Edellistä sukupolvea (1920 aikaan)
https://www.genecards.org/cgi-bin/carddisp.pl?gene=PREP&keywords=prolyl,endopeptidase
Article| Volume 94, ISSUE 2, P161-170, July 24, 1998
Mainitaan amnesiasairauksiin assosiaatiota 1998.
https://www.frontiersin.org/articles/10.3389/fnmol.2017.00456/full
https://www.genecards.org/cgi-bin/carddisp.pl?gene=EGR1&keywords=EGR
The protein encoded by this gene belongs to the EGR family of C2H2-type zinc-finger proteins. It is a nuclear protein and functions as a transcriptional regulator. The products of target genes it activates are required for differentitation and mitogenesis. Studies suggest this is a cancer suppressor gene. [provided by RefSeq, Dec 2014]
EGR1 (Early Growth Response 1) is a Protein Coding gene. Diseases associated with EGR1 include Ischemia and Monocytic Leukemia. Among its related pathways are PIP3 activates AKT signaling and Hepatocyte growth factor receptor signaling. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and transcription factor binding. An important paralog of this gene is EGR3.
Transcriptional regulator (PubMed:20121949). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'(EGR-site) in the promoter region of target genes (By similarity). Binds double-stranded target DNA, irrespective of the cytosine methylation status (PubMed:25258363, 25999311). Regulates the transcription of numerous target genes, and thereby plays an important role in regulating the response to growth factors, DNA damage, and ischemia. Plays a role in the regulation of cell survival, proliferation and cell death. Activates expression of p53/TP53 and TGFB1, and thereby helps prevent tumor formation. Required for normal progress through mitosis and normal proliferation of hepatocytes after partial hepatectomy. Mediates responses to ischemia and hypoxia; regulates the expression of proteins such as IL1B and CXCL2 that are involved in inflammatory processes and development of tissue damage after ischemia. Regulates biosynthesis of luteinizing hormone (LHB) in the pituitary (By similarity). Regulates the amplitude of the expression rhythms of clock genes: BMAL1, PER2 and NR1D1 in the liver via the activation of PER1 (clock repressor) transcription. Regulates the rhythmic expression of core-clock gene BMAL1 in the suprachiasmatic nucleus (SCN) (By similarity). ( EGR1_HUMAN,P18146 )
Google:
The phosphorylation of thiamine (B1) occurs by two main enzymes: thiamine diphosphokinase, which catalyzes the formation of thiamine pyrophosphate (TPP) using ATP,
and
https://www.genecards.org/cgi-bin/carddisp.pl?gene=TPK1&keywords=thiamine,triphosphate,synthase
The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine (B1) to thiamine pyrophosphate (ThDP) , a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5. [provided by RefSeq, Apr 2017]
TPK1 (Thiamin Pyrophosphokinase 1) is a Protein Coding gene. Diseases associated with TPK1 include Thiamine Metabolism Dysfunction Syndrome 5 and Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency. Among its related pathways are Metabolism of water-soluble vitamins and cofactors and Metabolism. Gene Ontology (GO) annotations related to this gene include kinase activity and thiamine binding.
LÄHDE: Martin A. Crook, in Laboratory Assessment of Vitamin Status, 2019
Thiamine TPP is produced by thiamine diphosphokinase and is an essential cofactor for the decarboxylation of 2-oxoacids, such as the conversion of pyruvate to acetyl coenzyme a and also other pathways including pyruvate dehydrogenase (PDH), α-ketogluterate dehydrogenase (KGDH), and branched-chain α-keto acid dehydrogenase (BCKDH), (Fig. 6.2). In thiamine deficiency, pyruvate cannot be metabolized and accumulates in the blood. Thiamine TPP is also an essential cofactor for transketolase in the pentose-phosphate pathway
Thiamine is essential for the optimal function of the nervous system and repair of myelin nerve sheaths. In turn magnesium is an important cofactor for thiamine-dependent enzymes.2–9 In addition, other reputed noncofactor roles of thiamine compounds are shown within the oxidative stress response, gene regulation, cholinergic system, immune function, chloride channels, and neurotransmission.2–6
LÄHDE: Barbara Plecko, Robert Steinfeld, in Swaiman's Pediatric Neurology (Sixth Edition), 2017
Autosomal-recessive thiamine pyrophosphokinase deficiency (OMIM 606370) presents with a late-onset Leigh-like disease and basal ganglia changes on MRI. During acute episodes, elevated blood and CSF lactate and enhanced excretion of α-ketoglutarate are consistent findings. Thiamine pyrophosphate (TPP) concentrations in blood and muscle are reduced, and diagnosis is confirmed by sequencing of the TPK1 gene. Thiamine supplementation at 100- to 200 mg/day was of limited benefit in symptomatic patients. Earlier intervention with doses around 500 mg/day may be associated with better prognosis.
LÄHDE: GeneGards:
Orphanet: 58 Childhood encephalopathy due to thiamine pyrophosphokinase (TPK1) deficiency is a rare inborn error of metabolism disorder characterized by early-onset, acute, encephalopathic episodes (frequently triggered by viral infections), associated with lactic acidosis and alpha-ketoglutaric aciduria, which typically manifest with variable degrees of ataxia, generalized developmental regression (which deteriorates with each episode) and dystonia. Other manifestations include spasticity, seizures, truncal hypotonia, limb hypertonia, brisk tendon reflexes and reversible coma.
MalaCards based summary: Childhood Encephalopathy Due to Thiamine Pyrophosphokinase Deficiency and has symptoms including ataxia and muscle spasticity. An important gene associated with Childhood Encephalopathy Due to Thiamine Pyrophosphokinase Deficiency is TPK1 (Thiamin Pyrophosphokinase 1). Affiliated tissues include whole blood and brain.
LÄHDE:
Thiamine triphosphate (ThTP) was discovered over 60 years ago and it was long thought to be a specifically neuroactive compound. Its presence in most cell types, from bacteria to mammals, would suggest a more general role but this remains undefined. In contrast to thiamine diphosphate (ThDP), ThTP is not a coenzyme. In E. coli cells, ThTP is transiently produced in response to amino acid starvation, while in mammalian cells, it is constitutively produced at a low rate. Though it was long thought that ThTP was synthesized by a ThDP:ATP phosphotransferase, more recent studies indicate that it can be synthesized by two different enzymes: (1) adenylate kinase 1 in the cytosol and (2) FoF1-ATP synthase in brain mitochondria. Both mechanisms are conserved from bacteria to mammals. Thus ThTP synthesis does not seem to require a specific enzyme. In contrast, its hydrolysis is catalyzed, at least in mammalian tissues, by a very specific cytosolic thiamine triphosphatase (ThTPase), controlling the steady-state cellular concentration of ThTP. In some tissues where adenylate kinase activity is high and ThTPase is absent, ThTP accumulates, reaching ≥ 70% of total thiamine, with no obvious physiological consequences. In some animal tissues, ThTP was able to phosphorylate proteins, and activate a high-conductance anion channel in vitro. These observations raise the possibility that ThTP is part of a still uncharacterized cellular signaling pathway. On the other hand, its synthesis by a chemiosmotic mechanism in mitochondria and respiring bacteria might suggest a role in cellular energetics.
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Retinan regulatiivisen genomin säätelygeenien joukosta TCF4 omaa onkogeenisyyden alueella assoisaatiota yleistyneeseenamyotrofiaan ja mm. geeniin VAMP1. https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCF4&keywords=TCF4
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Synonyms: Diffuse amyotrophy, Diffuse muscle atrophy, Diffuse muscle wasting, Diffuse skeletal
muscle wasting, Generalised amyotrophy, Generalised muscle atrophy, Generalised muscle degeneration, Generalized muscle atrophy, Generalized muscle degeneration, Muscle atrophy, diffuse, Muscle atrophy, generalised, Muscle atrophy, generalized, Muscular atrophy, generalised, Muscular atrophy, generalized
OMIM:610006 2-Methylbutyryl-Coa dehydrogenase deficiency ACADSB [36 ]
ORPHA:466794Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome SCYL1 [57410 ]
OMIM:300523 Allan-Herndon-Dudley syndrome SLC16A2 [6567 ]
ORPHA:79279 Alpha-N-acetylgalactosaminidase deficiency type 1 NAGA [4668 ]
ORPHA:157954 ANE syndrome RBM28 [55131 ]
ORPHA:251282 Autosomal dominant spastic ataxia type 1, VAMP1 [6843 ]
Gene Location: 12p13.31
Definition
Synapotobrevins,
syntaxins, and the synaptosomal-associated protein SNAP25 are the main
components of a protein complex involved in the docking and/or fusion of
synaptic vesicles with the presynaptic membrane. The protein encoded by
this gene is a member of the vesicle-associated membrane protein
(VAMP)/synaptobrevin family. Mutations in this gene are associated with
autosomal dominant spastic ataxia 1. Multiple alternative splice
variants have been described, but the full-length nature of some
variants has not been defined. [provided by RefSeq, Jul 2014]
Onko jotain yhteyttä VAMP1 geenin jollain geenimutaatiolla aikuisuudessa ilmenevään amyotrofiseen lateroskleroosiin?
HAKU PubMwd
Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS.
The underlying mechanisms that determine gene expression and chromatin accessibility in retinogenesis are poorly understood. Herein, single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing are performed on human embryonic eye samples obtained 9–26 weeks after conception to explore the heterogeneity of retinal progenitor cells (RPCs) and neurogenic RPCs. The differentiation trajectory from RPCs to 7 major types of retinal cells are verified. Subsequently, diverse lineage-determining transcription factors are identified and their gene regulatory networks are refined at the transcriptomic and epigenomic levels. Treatment of retinospheres, with the inhibitor of RE1 silencing transcription factor, X5050, induces more neurogenesis with the regular arrangement, and a decrease in Müller glial cells. The signatures of major retinal cells and their correlation with pathogenic genes associated with multiple ocular diseases, including uveitis and age-related macular degeneration are also described. A framework for the integrated exploration of single-cell developmental dynamics of the human primary retina is provided.
The eye is a vital and highly specialized visual organ, and the retina is the most important component of vision production in the eye. The retina primarily comprises six types of neurons and several types of glial cells.
Therein, photoreceptor cells, including cones and rods in the outer nuclear layer (ONL), receive and process light signals from the external environment.
The interneurons, including amacrine cells (ACs), bipolar cells (BCs), and horizontal cells (HCs) in the inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL), deliver signals from the photoreceptor cells to retinal ganglion cells (RGCs) in the ganglion cell layer (GCL).
Inside the RGCs, these light signals are converted to electrical signals and transmitted to the brain.[1]
The primary types of retinal glial cells include Müller glial cells (MGCs) and microglia.
MGCs mainly act as mediators to assist photoreceptor cells in light absorption, provide nutrients to neurons, and remove metabolic waste,[2, 3]
whereas microglia are resident immune cells in the retina and central nervous system that have a critical role in the maintenance of normal homeostasis and immune surveillance of these systems.[4]
The retina primarily develops from retinal progenitor cells (RPCs), which differentiate into six classes of neurons and one class of glial cells at chronologically separate, yet frequently overlapping, intervals during development. Before becoming terminal cells, RPCs typically transition through a precursor cell stage. Distinct evolutionary fates are selected as the RPCs reach saddle points, where they segregate into different and progressively restricted precursor cell states and finally develop and mature into terminal cells.[5-9] Although terminal-cell specification has received considerable attention, it remains unclear how heterogeneity develops within RPCs.
The general process of retinal development is meticulously regulated by cell-type-specific transcription factors (TFs) that recruit chromatin effectors to repurpose the chromatin and promote new retinal cellular characteristics.[10]
Dysregulation of any step in this process can cause varying degrees of visual dysfunction and congenital diseases, including retinoblastoma, Leber congenital amaurosis, and autosomal recessive retinitis pigmentosa.[10-13]
Meanwhile, the development of retinal cell lineages remains to be investigated, and prospective critical factors have not yet been thoroughly characterized.
Recently, the single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) have proven effective for the analysis of human embryonic retinal development. More specifically, scRNA-seq has been employed to investigate the differentiation trajectory of RPCs and unique subpopulations of embryonic retinal cells. The associated studies have reported that myriad TFs have crucial roles in directing the development of specific lineages, such as nuclear factor I (NFI) in the regulation of cell-cycle exit and generation of late-born retinal cell types, and atonal bHLH transcription factor 7 (ATOH7) in the specification of cone photoreceptors.[14-17]
Meanwhile, gene expression patterns of important lineage-defined TFs are primarily regulated by epigenetic programs that are influenced by changes in chromatin accessibility and can be detected by scATAC-seq. For instance, the sequences of various TF cascades responsible for determining cell fate have been verified at the epigenomic level from a developing human retina database using scATAC-seq.[18-20] However, integrated scRNA-seq and scATAC-seq datasets from the same human embryonic eye sample are lacking; hence, transcriptomic and epigenetic results have the potential to be better matched.
Here, we performed an integrative analysis of scATAC-seq and scRNA-seq on individual cells obtained from human embryonic eyes to capture the dynamic transcriptomic and epigenetic landscapes of the developing human eye at single-cell resolution.
To this end, we probed the precursors of MGCs and the intrinsic connection among neurogenic RPCs (NPCs).
We then constructed developmental trajectories and gene regulatory networks (GRNs) for RPC-derived cells. (Figure1A).
In this way, we defined the continuous evolution of TF motif activity related to neuronal specification and identified the co-dependence of TF motif accessibility along these trajectories.
By investigating whether RE1 silencing transcription factor (REST) influences RPC and MGC fate, we found that treatment of retinospheres with a REST inhibitor induced neurogenesis with a regular spatial arrangement and decrease in MGCs.
Finally, we identified differences between embryonic macrophages and microglia and combined disease-related genes from retina-related diseases to characterize relationships between risk factors and specific retinal cell types.
Collectively, this study highlights neurogenic cell fate determination
processes and elucidates a portion of the gene regulation involved in
retinal development.
(Figure1A).
Using scRNA-seq, most cells were divided into 17 groups according to the normalized expression of known markers (Figure 1D,E; Table S2, Supporting Information). Due to the limited number of MGCs (38 cells, 0.0505% of total cell count) and microglia (11 cells, 0.0146% of total cell count) directly mapped to the chromatin landscape in scRNA-seq, subsequent analysis was not performed (Tables S3 and S4, Supporting Information). We then integrated the gene expression levels with corresponding gene activity scores and found that major cluster annotations in the retina of matched cells were consistent. A group of RPCs expressing CCND1, HES1, and SOX2 was identified, and several NPC markers, including ATOH7, HES6, and DLL3, were expressed by cells in one scRNA-seq cluster. Additionally, a group of RGCs expressing NEFM, SNCG, and GAP43, as well as genes related to HC identification (ONECUT1 and ONECUT2), was detected. Moreover, a group of cells expressing AC-related genes (GAD2 and TFAP2A) was observed. Among the BC clusters, a group of cells expressing VSX1 and TMEM215, and distinct clusters of photoreceptor cells, including cones (expressing PRDM1 and THRB) and rods (expressing NRL, RHO) were detected. We further annotated a cluster of cells highly expressing RGR, GPX3, and RLBP1 as MGCs and determined that RGR might be more specific to MGCs than RLBP1 during the embryonic period. Furthermore, we observed gene expression in clusters of retinal pigment epithelia (RPE) (RPE65 and TTR), fibroblasts (DCN and MGP), melanocytes (PMEL and TYRP1), endothelial cells (PECAM1 and ENG), lens cells (CRYGC and LIM2), and corneal epithelium (KRT5). Numerous markers exhibited dynamic gene activity scores in related scATAC-seq clusters (Figure 1F,G). The emergence of these major retinal cell types reflected normal retinal development (Figure S1A, Supporting Information).
Considering that RPCs have a two-branch developmental tendency, including glial cell orientation and neuronal orientation,[6, 14, 16] we extracted RPCs, NPCs, and MGCs, as well as six major neurons for pseudo-time analysis via two different approaches (Palantir and Monocle3). The results verified that RPCs could differentiate into glia or NPCs, and transitional NPCs could develop into neurons of three lineages (Figure 1H,I; Figure S1B, Supporting Information).
Collectively, we generated a collaborative database that describes retinal development, laying the groundwork for subsequent analyses.
To identify which TFs are crucial for the differentiation of RPCs into major retinal cells and for the maintenance of their specific cell end-states, we performed Python implementation of a single-cell regulatory network of inference and clustering (SCENIC) analysis. Moreover, we assessed the relative accessibility to chromatin and enrichment of motifs for these TFs (Figure 2).
The results predicted a series of TFs, with highly similar transcriptomic and epigenomic levels, as vital for the fate of specific cell types (Figure 2A–C; Figure S2A, Supporting Information). UMAP embedding of SCENIC TF activity revealed four developmental branch endpoints derived from RPCs, which were demarcated and represented by respective TFs reported to affect the development of related lineages (Figure 2D), such as SOX8 for the MGC lineage, POU4F3 for RGC lineage, TFAP2B for HC/AC lineage, and LHX4 and NEUROD1 for BC/PH lineage.[21, 23-25]
Next, we screened critical cell-type-specific TFs at the epigenetic level from the top predicted TFs; the 10 genes regulated by at least two key TFs, according to the weight value, were selected to depict the top GRNs of related TFs for each cell linage (Figure 2E; Figure S2B,C, Supporting Information). For instance, the Iroquois homeobox protein family TFs (IRX1 and IRX2) exhibited a marked influence on genes required for RGC development, such as EBF3, NRN1, and NEFL,[26, 22] whereas ONECUT family members had regulatory effects on HC/AC lineage-specific factors, including PROX1 and BARHL2.[27-29]
In summary, we identified fate-determining TFs for RPCs and their products, constructed.... more in link
