scholarly journals The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophy

2010 ◽  
Vol 29 (7) ◽  
pp. 1235-1247 ◽  
Author(s):  
Simona Pedrotti ◽  
Pamela Bielli ◽  
Maria Paola Paronetto ◽  
Fabiola Ciccosanti ◽  
Gian Maria Fimia ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Splicing Silencer ◽  
Splicing Regulator

scholarly journals Antisense oligonucleotide mediated therapy of spinal muscular atrophy

2013 ◽  
Vol 4 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Senthilkumar Sivanesan ◽  
Matthew Howell ◽  
Christine DiDonato ◽  
Ravindra Singh
Keyword(s):  
Spinal Muscular Atrophy ◽  
Antisense Oligonucleotide ◽  
Muscular Atrophy ◽  
Essential Gene ◽  
Genetic Diseases ◽  
Survival Motor Neuron ◽  
Splicing Silencer ◽  
Substantial Progress ◽  
The Many

AbstractSpinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations of survival motor neuron 1 (SMN1), an essential gene. SMN2, a nearly identical copy, can compensate for SMN1 loss if SMN2 exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation of SMN exon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction of SMN2 exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restore SMN2 exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promote SMN2 exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.

scholarly journals Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy

2018 ◽  
Vol 32 (15-16) ◽  
pp. 1045-1059 ◽  
Author(s):  
Meaghan Van Alstyne ◽  
Christian M. Simon ◽  
S. Pablo Sardi ◽  
Lamya S. Shihabuddin ◽  
George Z. Mentis ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuron Death ◽  
Motor Neuron Death

scholarly journals Alternative Splicing Events Are a Late Feature of Pathology in a Mouse Model of Spinal Muscular Atrophy

PLoS Genetics ◽  
2009 ◽  
Vol 5 (12) ◽  
pp. e1000773 ◽  
Author(s):  
Dirk Bäumer ◽  
Sheena Lee ◽  
George Nicholson ◽  
Joanna L. Davies ◽  
Nicholas J. Parkinson ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Alternative Splicing Events

scholarly journals Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1346
Author(s):  
Jan Lejman ◽  
Grzegorz Zieliński ◽  
Piotr Gawda ◽  
Monika Lejman
Keyword(s):  
Alternative Splicing ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Biological Information ◽  
Survival Motor Neuron Protein ◽  
Attractive Therapeutic Target

It has been estimated that 80% of the pre-mRNA undergoes alternative splicing, which exponentially increases the flow of biological information in cellular processes and can be an attractive therapeutic target. It is a crucial mechanism to increase genetic diversity. Disturbed alternative splicing is observed in many disorders, including neuromuscular diseases and carcinomas. Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. Homozygous deletion in 5q13 (the region coding for the motor neuron survival gene (SMN1)) is responsible for 95% of SMA cases. The nearly identical SMN2 gene does not compensate for SMN loss caused by SMN1 gene mutation due to different splicing of exon 7. A pathologically low level of survival motor neuron protein (SMN) causes degeneration of the anterior horn cells in the spinal cord with associated destruction of α-motor cells and manifested by muscle weakness and loss. Understanding the regulation of the SMN2 pre-mRNA splicing process has allowed for innovative treatment and the introduction of new medicines for SMA. After describing the concept of splicing modulation, this review will cover the progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of SMA using the mechanism of alternative splicing.

scholarly journals The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

2020 ◽  
Vol 15 ◽  
pp. 263310552097398
Author(s):  
Ravindra N Singh ◽  
Eric W Ottesen ◽  
Natalia N Singh
Keyword(s):  
Spinal Muscular Atrophy ◽  
Small Molecule ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Smn1 Gene ◽  
The Third ◽  
Splicing Silencer ◽  
Phenotypic Spectrum ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is 1 of the leading causes of infant mortality. SMA is mostly caused by low levels of Survival Motor Neuron (SMN) protein due to deletion of or mutation in the SMN1 gene. Its nearly identical copy, SMN2, fails to compensate for the loss of SMN1 due to predominant skipping of exon 7. Correction of SMN2 exon 7 splicing by an antisense oligonucleotide (ASO), nusinersen (Spinraza™), that targets the intronic splicing silencer N1 (ISS-N1) became the first approved therapy for SMA. Restoration of SMN levels using gene therapy was the next. Very recently, an orally deliverable small molecule, risdiplam (Evrysdi™), became the third approved therapy for SMA. Here we discuss how these therapies are positioned to meet the needs of the broad phenotypic spectrum of SMA patients.

scholarly journals Transcriptomic comparison of Drosophila snRNP biogenesis mutants: implications for Spinal Muscular Atrophy

2016 ◽  
Author(s):  
Eric L. Garcia ◽  
Ying Wen ◽  
Kavita Praveen ◽  
A. Gregory Matera
Keyword(s):  
Alternative Splicing ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Point Mutations ◽  
Survival Motor Neuron ◽  
Transgenic Expression ◽  
Shared Set ◽  
Splicing Defects ◽  
Smn Protein ◽  
Processing Differences

AbstractSpinal Muscular Atrophy (SMA) is caused by deletion or mutation of the Survival Motor Neuron 1 gene (SMN1)1, but the mechanism whereby reduced levels of SMN protein lead to disease is unknown. SMN functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) and potential splicing defects have been uncovered in various animal models of SMA. We used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or Smn gene specific in Drosophila. Although more numerous, the processing changes in Ars2 mutants were generally distinct from those identified in Phax and Smn animals. Phax and Smn null mutants exhibited comparable reductions in steady-state snRNA levels, and direct comparison of their transcriptomes uncovered a shared set of alternative splicing changes. Transgenic expression of Phax and Smn in the respective mutant backgrounds significantly rescued both snRNA levels as well as alternative splicing. When compared to the Smn wild-type rescue line, three additional disease models (bearing SMA-causing point mutations in Smn) displayed only small-to-indistinguishable differences in snRNA levels and the identified splicing disruptions. Comparison of these intermediate SMA models revealed fewer than 10% shared splicing differences. Instead, the three Smn point mutants displayed common increases in stress responsive transcripts that correlated with phenotypic severity. These findings uncouple organismal viability defects from the general housekeeping function of SMN and suggest that SMN-specific changes in gene expression may be important for understanding how loss of SMN ultimately causes disease.

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