| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Q16637 | Region | 156 | 222 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=210;End=241 |
| Q16637 | Region | 156 | 222 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=210;End=241 |
| Q16637 | Region | 240 | 267 | Note=P2 (binding site for SNRPB) | Type=Deletion;Start=210;End=241 |
| Q16637 | Region | 240 | 267 | Note=P2 (binding site for SNRPB) | Type=Deletion;Start=210;End=241 |
| Q16637 | Region | 252 | 280 | "Note=Involved in homooligomerization;Ontology_term=ECO:0000269 | ECO:0000269 |
| Q16637 | Region | 252 | 280 | "Note=Involved in homooligomerization;Ontology_term=ECO:0000269 | ECO:0000269 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Substitution;Start=279;End=282 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Deletion;Start=283;End=294 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Substitution;Start=279;End=282 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Deletion;Start=283;End=294 |
| Q16637 | Compositional bias | 190 | 222 | Note=Pro residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=210;End=241 |
| Q16637 | Compositional bias | 190 | 222 | Note=Pro residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=210;End=241 |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| Q16637-1 | 0.824 | 63 | 0.831 | 142.345 | 0.58 | 0.607 | 0.85 | 0.563 | 0.857 | 0.657 | 0.866 | 87,88,89,90,91,92,116,118,121,138,139,141,142,143
|
| Q16637-2 | 0.884 | 74 | 0.906 | 159.152 | 0.557 | 0.622 | 0.853 | 0.643 | 0.846 | 0.761 | 1.425 | 86,87,88,89,90,91,92,116,118,121,138,139,141,142,1
43
|
| Q16637-3 | 1.083 | 101 | 1.183 | 318.304 | 0.563 | 0.656 | 0.876 | 1.587 | 0.462 | 3.433 | 2.345 | 190,191,193,194,246,247,248,249,250,251,253,254,25
7,258,260,261,262,264,265,267,268,269
|
| Q16637-4 | 0.897 | 76 | 0.914 | 167.041 | 0.528 | 0.64 | 0.91 | 0.596 | 0.888 | 0.671 | 0.775 | 84,85,86,87,88,89,90,91,92,116,118,121,137,138,139
,141,142,143,144
|
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Substitution;Start=279;End=282 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Deletion;Start=283;End=294 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Substitution;Start=279;End=282 |
| Q16637 | Region | 279 | 294 | Note=Required for interaction with SYNCRIP;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:11574476;Dbxref=PMID:11574476 | Type=Deletion;Start=283;End=294 |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| SMN1 | 10339583 | A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. | SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNDelta7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome. | D009134 | Muscular Atrophy, Spinal |
| SMN1 | 11313744 | Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype. | Autosomal recessive spinal muscular atrophy (SMA) is a common motor neuron disease caused by absence or mutation in the survival motor neuron (SMN1) gene. SNM1 and a nearly identical copy, SMN2, encode identical proteins, but SMN2 only produces a little full length protein due to alternative splicing. The level of functional SMN protein and the number of SMN2 genes correlate with the clinical phenotype ranging from severe to very mild. Here, we report on premature termination mutations in SMN1 exon 3 (425del5 and W102X) which induce skipping of the mutated exon. The novel nonsense mutation W102X was detected in two patients with a relatively mild phenotype who had only two copies of the SMN2 gene, a number that has previously been found associated with the severe form of SMA. We show that the shortened transcripts are translated into predicted in frame protein isoforms. Aminoglycoside treatment suppressed the nonsense mutation in cultured cells and abolished exon skipping. Fibroblasts from both patients show a high number of nuclear structures containing SMN protein (gems). These findings suggest that the protein isoform lacking the exon 3 encoded region contributes to the formation of the nuclear protein complex which may account for the milder clinical phenotype. | D009134 | Muscular Atrophy, Spinal |
| SMN1 | 11875052 | SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2 beta 1. | Proximal spinal muscular atrophy (SMA) is caused by the homozygous loss of survival motor neuron (SMN1). SMN2, a nearly identical copy gene, is present in all SMA patients; however this gene cannot provide protection from disease due to the aberrant splicing of a critical exon. SMN1-derived transcripts are exclusively full-length, whereas SMN2-derived transcripts predominantly lack SMN exon 7. A single non-polymorphic nucleotide difference (C in SMN1; T in SMN2) is responsible for the alternative splicing patterns. We have previously shown that transient expression of an SR-like splicing factor, hTra2 beta 1, stimulates inclusion of exon 7 in SMN2-derived mini-gene transcripts through an interaction with the AG-rich exonic splice enhancer within exon 7. We now demonstrate that a second splicing factor, SRp30c, can stimulate SMN exon 7-inclusion and that this activity required the same AG-rich enhancer as hTra2 beta 1. SRp30c did not directly associate with SMN exon 7; rather its association with the exonic enhancer was mediated by a direct interaction with hTra2 beta 1. In the absence of the hTra2 beta 1 binding site, SRp30c failed to complex with SMN exon 7. Taken together, these results identify SRp30c as a modulator of SMN exon 7-inclusion and provide insight into the molecular regulation of this critical exon. | D009134 | Muscular Atrophy, Spinal |
| SMN1 | 19179398 | Splice-site pairing is an intrinsically high fidelity process. | The extensive alternative splicing in higher eukaryotes has initiated a debate whether alternative mRNA isoforms are generated by an inaccurate spliceosome or are the consequence of highly degenerate splice sites within the human genome. Here, we established a quantitative assay to evaluate the accuracy of splice-site pairing by determining the number of incorrect exon-skipping events made from constitutively spliced pre-mRNA transcripts. We demonstrate that the spliceosome pairs exons with an astonishingly high degree of accuracy that may be limited by the quality of pre-mRNAs generated by RNA pol II. The error rate of exon pairing is increased by the effects of the neurodegenerative disorder spinal muscular atrophy because of reduced levels of Survival of Motor Neuron, a master assembler of spliceosomal components. We conclude that all multi-intron-containing genes are alternatively spliced and that the reduction of SMN results in a general splicing defect that is mediated through alterations in the fidelity of splice-site pairing. | D009134 | Muscular Atrophy, Spinal |
| SMN1 | 21826391 | Optimization of SMN trans-splicing through the analysis of SMN introns. | Spinal muscular atrophy (SMA), a neurodegenerative disease, is the leading genetic cause of infantile death and is caused by the loss of survival motor neuron 1 (SMN1). Humans carry a duplicated copy gene, SMN2, which produces very low levels of functional protein due to an alternative splicing event. This splicing difference is the reason that SMN2 cannot prevent SMA development when SMN1 is deleted. SMN2 generates a transcript lacking exon 7 and consequently gives rise to an unstable truncated SMN protein that cannot protect from SMA. To increase full-length SMN protein, we utilize a strategy referred to as trans-splicing. This strategy relies upon pre-mRNA splicing occurring between two separate molecules: (1) the endogenous target RNA and (2) the therapeutic RNA that provides the correct RNA sequence via a trans-splicing event. The initial trans-splicing RNA targeted intron 6 and replaced exon 7 with the SMN1 exon 7 in SMN2 pre-mRNA. To determine the most efficient intron for SMN trans-splicing event, a panel of trans-splicing RNA molecules was constructed. Each trans-splicing RNA molecule targets a specific intron within the SMN2 pre-mRNA and based on the target intron, replaces the downstream exons including exon 7. These constructs were examined by RT-PCR, immunofluorescence, and Western blotting. We have identified intron 3 as the most efficient intron to support trans-splicing in cellular assays. The intron 3 trans-splicing construct targets intron 3 and replaces exons 4-7 and was distinguished based on its ability to produce the highest level of the trans-spliced RNA and full-length SMN protein in SMA patient fibroblasts. The efficiency of the intron 3 construct was further improved by addition of an antisense that blocks the 3' splice site at the intron 4/exon 5 junction. Most importantly, intracerebroventricular injection of the Int3 construct into SMNΔ7 mice elevated the SMN protein levels in the central nervous system. This research demonstrates an alternative platform to correct genetic defects, including SMN expression and examines the molecular basis for trans-splicing. | D004195 | Disease Models, Animal |
| SMN1 | 21826391 | Optimization of SMN trans-splicing through the analysis of SMN introns. | Spinal muscular atrophy (SMA), a neurodegenerative disease, is the leading genetic cause of infantile death and is caused by the loss of survival motor neuron 1 (SMN1). Humans carry a duplicated copy gene, SMN2, which produces very low levels of functional protein due to an alternative splicing event. This splicing difference is the reason that SMN2 cannot prevent SMA development when SMN1 is deleted. SMN2 generates a transcript lacking exon 7 and consequently gives rise to an unstable truncated SMN protein that cannot protect from SMA. To increase full-length SMN protein, we utilize a strategy referred to as trans-splicing. This strategy relies upon pre-mRNA splicing occurring between two separate molecules: (1) the endogenous target RNA and (2) the therapeutic RNA that provides the correct RNA sequence via a trans-splicing event. The initial trans-splicing RNA targeted intron 6 and replaced exon 7 with the SMN1 exon 7 in SMN2 pre-mRNA. To determine the most efficient intron for SMN trans-splicing event, a panel of trans-splicing RNA molecules was constructed. Each trans-splicing RNA molecule targets a specific intron within the SMN2 pre-mRNA and based on the target intron, replaces the downstream exons including exon 7. These constructs were examined by RT-PCR, immunofluorescence, and Western blotting. We have identified intron 3 as the most efficient intron to support trans-splicing in cellular assays. The intron 3 trans-splicing construct targets intron 3 and replaces exons 4-7 and was distinguished based on its ability to produce the highest level of the trans-spliced RNA and full-length SMN protein in SMA patient fibroblasts. The efficiency of the intron 3 construct was further improved by addition of an antisense that blocks the 3' splice site at the intron 4/exon 5 junction. Most importantly, intracerebroventricular injection of the Int3 construct into SMNΔ7 mice elevated the SMN protein levels in the central nervous system. This research demonstrates an alternative platform to correct genetic defects, including SMN expression and examines the molecular basis for trans-splicing. | D009134 | Muscular Atrophy, Spinal |
Gene summary
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