, suggesting they are not used or only produce an incomplete polypeptide. [ 21 ]


The promoter that aligns best with the start of the mRNA transcript is potentially bound to by many  transcription factors , including  Transcription factor II B ,  Nuclear factor Y ,  Early growth response 1 , and  Krueppel-like factor 6 . [ 21 ]  It does not contain a  TATA box .


SKIDA1 is regulated by  microRNAs . miR-93 binds to the SKIDA1  3'-UTR . [ 22 ]  Multiple microRNAs are predicted to bind to the SKIDA1 3'-UTR, including  miR-130 ,  miR-301 ,  miR-454 , and  miR-494 . [ 23 ]


SKIDA1 is  SUMOylated  at five sites. [ 24 ]  Additional sites are predicted to be SUMOylated. [ 25 ] [ 26 ]  SKIDA1 is also predicted to be  phosphorylated  and  O-GlcNAcylated . [ 27 ] [ 28 ]


SKIDA1 is predicted to be localized primarily in the  nucleus  and less so in the  cytosol . [ 8 ]


SKIDA1 is expressed at high levels in the  brain ,  thyroid , and  testes . It's expressed at medium to low levels in  adipose tissue ,  lymph nodes , and  skeletal muscle . [ 29 ] [ 30 ] [ 31 ] [ 32 ]  In mice, it's noted to have medium-to-high expression in the  olfactory bulb ,  retina , and  salivary gland . [ 29 ]


SKIDA1 expression changes during organism development. Expression is low in the  zygote , peaks during  embryonic development , and is low post-birth. In the  house mouse , it's expressed most during  organogenesis . [ 33 ]  In the fetus, its expression is low in the liver but not other organs. [ 34 ]  Expression in the adult liver is much higher. In contrast, SKIDA1 expression in the fetal brain is higher than in the adult brain. [ 32 ]


SKIDA1 in the  African clawed frog  is expressed faintly in the marginal zone of  gastrulae . During  neurulation , it's expressed in the brain and  cranial neural crest . During tailbud, SKIDA1 expression increases in  sensory placodes . By the end of tailbud, neural expression has faded except in the  olfactory organ . [ 35 ]


SKIDA1 is predicted to function primarily in the nucleus and also in the cytosol. [ 8 ]


SKIDA1 knockouts in mice have significant differences from wild-type mice in the skeletal, neurological, reproductive, and immune systems. Other significant differences include effected hearing, an enlarged thymus, and increased pre-weaning mortality. [ 36 ]  Some, but not all, of these effects were found in heterozygous knockouts.


SKIDA1 expression is associated with multiple types of cancer. It is over-expressed in  epithelial ovarian cancer  cells. [ 37 ]  Its expression is altered by various cancer-treatment compounds: human alpha-lactalbumin made lethal to tumor cells; oleate salts;  metformin ; and  aspirin . [ citation needed ]  In cell lines of cancerous cells, altered expression is associated with resistance to  dasatinib  and  docetaxel , which are used to treat cancer. [ 38 ] [ 39 ]


Altered methylation of SKIDA1 is associated with human  pancreatic cancer ,  rheumatoid arthritis , and  lupus erythematosus . [ 40 ] [ 41 ]  Additionally, SKIDA1 is expressed less in women with  Down syndrome  compared to their identical twins without Down syndrome. [ 42 ]  Its expression is dramatically reduced in brains affected by untreated HIV1-associated neurocognitive disorders (HAND) in comparison to healthy brains and brains affected by HAND but treated with  antiretrovirals . [ 43 ]


NM_024959 NM_001330466 NM_001358345


NM_001177594 NM_001177595 NM_133221


NP_001317395 NP_079235 NP_001345274


NP_001171065 NP_001171066 NP_573484


Solute carrier family 8 (sodium/lithium/calcium exchanger), member B1  is a  protein  that in humans is encoded by the SLC8B1  gene . [ 5 ]


SLC24A6 belongs to a family of  Potassium-dependent sodium-calcium exchangers  that maintain cellular  calcium  homeostasis through the electrogenic countertransport of 4 sodium ions for 1 calcium ion and 1 potassium ion. [ 6 ]


SLX4 interacting protein  is a  protein  that in humans is encoded by the SLX4IP  gene . [ 5 ]


SLX4 interacting protein (SLX4IP) exists in a  monomeric  form, and interacts with the  SLX4 - XPF - ERCC1  multiprotein complex, which is responsible for the assembly of a  Holliday junction resolvase  in the role of DNA repair and maintenance. [ 6 ]


SLX4IP has been shown to directly interact with the  N-terminal  end of the  SLX4  protein, which plays a role in the coordination of multiple different DNA structure-specific endonucleases. [ 7 ]


SLX4IP has also been shown to be involved in the control of alternative lengthening of  telomeres , through its accumulation and interactions with the  SLX4 ,  BLM  and  XPF  proteins. [ 8 ]


The SLX4IP gene is located on the short arm (p) of  chromosome 20  at position 12.2 (20p12.2). [ 9 ]  The human SLX4IP gene contains 14  exons , with the cDNA being 204,000 base pairs orientated on the plus strand. [ 9 ]  This codes for a protein of 408 amino acids with a molecular mass of 45,552  daltons . [ 10 ]


Homologs  of the SLX4IP gene have been found to be conserved in several non-human species including mice, rats, frogs, chickens, dogs, rhesus monkeys and chimpanzees. [ 11 ]   Orthologs  for the human SLX4IP gene have also been identified in 283 other organisms. [ 11 ]


The SLX4IP protein is expressed at its highest level in the skin and the testis, along with being expressed in 26 other tissues. [ 12 ]


Somatic and monoallelic deletions of the 5’ region of SLX4IP was shown to occur in 30% of patients with childhood  acute lymphoblastic leukemia  (ALL) and in cases of  ETV6 / RUNX1 -rearranged acute lymphoblastic leukemia, deletions were found in greater than 60% of cases. [ 13 ]  By analyzing the breakpoints of SLX4IP, characteristic illegitimate  V(D)J  mediated recombination was revealed. [ 13 ]  These deletions were found to be significantly biased towards the male gender. [ 13 ]


In order for cancer cells to retain their ability to proliferate without limitations, they can regulate the  telomeres  of their chromosomes by recombination via a process known as  alternative lengthening of telomeres  (ALT). [ 14 ]  This recombination has been shown to require the accumulation of SLX4IP at ALT telomeres due to its antagonization of promiscuous  BLM  activity. [ 8 ]  BLM is responsible for the extension of telomeres as it is a  RecQ  helicase vital to homologous recombination and DNA replication. [ 15 ]


In DNA,  Interstrand crosslinks  (ICLs) are required to be repaired due to their high toxicity, often leading to diseases such as  Fanconi anaemia . [ 16 ]  SLX4IP plays a role in the ICL repair functionality of the SLX4-XPF-ERCC1 complex, due to its simultaneous binding of both SLX4 and XPF-ERCC1, which maintains the stability of the complex and promotes interaction between the SLX4 and the XPF-ERCC1 regions. [ 6 ] [ 17 ]  When SLX4IP was depleted from treated cells, they were found to accumulate in the G2/M phase of the cell cycle where the resolution of holiday junctions during ICL repair regularly occurs. [ 17 ] [ 18 ]


The  HIV-1  auxiliary protein  Vpr  potently stops the host cells progression through its natural cycle at the  G2/M  transition stage. [ 19 ]  This arrest was found to be caused from its premature activation of the SLX4 structure-specific  endonuclease  complex, which SLX4IP directly interacts with. [ 20 ]  Through this research the SLX4 complex was also discovered to be involved with the regulation of innate immunity, due to its negative regulation of  type 1 interferon  production, both when induced spontaneously and HIV-1-mediated. [ 20 ]


SMIM15 (small integral membrane protein 15) is a protein in humans that is encoded by the SMIM15 gene. [ 5 ]  It is a transmembrane protein that interacts with PBX4. [ 6 ]  Deletions where SMIM15 is located have produced mental defects and physical deformities. [ 7 ] [ 8 ]  The gene has been found to have ubiquitous but variable expression in many tissues throughout the body. [ 5 ]


Small integral membrane protein 15 (SMIM15) is a protein in humans that is encoded by the SMIM15 gene. [ 5 ]  It has also been known under the aliases C5orf43 [ 5 ]  and GC05M060454. [ 5 ]  It is made up of 74 amino acids. It is located at 5q12.1. [ 5 ]  SMIM15 has 4741 base pairs with three exons [ 5 ] [ 9 ]


SMIM15 has zero isoforms [ 5 ]  The 5' UTR region spans 420 bases and the 3' UTR spans 2243 bases. [ 9 ]


Primary sequence of SMIM15 is: [ 11 ]  MFDIKAWAEY  VVEWAAKDPY  GFLTTVILAL  TPLFLASAVL  SWKLAKMIEA  REKEQKKKQK. RQENIAKAKR  LKKD


Molecular weight of SMIM15 has been found to be 8.6 kdal and it has a pI of 9.82. [ 12 ]  There are no significant compositional features compositional features like charge clusters, hydrophobic segments, charge runs, patterns, multiplets or periodicities. [ 13 ]


There is one transmembrane domain located from amino acids 20 – 42. [ 14 ] [ 15 ]


The other domains include a luminal domain from amino acids 1 - 19 and cytosolic domain from amino acids 43 - 74. [ 14 ] [ 15 ]


The secondary structure for SMIM15 is largely alpha-helical with alpha helices making up 62.16% (46 amino acids) of the protein. [ 16 ]  Random coil makes up 25.68% (19 amino acids) and extended strands make up 12.16% (9 amino acids) of the SMIM15 protein. [ 16 ]


There are a number of post-translational modifications of the SMIM15 protein, which are shown in the Conceptual Translation of Human SMIM15 as shown in figure 1.


The predicted sites for sumoylation are at positions: 5, 67, 69, 72, 73. [ 17 ]  It is known to affect protein stability, protect from degradation, cellular localization, protein-protein interactions and DNA binding.


The predicted sites for glycation are at positions: 5, 43, 58, 72, 73. [ 18 ]  Glycation can lead to the creation of AGE (advanced glycation end products. [ 19 ]  Glycation is a process in which proteins react with reducing sugar molecules, which will lead to impairment of the function and changes the characteristics of the protein. [ 20 ] [ 21 ]


Finally, there are four predicted sites for phosphorylation of tyrosine on position 20, threonine on positions 25 and 31, and serine on position 41. [ 22 ]  Phosphorylation will affect different cellular processes and thus regulating protein function. [ 23 ]


SMIM15 has a transmembrane domain found within amino acids 20–42. There are cleavage sites at the C-terminous and nuclear localization signals. [ 24 ]


SMIM15 has been found to have ubiquitous but variable expression in many different tissues throughout the body. [ 5 ]  it has the highest level of expression within the prostate. [ 25 ]  There are lower levels of expression within skeletal muscles compared to other tissues within the body. [ 26 ]


SMIM15 has one CpG island within the promoter. SMIM15 has lower levels of H3K4Me1 but higher levels of H3K4Me3 and H3K27Ac across all of their cell lines [ 27 ]


The Promoter region for SMIM15 is 1049 base pairs long. [ 10 ]  and it is known as GXP_922465. There are 431 different transcription binding factor sites, [ 10 ]  some of these binding factors include GATA1, TGIF, LMX1A, and NKX61 [ 10 ]


There are no known micro-RNA targets in the 3' UTR. [ 10 ]  mRNA secondary structures exhibited a high number of predicted stem-loop structures. This could indicate high stability of the mRNA transcript, and some binding sites for regulatory mechanisms.


The function of SMIM15 is currently not well understood.


There is only one interacting protein currently identified. [ 28 ] [ 29 ]  This protein is PBX4 which is known for playing critical roles in embryonic development and cellular differentiation both as Hox cofactors and through Hox - independent pathways. [ 6 ]  PBX4 is also a member of the pre-B cell leukemia transcription factor family. [ 6 ] [ 30 ]


Deletion of 5q12.1 can lead to the development of mental retardation and ocular defects. [ 7 ]  Another deletion in the 5q12.1 - 5q12.3 region lead to mental-motor retardation and dysmorphia. [ 8 ]  In terms of diseases, Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. The interval 5q12.1-5q13.3 as linked to low caries susceptibility in Filipino families. [ 31 ]


SMIM15 is conserved in both vertebrates and invertebrates. It is not found in insects or fungi. SMIM15 does not have any paralogs [ 5 ]  and the farthest known relative of the Homo sapiens SMIM15 is found within Trichoplax sp.H2 with a date of divergence 747 MYA [ 32 ]


NM_001145432 NM_001394130


Small integral membrane protein (SMIM) 20  is a  protein  that in humans is encoded by the SMIM20  gene . [ 5 ]  SMIM20 acts as a  prohormone  to the peptide hormone phoenixin which was discovered for the first time in 2013 in rodent sensory ganglia. [ 6 ]


In the study of the  evolution of nervous systems , SMIM20 together with  NUCB2  have been found to have deep  homology  across all lineages that preceded creatures with central nervous systems,  bilaterians ,  cnidarians ,  ctenophores , and  sponges  as well as in choanoflagellates. [ 7 ] [ 8 ]


SMIM23  or  Small Integral Membrane Protein 23  is a  protein  which in humans is encoded by the SMIM23 or c5orf50 gene. The longer  mRNA   isoform  is 519  nucleotides  which translates to 172  amino acids  of a protein. [ 1 ]  In recent advancements, researchers have identified this gene, along with a few others, could potentially play a role in how facial morphology arises in humans. [ 2 ]


SMIM23 is a protein-encoding gene. Basic information about its aliases and chromosome location are given in the table. The schematic of the chromosome helps to visualize the location of the gene.


While the gene has two  splice isoforms  (isoforms X1 and X2), it has three exon/exon boundaries indicating four  exons  (nucleotide 1-105, 106-157, 158-225, and 226-519). [ 3 ]


SMIM23 notably has a  transmembrane domain .


The predicted  isoelectric point  for the unmodified/unprocessed protein in mice is 5.779 while only the transmembrane region in humans has an isoelectric point of 5.928 [ 4 ]


The gene appears to be  Leucine  and  Glutamic Acid  rich though not at any usually high number. It is also weak in all other amino acids besides Alanine, Serine, and Glutamine. [ 5 ]


The region underlined in the conceptual translation was predicted to be an  Involucrin  repeat. [ 6 ]


The transmembrane region is 1674.2 daltons while the whole protein is 200008.51 Da. This is very similar to what was found with UniProt where predicted molecular weight was 20.025 kDa. [ 7 ]  Antibody kits were investigated to see banding pattern and weight changes that may have occurred  post translation . C5orf50  Polyclonal Antibody  from  ThermoFisher Scientific  has a  Western Blot  banding pattern at 40 kDa. [ 8 ]  This predicts that there is a significant amount of post-translational modification by addition of large components.


There are many  phosphorylation sites  along its sequence including two  protein kinase C  phosphorylation sites,  cAMP-  and  cGMP-dependent protein kinase  phosphorylation site, and a  tyrosine kinase  phosphorylation site. [ 9 ]  There is also a confident potential C-terminal GPI-Modification Site. [ 10 ]


There are two stretches of  alpha helices  from amino acid 33 to 49 and 89 to 136 based on evidence from various programs that predict  secondary structure . The most informative of all the programs from the ones investigated is PELE on Biology Workbench. [ 5 ]


A  3D protein structure  was predicted to look like a series of helices, [ 11 ]  similar to what was predicted by other programs.


This human integral membrane protein is predicted to be found in the  endoplasmic reticulum . [ 12 ]  The same kind of investigation of protein localization in other types of species returned conflicting results. Many programs predicted the protein to be present in the cytosol. [ 12 ]  This suggests the possibility of incorrect naming, i.e. the protein may not be integral membrane due to other predicted locations. This type of conclusion will require further information.


Not enough consensus exists as to where in the body SMIM23 is expressed. Databases indicate mainly in the  testes , [ 13 ]  but this may be due to the lack of data.


The  promoter  region of SMIM23 is approximately 1192 nucleotides long with various predicted  transcription factors . [ 14 ]


Regulation in the secondary structure is a predicted  stem-loop  in the 5'  UTR  region with a few areas of conservation across species. [ 15 ]


Novel research has suggested that how face shape arises in individuals may be influenced by a set of genes. This set includes SMIM23. [ 2 ]  Though in the paper the gene is referred to by an alias (C5orf50), it is clear that the scientists have gathered a list of five genes that likely determine facial shape. This is specifically people of European descent. These findings are supported by replicating phenotypes of each specific gene and statistical analysis. Just like findings elsewhere, the article mentions SMIM23 that likely codes for an unknown transmembrane protein. There have also been studies where a set of genes including SMIM23 may influence  human height . [ 16 ]  Furthermore, a great deal of research is being done on  chromosome 5  in general to understand roles of certain genes on it including SMIM23. [ 17 ]  This could one day provide insight into this gene’s specific roles on the chromosome itself.


The following proteins are predicted to interact with SMIM23.


Cilia And Flagella Associated Protein 43 also known as CFAP43 or WDR96 is the most confident of the predicted functional partners and is a tryptophan-aspartic acid repeat domain.


SFR1 is SWI5-dependent recombination repair 1 which is a component of the  SWI5-SFR1 complex , a complex required for double-strand break repair via homologous recombination.


COL17A1  is  collagen . Specifically type XVII, alpha 1. This may play a role in overall protein structure.


PRDM16  binds to DNA and acts as a  transcriptional regulator . It functions in the differentiation between white and  brown   adipose tissue . It can also be a repressor of  transforming growth factor-beta signaling . [ 18 ]


There are no known  paralogs .


There are around 100+ known  orthologs  which range from primates to small ground animals. From these investigations and that of sequence similarity, [ 19 ]  an ortholog space can be discussed. The closest relatives to humans with the SMIM23 gene were in primates so two types of monkeys were picked which diverged around 29.4 million years ago and had sequence similarities in the high 70s. Slightly more distant relatives with the gene come from a wide variety of animals from horses, to sea mammals, to bats, and more which all have similarities between 62-69%. Lastly, some distantly related orthologs were included like the  Tasmanian devil  and various scavenger animals which have similarities between 40-61%.


It is interesting to see how some portions are still highly conserved (see conceptual translation above). The most interesting motif is  tryptophan  124,  leucine  125, and  aspartic acid  126. Lastly, in  BLAST  a protein family of unknown function was returned. There are two small conserved sequences part of the DUF4635 motif (LEQ and DLE). So though not completely conserved in the alignments done with SMIM23, these were labeled in the conceptual translation. [ 20 ]


The protein was not found in bacteria,  archaea ,  protists , plants, fungi, invertebrate, reptiles, and birds. All the found orthologs were under mammals. [ 3 ]  An unrooted phylogenetic tree [ 5 ]  of SMIM23 was created with a few close, moderately related, and distant orthologs (listed in table). Here, larger the distance (length of line), longer the time to last common ancestor. Sequence identity refers to similar amino acids while similarity refers to amino acid match.


SRY (sex determining region Y)-box 30  is a  protein  that in humans is encoded by the SOX30  gene .
 [ 1 ]


This gene encodes a member of the  SOX (SRY-related HMG-box) family  of  transcription factors  involved in the regulation of  embryonic development  and in the determination of the cell fate. The encoded protein may act as a  transcriptional regulator  after forming a protein complex with other proteins. The protein may be involved in the differentiation of developing  male germ cells . Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013].


SPMIP10  is a  protein  that in  Homo sapiens  is encoded by the SPMIP10  gene .


SPMIP10 (or Sperm Microtubule Inner Protein 10) is also known as Testis Expressed 43, C5orf48, Tseg7, Sperm Associated Microtubule Inner Protein 10, and Testis Specific Expressed Gene 73. [ 1 ]


SPMIP10 is located on the plus strand of the long arm of  chromosome 5 , band 23, sub-band 2 (5q23.2, see the ideogram of the SPMIP10 gene location on chromosome 5). [ 1 ]


SPMIP10 is a 478 bp long protein-coding gene. [ 2 ]  SPMIP10 contains three  exons . Exon 1 spans from position 1–116, exon 2 spans from positions 117–225, and exon 3 spans from positions 226–478 in the SPMIP10  DNA sequence . [ 2 ]


There are no known  isoforms  for SPMIP10 in humans. [ 2 ] [ 3 ]


SPMIP10 has a predicted  molecular weight  (Mw) of 15.5 kda and a theoretical  isoelectric point  (pI) of 9.3. Similar predicted molecular weights and theoretical isoelectric points are seen for various close orthologs (mammals, sequence identity >79%). Varying predicted molecular weights and theoretical isoelectric points are seen in distant orthologs (non-mammal vertebrates, sequence identity <79%). [ 4 ] [ 5 ] [ 6 ]


SPMIP10 protein in humans, as well as various closely related organism, has higher levels than normal of histidine and lower than normal levels of alanine. [ 5 ]


SPMIP10 contains a  domain of unknown function , DUF4513, from positions 33-452. [ 7 ]


SPMIP10 has a tertiary structure that includes both  beta sheets  and  alpha helices . [ 8 ] [ 9 ]  These structures, predicted by  AlphaFold  and  iTasser , are shown in the below images.


SPMIP10 mRNA expression data, obtained from  NCBI Gene , shows that SPMIP10 is expressed in varying amounts in both fetal (highest between the 10th and 15th week of development) and adult human tissues. [ 10 ]  There is SPMIP10 expression seen in heart tissues (approximately 0.049 RPKM) and kidney tissues (approximately 0.064 RPKM) at week 10 and in intestine tissues at 15 weeks (approximately 0.016 RPKM) in fetal tissues. [ 10 ]   RNA sequencing  (RNA-seq) of total SPMIP10 RNA from 20 human tissues showed expression levels at approximately 0.064 reads per kilobase, per million mapped reads (RPKM) in cerebellum tissue. Transcription profiling by  high throughput sequencing  of 16 human tissues indicated high tests expression (approximately 6.5 RPKM) and low expression levels in lymph node and thyroid tissues. [ 10 ]  RNA-seq of 95 human individuals showed the highest expression levels of SPMIP10 mRNA expression in the testis at approximately 4.6 RPKM with minute amounts seen in colon and small intestine tissue samples. [ 10 ]


An experiment, from the  Allen Brain Atlas  site, indicated low amounts of SPMIP10 expression throughout various structures in the human brain (see SPMIP10  Microarray  Expression Schematic in the Human Brain). [ 11 ]  Higher amounts of expression for SPMIP10 in the human brain were found in the  posterior lobe ,  parietal lobe , and the  amygdala . Higher amounts were primarily seen concentrated in the posterior lobe. [ 11 ]  Table 1 summarizes these findings.


There is no  5’ UTR  for SPMIP10 because its first exon begins at the start of translation. [ 7 ]


3’ UTR


The  3' UTR  sequence of SPMIP10 in humans is highly conserved in various  mammals . It is predicted to contain 3  stem loops . [ 12 ] [ 13 ] [ 14 ]


Utilizing UCSC Genome Browser, a transcription initiation site (Tex43_1) for SPMIP10 was located at positions 126,631,722 - 126,631,782 on chromosome 5 along with two  enhancers  (E2405703 and E2405704). [ 15 ]  These findings are depicted in the SPMIP10 Transcription Regulation Diagram.


SPMIP10 protein is predicted to be localized in the  nucleus  and  cytoplasm , primarily. DEEPLOC-2.0 indicates that SPMIP10 is located in the cytoplasm and contains a  nuclear export signal  at positions 130-134 of the protein. [ 16 ] [ 17 ]


SPMIP10 has predicted  SUMOylation  sites (positions 107, 13, 65, 25, 54, 29, and 41),  O-glycosylation  sites (positions 10 and 122), and  phosphoprotein-binding domains  ( SH2 / LCK  at position 30, SH2/ CISH  at position 30, and PBD at position 24). The locations of these  modifications  are labeled in the Annotated Conserved Post-translational Modifications for SPMIP10 Diagram. [ 18 ] [ 19 ] [ 20 ] [ 21 ]


There are no known  paralogs  of SPMIP10 in humans. [ 3 ] [ 7 ]


The SPMIP10 protein is only found in  vertebrates . [ 6 ]  Species containing the SPMIP10 protein include mammals (26.5-100% identity),  reptiles  (40.9-48.1% identity),  birds  (23.2-41.8% identity),  amphibians  (27.7-37.1% identity), and  fish  (27.9-35.5% identity). Table 2 contains twenty  orthologs  and their respective  sequence identity  in relation to SPMIP10 in humans. [ 3 ] [ 6 ] [ 22 ]


Graph 1 shows the corrected sequence divergence vs estimated date of divergence for SPMIP10 compared to  Cytochrome C  and  Fibrinogen Alpha . SPMIP10 evolves at a pace similar to that of Fibrinogen Alpha than.


On the  B-tubule  of the  flagellum   microtubule  doublets,  ENKUR  protein interacts with the loop region of the SPMIP10 protein providing flagellum reinforcement in mammalian sperm. [ 23 ]  SPMIP10 binds closely to ENKUR and envelops itself around the inter-promoter interface of CCDC105, in this regard, SPMIP10 functions as a “staple” while interacting with  protofilaments A12 and A11 . [ 23 ]  SPMIP10 enveloping of CCDC105 provides the  promoter  with stabilization. [ 24 ]


A 4bp deletion, resulting in a  frameshift mutation  (introducing a premature stop condone 33 aa further), of SPMIP10 in mice has been shown to slightly decrease sperm velocity and motility, however not lower rates of fertilization. [ 25 ]   Wild-type  mouse sperm maintained flexibility at both the mid and end pieces of the flagellum, while the SPMIP10 knock-out mouse sperm showed reduced flexibility at the endpiece of the flagellum. [ 25 ]


The  duplication  of SPMIP10 correlates with  karyotypically  balanced  chromosomal rearrangements  associates with decreased  cognitive abilities  as well as craniofacial and hand  dysmorphisms . [ 26 ]


The depletion of p63 in ME180 cells (human  cervical adenocarcinoma  epithelial cells) correlates with a decrease of SPMIP10 expression. Wild-type ME180 cells have slightly higher amounts of SMPIP10 expression on average than those that experienced a depletion of p63. [ 27 ]


Diseased cells expressing low levels of EVI1 have higher mean expression of SPMIP10 than diseased cells expressing elevated levels. [ 28 ]


2FH5 ,  2GO5 ,  5L3Q


NM_003139 NM_001177842


NP_001171313 NP_003130


SRP receptor alpha subunit  is a  protein  that in humans is encoded by the SRPRA  gene .
 [ 5 ]


The gene encodes a subunit of the  endoplasmic reticulum   signal recognition particle receptor  that, in conjunction with the  signal recognition particle , is involved in the targeting and translocation of signal sequence tagged secretory and membrane proteins across the  endoplasmic reticulum . Alternative splicing results in multiple  transcript variants .


Stimulated by retinoic acid 8  ( Stra8 ) is a gene coding for a protein of the same name that is activated only upon stimulation by  retinoic acid  and expresses a  cytoplasmic  protein in the gonads of male and female vertebrates. [ 1 ]  It plays a key role in  gametogenesis  by inducing meiosis.


The  Stra8  gene is 26,749 base pairs in length and the Stra8 protein is 36.9 kDa or 330 amino acids. Its protein structure contains a series of  alpha helices .


Stra8 functions to initiate the transition between  mitosis  and  meiosis . It does so by forming a complex with the protein MEIOSIN, also initiated by the presence of retinoic acid, to transcribe genes responsible for meiotic activation. [ 2 ]   Both males and females are left infertile if Stra8 signaling is absent due to  spermatogenesis  and  oogenesis  remaining uninitiated. [ 3 ]


As implied by its full name,  Stra8  is induced by the presence of retinoic acid. The promoter for  Stra8  contains a retinoic acid responsive element that induces expression of the  Stra8  gene. [ 4 ]  During fetal development, retinoic acid is supplied from the  mesonephros . [ 5 ]


Male expression of Stra8 is limited by  CYP26B1  activity from fetal to prepubescent development, thus matching the need of spermatogenesis beginning at puberty compared to embryonic oogenesis in females. [ 3 ]  Following prepubescence, CYP26B1 is no longer expressed, preventing the degradation of retinoic acid and allowing Stra8 to fulfill its function and initiate spermatogenesis. The mechanisms behind the gradual decrease in CYP26B1 expression remains to be elucidated.


Sperm of mice that had induced null mutations for the  Stra8  gene were able to undergo mitotic divisions, and while some sperm were able to transition into the early stages of meiosis I, they could not transition into further sub-stages. Errors in chromosome pairing and chromosome condensation were observed following these failures. [ 6 ]


Female expression of Stra8 is uninhibited by CYP26B1 in the primordial germ cells, initiating meiosis. [ 7 ]  This process may also be referred to as oocytogenesis. The primary oocytes formed will then become arrested in meiosis (prophase I) until  menarche .


In female mice, loss of Stra8 signaling shows failure to enter into meiosis. [ 8 ]


Products that contain retinoic acid (alternatively retinol or vitamin A) have the potential to cause severe birth defects when used during pregnancy. [ 9 ]  Induction of  Stra8  by retinoic acid can result in premature cell differentiation in the embryo.


A  structural gene  is a  gene  that codes for any RNA or protein product other than a regulatory factor (i.e.  regulatory protein ). A term derived from the  lac  operon , structural genes are typically viewed as those containing sequences of DNA corresponding to the amino acids of a protein that will be produced, as long as said protein does not function to regulate gene expression. Structural gene products include enzymes and structural proteins. Also encoded by structural genes are non-coding RNAs, such as  rRNAs  and  tRNAs  (but excluding any regulatory  miRNAs  and  siRNAs ).


In  prokaryotes , structural genes of related function are typically adjacent to one another on a single strand of DNA, forming an  operon . This permits simpler regulation of gene expression, as a single regulatory factor can affect transcription of all associated genes. This is best illustrated by the well-studied  lac  operon, in which three structural genes ( lacZ ,  lacY , and  lacA ) are all regulated by a single promoter and a single operator. Prokaryotic structural genes are transcribed into a polycistronic mRNA and subsequently translated. [ 1 ]


In  eukaryotes , structural genes are not sequentially placed. Each gene is instead composed of coding  exons  and interspersed non-coding  introns . Regulatory sequences are typically found in non-coding regions upstream and downstream from the gene. Structural gene mRNAs must be spliced prior to translation to remove intronic sequences. This in turn lends itself to the eukaryotic phenomenon of  alternative splicing , in which a single mRNA from a single structural gene can produce several different proteins based on which exons are included. Despite the complexity of this process, it is estimated that up to 94% of human genes are spliced in some way. [ 2 ]  Furthermore, different splicing patterns occur in different tissue types. [ 3 ]


An exception to this layout in eukaryotes are genes for histone proteins, which lack introns entirely. [ 4 ]  Also distinct are the rDNA clusters of structural genes, in which 28S, 5.8S, and 18S sequences are adjacent, separated by short internally transcribed spacers, and likewise the 45S rDNA occurs five distinct places on the genome, but is clustered into adjacent repeats. In eubacteria these genes are organized into operons. However, in archaebacteria these genes are non-adjacent and exhibit no linkage. [ 5 ]


The identification of the genetic basis for the causative agent of a disease can be an important component of understanding its effects and spread. Location and content of structural genes can elucidate the evolution of virulence, [ 6 ]  as well as provide necessary information for treatment. Likewise understanding the specific changes in structural gene sequences underlying a gain or loss of virulence aids in understanding the mechanism by which diseases affect their hosts. [ 7 ]


For example,  Yersinia pestis  (the  bubonic plague ) was found to carry several virulence and inflammation-related structural genes on plasmids. [ 8 ]  Likewise, the structural gene responsible for  tetanus  was determined to be carried on a plasmid as well. [ 9 ]   Diphtheria  is caused by a bacterium, but only after that bacterium has been infected by a bacteriophage carrying the structural genes for the toxin. [ 10 ]


In  Herpes simplex virus , the structural gene sequence responsible for virulence was found in two locations in the genome despite only one location actually producing the viral gene product. This was hypothesized to serve as a potential mechanism for strains to regain virulence if lost through mutation. [ 11 ]


Understanding the specific changes in structural genes underlying a gain or loss of virulence is a necessary step in the formation of specific treatments, as well the study of possible medicinal uses of toxins. [ 10 ]


As far back as 1974, DNA sequence similarity was recognized as a valuable tool for determining relationships among taxa. [ 12 ]  Structural genes in general are more highly conserved due to functional constraint, and so can prove useful in examinations of more disparate taxa. Original analyses enriched samples for structural genes via hybridization to mRNA. [ 13 ]


More recent phylogenetic approaches focused on structural genes of known function, conserved to varying degrees. rRNA sequences frequent targets, as they are conserved in all species. [ 14 ]  Microbiology has specifically targeted the 16S gene to determine species level differences. [ 15 ]  In higher-order taxa, COI is now considered the “barcode of life,” and is applied for most biological identification. [ 16 ]


Despite the widespread classification of genes as either structural or regulatory, these categories are not an absolute division. Recent genetic discoveries call into question the distinction between regulatory and structural genes. [ 17 ]


The distinction between regulatory and structural genes can be attributed to the original 1959 work on Lac operon protein expression. [ 18 ]  In this instance, a single regulatory protein was detected that affected the transcription of the other proteins now known to compose the Lac operon. From this point forward, the two types of coding sequences were separated. [ 18 ]


However, increasing discoveries of gene regulation suggest greater complexity. Structural gene expression is regulated by numerous factors including  epigenetics  (e.g. methylation), RNAi, and more. Regulatory and structural genes can be epigenetically regulated identically, so not all regulation is coded for by “regulatory genes”. [ 17 ]


There are also examples of proteins that do not decidedly fit either category, such as  chaperone proteins . These proteins aid in the folding of other proteins, a seemingly regulatory role. [ 19 ] [ 20 ]  Yet these same proteins also aid in the movement of their chaperoned proteins across membranes, [ 21 ]  and have now been implicated in immune responses (see  Hsp60 )  [ 22 ]  and in the apoptotic pathway (see  Hsp70 ). [ 23 ]


More recently, microRNAs were found to be produced from the internal transcribed spacers of rRNA genes. [ 24 ]  Thus an internal component of a structural gene is, in fact, regulatory. Binding sites for microRNAs were also detected within coding sequences of genes. Typically interfering RNAs target the 3’UTR, but inclusion of binding sites within the sequence of the protein itself allows the transcripts of these proteins to effectively regulate the microRNAs within the cell. This interaction was demonstrated to have an effect on expression, and thus again a structural gene contains a regulatory component. [ 25 ]


In the field of  genetics , a  suicide gene  is a  gene  that will cause a  cell  to kill itself through the process of  apoptosis  (programmed cell death). Activation of a suicide gene can cause death through a variety of pathways, but one important cellular "switch" to induce apoptosis is the  p53  protein. Stimulation or introduction (through  gene therapy ) of suicide genes is a potential way of treating  cancer  or other proliferative diseases.


Suicide genes form the basis of a strategy for making cancer cells more vulnerable or sensitive to  chemotherapy . The approach has been to attach parts of genes expressed in cancer cells to other genes for enzymes not found in mammals that can convert a harmless substance into one that is toxic to the  tumor . [ 1 ]  Most suicide genes mediate this sensitivity by coding for viral or bacterial enzymes that convert an inactive drug into toxic  antimetabolites  that inhibit the synthesis of nucleic acid. Suicide genes must be introduced into the cells in ways that ensure their uptake and expression by as many cancer cells as possible, while limiting their expression by normal cells. Suicide gene therapy for cancer requires the vector to have the capacity to discriminate between target and non target cells, between the cancer cells and normal cells. [ 2 ]


Cell death can majorly occur by either  necrosis  or  apoptosis . Necrosis occurs when a cell is damaged by an external force, such as poison, a bodily injury, an infection or getting cut off from blood supply. When cells die from necrosis, it's a rather messy affair. The death causes  inflammation  that can cause further distress of injury within the body. Whereas, apoptosis causes degradation of cellular components without eliciting an inflammatory response. [ 3 ]


Many cells undergo programmed cell death, or apoptosis, during fetal development. A form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding. Apoptosis plays a crucial role in developing and maintaining the health of the body by eliminating old cells, unnecessary cells, and unhealthy cells. The human body replaces perhaps one million cells per second. When a cell is compelled to commit suicide, proteins called  caspases  go into action. They break down the cellular components needed for survival, and they spur production of enzymes known as DNase, which destroy the DNA in the nucleus of the cell. The cell shrinks and sends out distress signals, which are answered by  macrophages . The macrophages clean away the shrunken cells, leaving no trace, so these cells do not damage surrounding necrotic cells do. Apoptosis is also essential to  prenatal development . For example, in embryos, fingers and toes are initially connected to adjacent digits by tissue.  The cells of this connecting tissue undergo apoptosis to produce separate digits. In brain development, initially millions of extra neurons are created.  The cells that don't form synaptic connections undergo apoptosis. Programmed cell death is also necessary to start the process of menstruation. That's not to say that apoptosis is a perfect process. Rather than dying due to injury, cells that go through apoptosis die in response to signals within the body. When cells recognize viruses and gene mutations, they may induce death to prevent the damage from spreading. Scientist are trying to learn how they can modulate apoptosis, so that they can control which cells live and which undergo programmed cell death. Anti-cancer drugs and radiation, for example, work by triggering apoptosis in diseased cells. Many diseases and disorders are linked with the life and death of cells—increased apoptosis is a characteristic of AIDS, Alzheimer's, and Parkinson's disease, while decreased apoptosis can signal lupus or cancer. Understanding how to regulate apoptosis could be the first step to treating these conditions. [ 4 ]


Too little or too much apoptosis can play a role in many diseases. When apoptosis does not work correctly, cells that should be eliminated may persist and become immortal, for example, in cancer and leukemia. when apoptosis works overly well, it kills too many cells and inflicts grave tissue damage. This is the case in strokes and neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Also known as programmed cell death and cell suicide. [ 5 ]


The ultimate goal of cancer therapy is the complete elimination of all cancer cells, while leaving all healthy cells unharmed. One of the most promising therapeutic strategies in this regard is cancer suicide gene therapy (CSGT), which is rapidly progressing into new frontiers. The therapeutic success, in CSGT, is primarily contingent upon precision in delivery of the therapeutic transgenes to the cancer cells only. This is addressed by discovering and targeting unique or / and over-expressed biomarkers displayed on the cancer cells and cancer stem cells. Specificity of cancer therapeutic effects is further enhanced by designing the DNA constructs, which put the therapeutic genes under the control of the cancer cell specific promoters. The delivery of the suicidal genes to the cancer cells involves viral, as well as synthetic vectors, which are guided by cancer specific antibodies and ligands. The delivery options also include engineered stem cells with tropisms towards cancers. Main mechanisms inducing cancer cells' deaths include: transgenic expression of thymidine kinases, cytosine deaminases, intracellular antibodies, telomeraseses, caspases, DNases. Precautions are undertaken to eliminate the risks associated with transgenesis. Progress in genomics and proteomics should help us in identifying the cancer specific biomarkers and metabolic pathways for developing new strategies towards clinical trials of targeted and personalized gene therapy of cancer. By introducing the gene into a malignant tumor, the tumor would reduce in size and possibly disappear completely, provided all the individual cells have received a copy of the gene.


When the DNA sample in the virus is taken from the patient's own healthy cells, the virus does not need to be able to differentiate between cancer cells and healthy ones. In addition, the advantage is that it is also able to prevent metastasis upon the death of a tumor.


One of the challenges of cancer treatment is how to destroy malignant tumors without damaging healthy cells. A new method that shows great promise for accomplishing this employs the use of a suicide gene. A suicide gene is a gene which will cause a cell to kill itself through apoptosis. Suicide gene therapy involves delivery of a gene which codes for a cytotoxic product into tumor cells. [ 6 ]  This can be achieved by two approaches, indirect gene therapy and direct gene therapy. Indirect gene therapy employs enzyme-activated prodrug, in which the enzyme converts the prodrug to a toxic substance and the gene coding for this enzyme is delivered to the tumor cells. For example, a commonly studied strategy based on transfection of herpes simplex virus thymidine kinase (HSV-TK) along with administration of ganciclovir (GSV), in which HSK-TK assists in converting GCV to a toxic compound that inhibits DNA synthesis and causes cell death. [ 7 ] [ 6 ] [ 8 ]  Whereas, direct gene therapy employs a toxin gene or a gene which has the ability to correct mutated proapoptotic genes, which can in turn induce cell death via apoptosis.  For instance, the most researched immunotoxin for cancer therapy is the diphtheria toxin as it inhibits protein synthesis by inactivating elongation factor 2 (EF-2) which in turn inhibits protein  translation , [ 6 ] [ 9 ]  Moreover,  p53  is identified to be frequently abnormal in human tumors and studies show that restoring function of p53 can cause apoptosis of cancer cells. [ 6 ]  Suicide gene therapy is not necessarily expected to eliminate the need for chemotherapy and radiation treatment for all cancerous tumors. The damage inflicted upon the tumor cells, however, makes them more susceptible to the chemo or radiation. This approach has already proven effective against prostate and bladder cancers. The application of suicide gene therapy is being expanded to several other forms of cancer as well. Cancer patients often experience depressed immune systems, so they can suffer some side effects of the use of a virus as a delivery agent. [ citation needed ]


Suicide gene delivery can be broadly classified into three groups which include viral vectors, synthetic vectors and cell-based vectors. [ 6 ]  The most efficient vehicles for gene delivery are viral vectors. Widely used viruses for gene therapy include retrovirus, adenovirus (Ads), lentivirus and Aden-associated viruses (AAVs). Non-viral vectors like synthetic vectors were used to combat certain disadvantages of viral vectors like immunogenicity, insertional mutagenesis to name a few. Synthetic vectors refer to use of  nanoparticles , like gold nanoparticles, to delivery genes to target cells. [ 10 ]  Lastly, cell-based vectors employ stem cells as carriers of suicide genes. In the last few years, cell-mediated gene therapy for cancer using mesenchymal stem cells (MSCs) was patented. [ 11 ]


The bystander effect (BE) is phenomenon as a result of which it is possible to kill untransfected tumor cells located adjacent to transduced cells in suicide gene therapy. [ 8 ] [ 12 ] [ 13 ]  As hundred percent transduction of all tumor cells is very difficult to achieve, BE is critical feature of suicide gene therapy.


The drug is supposed to show high specificity towards cancer in order to effective, but studies have shown this to be rarely achieved. Moreover, expression of suicide gene was under control of tumor-specific promoters like  human telomerase  (hTERT),  osteocalcin ,  carcinoembryonic antigen ; however, only hTERT promoter was found to enter clinic trials. [ 14 ]  This is majorly because of the low transcriptional power of these tumor-specific promoters for suicide gene expression. Additionally, poor accessibility to target cells is an important limitation of suicide gene therapy. Another major hurdle of suicide gene therapy is partial vector specificity to target affected cells. Finally, lack of specific animal models to predict the clinical outcome and other effects of SGT.


Suicide genes are often utilized in biotechnology to assist in molecular cloning. Vectors incorporate suicide genes for an organism  (such as  E. coli ). The cloning project focuses on replacing the suicide gene by the desired fragment. Selection of vectors carrying the desired fragment is improved since vectors retaining the suicide gene result in cell death.


A  supergene  is a  chromosomal  region encompassing multiple neighboring  genes  that are inherited together because of close  genetic linkage , i.e. much less recombination than would normally be expected. [ 1 ]  This mode of inheritance can be due to genomic rearrangements between supergene variants.


A supergene region can contain few, functionally related genes that clearly contribute to a shared phenotype. [ 2 ]


Supergenes have  cis-effects  due to multiple  loci  (which may be within a gene, or within a single gene's  regulatory region ), and tight linkage.  They are classically  polymorphic , whereby different supergene variants code for different phenotypes.


Classic supergenes include many  sex chromosomes , the  Primula   heterostyly  locus, which controls " pin " and " thrum " types, and the locus controlling  Batesian mimetic  polymorphism in  Papilio memnon  butterflies. Recently discovered supergenes are responsible for complex phenotypes including color-morphs in the  white-throated sparrow . [ 3 ] [ 4 ] [ 5 ]


Primula supergene.  Pin and thrum morphs of Primula have effects on genetic compatibility (pin  style  x thrum  pollen , or thrum style x pin pollen matings are successful, while pin x pin, and thrum x thrum matings are rarely successful due to pollen-style  incompatibility ), and have different style length,  anther  height in the  corolla  tube, pollen size, and  papilla  size on the  stigma . Each of these effects is controlled by a different locus in the same supergene, but recombinants are occasionally found with traits combining those of "pin" and "thrum" morphs.


The earliest use of the term "supergene" may be in an article by A. Ernst (1936) in the journal Archiv der Julius Klaus-Stiftung für Vererbungsforschung, Sozialanthropologie und Rassenhygiene. [ 6 ]


Classically, supergenes were hypothesized to have evolved from less tightly-linked genes coming together via  chromosomal rearrangement  or reduced  crossing over , due to selection for particular multilocus  phenotypes . For instance, in Batesian mimicry supergenes in species such as  Papilio memnon , genes are required to affect hind-wing, fore-wing, and body colour, and also the presence or absence of long projections (the "tails" of swallowtail butterflies).


The case for the accumulative origin for supergenes was originally based on the work of Nabours on  polymorphism  for colour and pattern in grouse locusts (Tetrigidae). In  Acridium arenosum  the colour-patterns are controlled by thirteen genes on the same chromosome, which reassort (recombine) fairly easily. They also occur in  Apotettix eurycephalus  where they form two tightly linked groups, between which there is 7% crossing-over. Furthermore, in  Paratettix texanus  there appears to be complete suppression of crossing-over among 24 out of 25 of the colour-pattern genes, which can be distinguished by comparing their effects with those found in other species. Analysis of Nabour's data by  Darlington  &  Mather  concluded that the genes responsible for the morphs of  Paratettix texanus  have been gradually aggregated into a group which acts as a single switch-mechanism. [ 7 ] [ 8 ] [ 9 ]  This explanation was accepted by  E.B. Ford  and incorporated into his accounts of ecological genetics. [ 10 ] [ 11 ]


This process might involve suppression of crossing-over,  translocation  of chromosome fragments and possibly occasional  cistron  duplication. That crossing-over can be suppressed by selection has been known for many years; Detlefsen and Roberts were able to reduce recombination between the loci for white eyes (w) and miniature wings (m) in  Drosophila melanogaster  from the normal 36% to 6% in one line and 0.6% in another. [ 12 ] [ 13 ]


Debate has tended to centre round the question, could the component genes in a super-gene have started off on separate chromosomes, with subsequent reorganization, or is it necessary for them to start on the same chromosome? Many scientists today believe the latter, because some  linkage disequilibrium  is initially needed to select for tighter linkage, and linkage disequilibrium requires both the previous existence of polymorphisms via some other process, like natural selection, favouring gene combinations. [ 14 ]  If genes are weakly linked, it is probable that the rarer advantageous  haplotype  dies out, leading to the loss of polymorphism at the other locus.


Most people, following  J.R.G. Turner , therefore argue that supergenes arose  in situ  due to selection for correlated and epistatic traits, which just happened to have been possible to select via the existence of suitable loci closely linked to the original variant. [ 15 ]    Turner calls this a "sieve" explanation, and the Turner explanation might be called the "Turner sieve" hypothesis. [ 16 ]   Maynard Smith  agreed with this view in his authoritative textbook. [ 17 ]  Nevertheless, the question is not definitively settled. The problem is connected to an even larger question, the evolution of  evolvability .


Genomic rearrangements such as inversions can suppress recombination.


Suppressed recombination leads to accumulation of repetitive elements (including to degenerative expansion) in early supergene evolution [Ref Papaya, Fire ant], and to changes in gene expression [ref Fire ant, anther smut].


Gene complexes , in contrast, are simply tightly linked groups of genes, often created via  gene duplication  (sometimes called  tandem duplication  if the duplicates remain side-by-side). Here, each gene has similar though slightly diverged function.  For example, the human  major histocompatibility complex (MHC)  region is a complex of tightly linked genes all acting in the immune system, but has no claim to be a supergene, even though the component genes very likely have epistatic effects and are in strong disequilibrium due in part to selection.


Berdan EL, Flatt T, Kozak
GM, Lotterhos KE, Wielstra B. 2022 Genomic
architecture of supergenes: connecting form
and function. Phil. Trans. R. Soc. B 377:
20210192


NM_001178088 NM_003898


NM_001357665 NM_001357667


NP_001171559 NP_003889


NP_001344594 NP_001344596


Synaptojanin 2  is a  protein  that in humans is encoded by the SYNJ2  gene . [ 5 ]


The gene is a member of the  inositol-polyphosphate 5-phosphatase  family. The encoded protein interacts with the  ras-related C3 botulinum toxin substrate 1 , which causes translocation of the encoded protein to the  plasma membrane  where it inhibits  clathrin -mediated  endocytosis . Alternative splicing results in multiple  transcript variants . [provided by RefSeq, May 2010].


Tandemly arrayed genes  ( TAGs ) are a  gene cluster  created by  tandem duplications , [ 1 ]  a process in which one gene is duplicated and the copy is found adjacent to the original. [ 2 ]  They serve to encode large numbers of  genes  at a time.


TAGs represent a large proportion of genes in a genome, including between 14% and 17% of the human, mouse, and rat genomes. [ 2 ]  TAG clusters may have as few as two genes, with small clusters predominating, but may consist of hundreds of genes. [ 2 ]  An example are tandem clusters of  rRNA  encoding genes. These genes are transcribed faster than they would be if only a single copy of the gene was available. Additionally, a single RNA gene may not be able to provide enough RNA, but tandem repeats of the gene allow sufficient RNA to be produced. For example, cells in a  human embryo  contain between five and ten million  ribosomes , and cell number doubles within 24 hours. In order to provide the necessary ribosomes, multiple  RNA polymerases  must consecutively transcribe multiple rRNA genes. [ 3 ]


In some species, such as  Arabidopsis thaliana  and  Oryza sativa , most TAGs are the result of unequal  chromosomal crossover  during  genetic recombination . [ 4 ]


1TGH ,  1C9B ,  1JFI ,  1NVP ,  4ROC ,  4ROE ,  4ROD ,  5IY9 ,  5IYA ,  5FUR ,  5IYC ,  5IYB ,  5IY7 ,  5IY8 ,  5IYD ,  5IY6


NM_003194 NM_001172085


NP_001165556 NP_003185


The  TATA-binding protein  ( TBP ) is a  general transcription factor  that binds to a  DNA  sequence called the  TATA box .  This DNA sequence is found about 30  base pairs  upstream of the  transcription start site  in some  eukaryotic   gene   promoters . [ 5 ]


TBP is a member of a small gene family of TBP-related factors. [ 6 ]  The first TBP-related factor (TRF/TRF1) was identified in the fruit fly  Drosophila , but appears to be fly or insect-specific. Subsequently  TBPL1 /TRF2 was found in the genomes of many  metazoans , whereas  vertebrate  genomes encode a third vertebrate family member,  TBPL2 /TRF3. In specific cell types or on specific promoters TBP can be replaced by one of these TBP-related factors, some of which interact with the TATA box similarly to TBP.


TBP is a subunit of the eukaryotic  general transcription factor   TFIID . TFIID is the first protein to bind to DNA during the formation of the  transcription preinitiation complex  of  RNA polymerase II  (RNA Pol II). [ 7 ]  As one of the few proteins in the preinitiation complex that binds DNA in a sequence-specific manner, it helps position RNA polymerase II over the  transcription start site  of the gene. However, it is estimated that only 10–20% of human promoters have TATA boxes - the majority of human promoters are  TATA -less  housekeeping gene   promoters  - so TBP is probably not the only protein involved in positioning RNA polymerase II.. The binding of TBP to these promoters is facilitated by housekeeping gene regulators. [ 8 ] [ 9 ]  Interestingly, transcription initiates within a narrow region at around 30 bp downstream of TATA box on TATA-containing promoters, [ 10 ]  while transcription start sites of TATA-less promoters are dispersed within a 200 bp region. [ 11 ] [ 9 ]


Binding of TFIID to the  TATA box  in the  promoter  region of the gene initiates the recruitment of other factors required for RNA Pol II to begin transcription. Some of the other recruited transcription factors include  TFIIA ,  TFIIB , and  TFIIF . Each of these transcription factors contains several protein subunits.


TBP is also important for transcription by  RNA polymerase I  and  RNA polymerase III , and is therefore involved in transcription initiation by all three RNA polymerases. [ 12 ]


TBP is involved in  DNA melting  (double strand separation) by bending the  DNA  by 80° (the AT-rich sequence to which it binds facilitates easy melting). The TBP is an unusual protein in that it binds the minor groove using a β sheet.


Another distinctive feature of TBP is a long string of glutamines in the N-terminus of the protein. This region modulates the DNA binding activity of the C-terminus, and modulation of DNA-binding affects the rate of transcription complex formation and initiation of transcription. Mutations that expand the number of CAG repeats encoding this  polyglutamine tract , and thus increase the length of the polyglutamine string, are associated with  spinocerebellar ataxia  17, a  neurodegenerative disorder  classified as a  polyglutamine disease . [ 13 ]


When TBP binds to a  TATA box  within the  DNA , it distorts the DNA by inserting amino acid side-chains between base pairs, partially unwinding the helix, and doubly kinking it. The distortion is accomplished through a great amount of surface contact between the protein and DNA. TBP binds with the negatively charged phosphates in the DNA backbone through positively charged  lysine  and  arginine  amino acid residues. The sharp bend in the DNA is produced through projection of four bulky  phenylalanine  residues into the minor groove. As the DNA bends, its contact with TBP increases, thus enhancing the DNA-protein interaction.


The strain imposed on the DNA through this interaction initiates melting, or separation, of the strands. Because this region of DNA is rich in  adenine  and  thymine  residues, which base-pair through only two  hydrogen bonds , the DNA strands are more easily separated. Separation of the two strands exposes the bases and allows  RNA polymerase II  to begin transcription of the  gene .


TBP's C-terminus composes of a helicoidal shape that (incompletely) complements the T-A-T-A region of DNA. This incompleteness allows DNA to be passively bent on binding.


For information on the use of TBP in cells see:  RNA polymerase I ,  RNA polymerase II , and  RNA polymerase III .


TATA-binding protein has been shown to  interact  with:


The TATA-box  binding   protein  (TBP) is required for the initiation of  transcription  by RNA  polymerases  I, II and III, from  promoters  with or without a TATA box. [ 51 ] [ 52 ]  In the presence of a TATA-less promoter, TBP binds with the help of TBP-associated factors (TAFs). [ 53 ] [ 54 ]  TBP associates with a host of factors, including the general  transcription factors  TFIIA, -B, -D, -E, and -H, to form huge multi-subunit pre-initiation complexes on the core  promoter . Through its association with different  transcription  factors, TBP can initiate  transcription  from different RNA  polymerases . There are several related TBPs, including TBP-like (TBPL)  proteins . [ 55 ]


The C-terminal core of TBP (~180 residues) is  highly conserved  and contains two 88-amino acid  repeats  that produce a saddle-shaped  structure  that straddles the DNA; this region  binds  to the TATA box and  interacts  with  transcription factors  and  regulatory   proteins  . [ 56 ]  By contrast, the N-terminal region varies in both length and  sequence .


A2RU30 E9PIT9


NM_001098815 NM_001136030 NM_001261844 NM_014796


NP_001338078 NP_001338079 NP_001338080 NP_001338081 NP_001338082 NP_001338083 NP_001338084


Thymocyte expressed, positive selection associated 1  is a  protein  that in humans is encoded by the TESPA1  gene . [ 4 ]


tinman , or  tin  is an Nk2- homeobox  containing  transcription factor  first isolated in  Drosophila  flies. The human homolog is the  Nkx2-5 gene .  tinman  is expressed in the precardiac  mesoderm  and is responsible for the  differentiation ,  proliferation , and specification of  cardiac   progenitor cells . [ 1 ] [ 2 ]  This gene is named after the character  Tin Woodman  who lacks a heart, as flies with nonfunctional  tinman  genes have cardiac deformities.


Homeobox genes are a group of  transcription factors  characterized by a homeodomain that initiates  gene expression  which regulates cell differentiation and development when it binds to a target  promoter . [ 3 ]   tinman  was first isolated in  Drosophila  and many vertebrate  homologs  have been discovered since and are considered part of a multigene family in  vertebrates . The human homolog is  Nkx2-5 .


tinman is dependent upon the JAK-STAT signalling of the precardiac mesoderm to differentiate into a more confined growth pattern for development of visceral mesoderm and the heart. [ 4 ]  It contributes to the looping of the heart during fetal cardiac development, but has also been found to contribute to the regulation of the heart's electrical system postnatally.


tinman is expressed very early in Drosophila during the development of the embryonic mesoderm and is required for formation of the   visceral and cardiac mesoderm . It is expressed transiently in the visceral mesoderm but continues to be expressed in the cardiac mesoderm. The two major cell types of the  Drosophila  heart, cardial and  pericardial  cells, express  tinman . [ 1 ]


In both  Drosophila  and vertebrates, the temporal and spatial expression of  tinman  is critical in determining cell lineage and patterning of the heart. In mutant or knockout organisms, the loss of  tinman  results in the lack of heart formation. In humans, mutations of Nkx2.5 result in some of the most common congenital heart defects. These include atrial and ventricular septal defects and  tetralogy of Fallot . [ 5 ]  Abnormal placental expression of Nkx2.5 has been associated with some cases of severe, early onset preeclampsia. [ 6 ]


Transmembrane protein 33  is a  protein  that in humans, is encoded by the TMEM33  gene , also known as  SHINC3 . [ 1 ]
Another name for the TMEM33 protein is  DB83 .


In humans, this gene’s  DNA  location is the short arm of  chromosome 4 , loci position: 4p13. [ 3 ]
The genomic range is 41937502-41956213, spanning 18.7 kb, on the positive strand. [ 3 ]
Transmembrane protein 33 is  ubiquitously  expressed, but is particularly highly expressed in the  blood ,  lymph nodes ,  bone , and  adipose tissue . [ 4 ] [ 5 ]