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The endogenous expression of porcine SMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of porcine SMN mRNA after knock-down or of human SMN mRNA after gene therapy.
first cloning and identification of the swine SMN1 gene and show that there is significant sequence homology between swine and human SMN throughout the coding region
No association was found between SMA clinical types and the deletion types of SMN1 exons 7 and 8
preliminary data show an intriguing expression profile of Gle1, MART3 and FUS genes in Spinal muscular atrophy (SMA), and suggest a critical role of FUS protein in the SMA pathogenesis.
Humans have a second SMN gene (SMN2) that is almost identical to SMN1. However, due to alternative splicing the majority of SMN2 mRNA is translated into a truncated, unstable protein that is quickly degraded. Because the presence of SMN2 provides a unique opportunity for therapy development in SMA patients, the mechanisms that regulate SMN2 splicing and mRNA expression have been elucidated in great d
The c.*211_*212del variant was also much more frequent in exon 8 of SMN2-SMN1 hybrids than in that of intact SMN1 genes (20 vs. 0.83%, p < 0.001), suggesting its association with chromosomal rearrangements.
study provides direct evidence that Gemin5 is involved in unassembled-U1 snRNA disposal under conditions of SMN deficiency.
it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadi
Spinal muscular atrophy (SMA)-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNDelta7S270A, but not wild-type (WT) SMNDelta7, provides a protective effect in SMA model mice and human motor neuron cell culture systems.
A rare variant c.835-5T>G in intron 6 of SMN1 was identified in a patient affected with type I spinal muscular atrophy.
Intron 2b-retained SMN transcript and intron3-retained SMN transcript were ubiquitously expressed in human cells and tissues. The intron-retained transcripts were mainly localized in the nucleus and decreased through non-nonsense-mediated decay pathway.
overexpressed exogenous SMN1 at the ribosomal DNA (rDNA) locus of induced pluripotent stem cells (iPSCs) generated from a SMA patient using an rDNA-targeting vector
Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg-Welander) is caused by mutation of the SMN1 gene.
While the above conclusions are firmly supported by the experimental data presented, we discuss and justify the need of deep proteomic techniques for the study of SMN complex components (orphan and bound) turn-over to understand the physiological relevant mechanisms of degradation of SMN and SMNDelta7 (SMN1 and SMN2)in the cell.
Results report exon 6B, a novel exon, generated by exonization of an intronic Alu-like sequence from both SMN1 and SMN2, and validate the expression of exon 6B-containing transcripts SMN6B and SMN6BDelta7 in human tissues and cell lines. hnRNP C is shown to be a potential regulator of its expression and demonstrate that SMN6B is a substrate of nonsense-mediated decay. Also, an interaction of SMN6B with Gemin2 was found.
Widespread intron retention and markers of the DNA damage response were observed with SMN1 depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons.
Study examined the effect of 2 mutations on SMN protein expression: a G-to-C transversion, leading to a tryptophan-to-serine substitution (p.Trp92Ser) in the Tudor domain; and a single thymine insertion between nucleotides 819 and 820 in exon 6 that causes a frameshift, changing all the amino acids of the C-terminal domain from the point of the mutation onward (p.Thr274Tyrfs). Mutations may affect stability and levels.
The authors show by NMR spectroscopy that both RNA recognition motifs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing.
Homozygous deletion of the SMN1 gene have been detected in more than 95% of spinal muscular atrophy patients
The increases of the SMN1 and SC35 1.7-kb mRNA levels reached about 4- and 6.5-fold in fibroblasts.
Loganin is capable of increas-ing the SMN protein level under SMN-deficient conditions both inin vitro and in vivo models of spinal muscular atrophy via Akt/mTOR pathway.
Activation of a cryptic 5' splice site in transcripts derived from SMN1 reversed a pathogenic G-to-C mutation at the first position of intron 7.
Controlled light (CL) exposure restores the expression of circadian rhythm genes and attenuates the severe spinal muscular atrophy (SMA) phenotype with beneficial effects on survival and weight.
To further assess the effects of Spinal muscular atrophy deficiency on the liver, we employed the severe Taiwanese model (Smn1-/-, SMN20/2TG) that has a mean survival of 10 days, with healthy heterozygous littermates (Smn1+/-, SMN20/2TG) as controls
We here present a comprehensive overview of SMN protein expression variation across different tissues and at different developmental time points in healthy control mice, as well as in two established mouse models of SMA. As SMN levels were determined using robust methodology we were able to make direct and reliable comparisons between a severe and an intermediate SMA model.
Of the six biomarkers, only COMP and DPP4 showed high and SPP1 moderate correlation with the spinal muscular atrophy phenotype. PLS3 overexpression neither influenced the SMN level nor the six biomarkers, supporting the hypothesis that PLS3 acts as an independent protective modifier.
Survival Motor Neuron (SMN) protein is required for normal mouse liver development
Widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction.
A proteomic profile of embryonic stem cells with low smn protein revealed thematic changes consistent with the developmental dysfunction seen in the pathophysiological development of patients with spinal muscular atrophy. Pathways associated with mRNA spicing, protein translation, post-translational modification and perhaps most striking, mitochondrial function and specifically mitochondrial dysfunction were highlighted.
miR-431 expression was highly increased, and a number of its putative mRNA targets were significantly downregulated in motor neurons after SMN loss. Further, we found that miR-431 regulates motor neuron neurite length by targeting several molecules previously identified to play a role in motor neuron axon outgrowth, including chondrolectin
To determine the dependence of oligodendrocyte (OL)on the Smn protein(SMN1), we utilized the Smn-/-;SMN2 (severe) mouse model. Our data suggest that despite the multi-functionality and ubiquitous expression of the Smn protein, it does not play a key role in myelination of the CNS, at least in the context of spinal muscular atrophy pathogenesis.
our studies show that this G-motif represents a novel and essential determinant for axonal localization of the Anxa2 mRNA mediated by the SMN complex.
A long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2.
SMN1 expression restoration is curative in a spinal muscular atrophy model mice.
Survival motor neuron 1, and survival motor neuron 2, depletion results in increased alternative splicing events.
these results demonstrate that SMN deficiency impacts spleen development and suggests a potential role for immunological development in Spinal muscular atrophy.
Itch monoubiquitinates SMN and monoubiquitination of SMN plays an important role in regulating its cellular localization.
muscle does not appear to require high levels of SMN above what is produced by two copies of SMN2
Findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. In addition, SMN high expression in neurons and glia has a major impact on survival.
This study identifies pathways related to the function of Smn and associated with differential motor unit vulnerability, thus presenting a number of exciting targets for future therapeutic development.
we established that the additional supply of Smn protein in motoneurons is necessary for proper axonogenesis in a cell-autonomous manner
In motor neurons, smn1 interacts with the RNA binding protein, HuD and regulates motoneuron development and function.
our finding that elevation of Pgk1 levels or activity, via injection of Pgk1 mRNA or treatment with terazosin respectively, robustly ameliorated MN pathology in smn morphant zebrafish provides an initial demonstration that these pathways are amenable to therapeutic intervention.
Since Gemin2 and SMN both function in snRNP biogenesis yet only SMN knockdown causes motor axon defects, these data are consistent with an additional role for SMN that is snRNP independent.
SMN deficiency affects splicing and abundance of nrxn2a. This may explain the pre-synaptic defects at neuromuscular endplates in SMA pathophysiology.
SMN is needed early in development of motoneuron dendrites and axons to develop normally and that this is essential for proper connectivity and movement.
These results show that survival motor neuron functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss.
Survival motor neuron has a novel function in motor neurons independent of small nuclear ribonucleoprotein (snRNP) biosynthesis.
Smn mutants in zebrafish survive to larval stages and exhibit presynaptic neuromuscular junction defects.
This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. However, mutations in this gene, the telomeric copy, are associated with spinal muscular atrophy\; mutations in the centromeric copy do not lead to disease. The centromeric copy may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Two transcript variants encoding distinct isoforms have been described.
survival of motor neuron 2, centromeric
, survival motor neuron 1
, survival motor neuron protein
, component of gems 1
, survival motor neuron 1 protein
, tudor domain containing 16A
, survival of motor neuron protein
, survival of motor neuron 1, telomeric
, survival motor neuron protein 1