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when the same mild SMN missense mutations are expressed in a mouse containing two SMN2 copies, functional SMN complexes are formed with the small amount of wild-type FL-SMN produced by SMN2 and the SMA phenotype is completely rescued. This contrasts with SMN missense alleles when studied in C. elegans, Drosophila and zebrafish
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
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.
Loss of SMN2 is associated with spinal muscular atrophy.
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.
Our work has not only expanded the number of pre-mRNA targets for RBM10, but identified RBM10 as a novel regulator of SMN2 alternative inclusion.
We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6.
Ongoing research may yield other treatments, especially for children who have not responded to Spinraza. A gene therapy delivered by adeno-associated virus type 9 (AAV9) is designed to replace or correct SMN1 . Cure SMA is supporting research in this area as well as studies of small molecules that correct SMN2 splicing or spur it to produce more protein.
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.
The spleen is disproportionately small in the murine model of spinal muscular atrophy with a deficiency in SMN2.
Low SMN2 expression is associated with Spinal Muscular Atrophy.
we have characterized SMN-C1, a low-molecular weight compound that corrects alternative splicing defects of SMN2 exon 7. We evaluated SMN-C1 pharmacokinetics in mice, the dose-response of SMN-C1 induction of SMN protein in two mouse models of SMA, the correlation between SMN-C1 PK and SMN protein induction in vivo, and demonstrated that the peripheral SMN protein levels correlated with CNS SMN protein levels
Deletion in SMN2 gene is associated with spinal muscular atrophy.
Thus, we can conclude that SMN2 methylation may regulate the SMA disease phenotype by modulating its transcription.
This study demonstrated that Deficiency of the Survival of SMN2 Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons
Inverse correlation was observed between SMN2, SERF1A and NAIP copy number polymorphism and spinal muscular atrophy type.
Loss of SMN2 expression is associated with Spinal muscular atrophy.
Depletion of two of the most potent inhibitors of SMP2 exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased SMN2 exon 7 inclusion and SMN protein level.
Smn complex deficiency caused constipation, delayed gastric emptying, slow intestinal transit and reduced colonic motility.
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. While mutations in the telomeric copy are associated with spinal muscular atrophy, mutations in this gene, the centromeric copy, do not lead to disease. This gene 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 full length 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. Four transcript variants encoding distinct isoforms have been described.
component of gems 1
, survival motor neuron protein
, tudor domain containing 16B
, gemin 1
, survival of motor neuron 2, centromeric L homeolog