1946 syntynyt Tampereella
Ylioppilastutkinto 1964 Lempäälä
Lääketietaan kandidaatti 1966 Turun yliopisto
Lääketieteen lisensiaatti 1972 Turun Yliopisto
Dietetiikan opiskelu 1998 - 2001 Göteborgin Yliopisto
Eläkkeelle 2010
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]
GeneCards Summary for EGR1 Gene
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.
UniProtKB/Swiss-Prot Summary for EGR1 Gene
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 )
The phosphorylation
of thiamine (B1) occurs by two main enzymes: thiamine diphosphokinase, which
catalyzes the formation of thiamine pyrophosphate (TPP) using ATP,
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]
ThiamineTPP is produced by thiamine diphosphokinase and is an essential cofactor for the decarboxylation of 2-oxoacids, such as the conversion of pyruvate to acetylcoenzyme 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
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:
TPK1 , Thiamin pyrophosphokinase 1 , (7q35)
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:
. 2014 Dec;29(4):1069-82.
doi: 10.1007/s11011-014-9509-4.
Epub 2014 Mar 4.
Thiamine triphosphate: a ubiquitous molecule in search of a physiological role
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 specificcytosolic
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.
Previously, we identified missense mutations in CCNF that are
causative of familial and sporadic amyotrophic lateral sclerosis (ALS)
and frontotemporal dementia (FTD). Hallmark features of these diseases
include the build-up of insoluble protein aggregates as well as the
mislocalization of proteins such as transactive response DNA binding
protein 43 kDa (TDP-43). In recent years, the dysregulation of SFPQ
(splicing factor proline and glutamine rich) has also emerged as a
pathological hallmark of ALS/FTD.
CCNF encodes for the protein cyclin F,
a substrate recognition component of an E3 ubiquitin ligase. We have
previously shown that ALS/FTD-linked mutations in CCNF cause disruptions
to overall protein homeostasis that leads to a build-up of K48-linked
ubiquitylated proteins as well as defects in autophagic machinery. To
investigate further processes that may be affected by cyclin F, we used a
protein-proximity ligation method, known as Biotin Identification
(BioID), standard immunoprecipitations and mass spectrometry to identify
novel interaction partners of cyclin F and infer further process that
may be affected by the ALS/FTD-causing mutation. Results demonstrate
that cyclin F closely associates with proteins involved with RNA
metabolism as well as a number of RNA-binding proteins previously linked
to ALS/FTD, including SFPQ. Notably, the overexpression of cyclin
F(S621G) led to the aggregation and altered subcellular distribution of
SFPQ in human embryonic kidney (HEK293) cells, while leading to altered
degradation in primary neurons. Overall, our data links ALS/FTD-causing
mutations in CCNF to converging pathological features of ALS/FTD and
provides a link between defective protein degradation systems and the
pathological accumulation of a protein involved in RNA processing and
metabolism.
Lee A, Rayner SL, Gwee
SSL, De Luca A, Shahheydari H, Sundaramoorthy V, Ragagnin A, Morsch M,
Radford R, Galper J, Freckleton S, Shi B, Walker AK, Don EK, Cole NJ,
Yang S, Williams KL, Yerbury JJ, Blair IP, Atkin JD, Molloy MP, Chung
RS.Cell Mol Life Sci. 2018 Jan;75(2):335-354. doi: 10.1007/s00018-017-2632-8. Epub 2017 Aug 29.PMID: 28852778
van Hummel A, Sabale M, Przybyla M, van der Hoven J, Chan G, Feiten AF, Chung RS, Ittner LM, Ke YD.Neuropathol Appl Neurobiol. 2023 Apr;49(2):e12902. doi: 10.1111/nan.12902.PMID: 36951214
Davidson JM, Wu SSL,
Rayner SL, Cheng F, Duncan K, Russo C, Newbery M, Ding K, Scherer NM,
Balez R, García-Redondo A, Rábano A, Rosa-Fernandes L, Ooi L, Williams
KL, Morsch M, Blair IP, Di Ieva A, Yang S, Chung RS, Lee A.Mol Neurobiol. 2023 May 27. doi: 10.1007/s12035-023-03355-2. Online ahead of print.PMID: 37243816
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?
Kim JY, Jang A, Reddy R, Yoon WH, Jankowsky JL.Hum Mol Genet. 2016 Nov 1;25(21):4661-4673. doi: 10.1093/hmg/ddw294.PMID: 28173107Free PMC article.
Four mutations in the VAMP/synaptobrevin-associated protein B (VAPB)
gene have been linked to amyotrophic lateral sclerosis (ALS) type 8. The
mechanism by which VAPB mutations cause motor neuron disease is
unclear, but studies of the most common P56S variant suggest both loss
of function and dominant-negative sequestration of wild-type protein.
Diminished levels of VAPB and its proteolytic cleavage fragment have
also been reported in sporadic ALS cases, suggesting that VAPB loss of
function may be a common mechanism of disease. Here, we tested whether
neuronal overexpression of wild-type human VAPB would attenuate disease
in a mouse model of familial ALS1. We used neonatal intraventricular
viral injections to express VAPB or YFP throughout the brain and spinal
cord of superoxide dismutase (SOD1) G93A transgenic mice. Lifelong
elevation of neuronal VAPB slowed the decline of neurological
impairment, delayed denervation of hindlimb muscles, and prolonged
survival of spinal motor neurons. Collectively, these changes produced a
slight but significant extension in lifespan, even in this highly
aggressive model of disease. Our findings lend support for a protective
role of VAPB in neuromuscular health.
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,
theselight signalsare 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 toassist
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.
A
single-cell regulatory atlas of the developing human retina. A)
Schematic of experimental design. B) Retinal structure schematic. C)
Immunofluorescence analysis of primary human retinal tissue validating
the expression of cell-type-specific markers, including NRL (rods); RGR
(MGCs); CALIBINDIN (HCs); PKC (BCs); CALRETININ (HCs, ACs, and RGCs);
and BRN3A (RGCs). Nuclei are counterstained with DAPI. Scale bar, 50 µm.
D) UMAP embedding of the retina scRNA-seq dataset, with individual
cells colored by age and annotated cell types. E) Violin plot showing
relative expression of transcripts with high specificity for individual
cell types ordered by cell type. F) UMAP embedding of the retina
scATAC-seq dataset, with individual cells colored by age and annotated
cell types. G) Coverage plots and gene score of known marker genes for
cell types. Gene color representing the direction of gene translation
(red: right; blue: left). H) UMAP embedding of the developmental
trajectories of RPCs, MGCs, and NPCs colored by pseudo-time. Red arrows
show two developmental directions from RPCs. I) UMAP embedding of the
developmental trajectories of RPCs and RPC-derived cells from scRNA-seq
colored by pseudo-time. White arrows show three neuronal lineages.
Abbreviations: PCW, post-conception weeks; RGCs, retinal ganglion cells;
HCs, horizontal cells; ACs, amacrine cells; BCs, bipolar cells; MGCs,
Müller glial cells; GCL, ganglion cell layer; ONL, outer nuclear layer;
OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner
plexiform layer.
Figure 2
Transcriptomic and epigenetic
patterns of GRNs in RPCs and their derived cells. Heatmap of A)
transcriptional expression, B) gene activity, and C) their motif
enrichment score of
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.
Construction of Gene Regulatory Networks in Retinal Progenitor Cell-Producing Cells at the Transcriptomic and Epigenetic Levels
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 (Figure2).
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
