SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

Dominguez, Catherine; Cunningham, David; Chandler, Dawn S.

doi:10.1007/s00439-017-1835-2

Cited by 8 publications

(2 citation statements)

References 193 publications

(276 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The contribution of VRK1 to neuropathogenesis can be a consequence of a defective organization of Cajal bodies (CB) by alteration of the regulation of coilin by VRK1, which is required for CB assembly and disassembly 19 . Coilin is associated to proteins such as SMN 43,54 , scaRNPs 54 or ataxin-1 39 that are implicated in severe neurological phenotypes such as muscular atrophy 55,56 and ataxias 39 . Ataxin-1 (SCA1) is a phosphorylated protein 57,58 , and in this context, VRK1 mutations might be a pathogenic alternative to expansion of poly-Q expansion in ataxin-1 59 .…”

Section: Discussionmentioning

confidence: 99%

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Martín-Doncel

Rojas

Cantarero

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic alleles are implicated, either in homozygosis or compound heterozygosis. In this report, to identify the common underlying pathogenic mechanism of VRK1 polymorphisms, we have studied all human VRK1 variants identified in these neurological phenotypes from a biochemical point of view by molecular modeling, protein stability and kinase activity assays. Molecular modelling predicted that VRK1 variant proteins are either unstable or have an altered kinase activity. The stability and kinase activity of VRK1 pathogenic variants detected two groups. One composed by variants with a reduced protein stability: R133C, R358X, L195V, G135R and R321C. The other group includes VRK1variants with a reduced kinase activity tested on several substrates: histones H3 and H2AX, p53, c-Jun, coilin and 53BP1, a DNA repair protein. VRK1 variants with reduced kinase activity are H119R, R133C, G135R, V236M, R321C and R358X. The common underlying effect of VRK1 pathogenic variants with reduced protein stability or kinase activity is a functional insufficiency of VRK1 in patients with neuromotor developmental syndromes. The G135 variant cause a defective formation of 53BP1 foci in response to DNA damage, and loss Cajal bodies assembled on coilin.

show abstract

Section: Discussionmentioning

confidence: 99%

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Martín-Doncel

Rojas

Cantarero

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…It is worth noting that Exon 6b is a new discovery and is generated by exonification of the Alu element in intron 6 [ 42 ]. Under certain conditions such as starvation, hypoxia, or oxidative stress, transcription of these genes may proceed differently [ 8 , 43 ]. Factors that regulate SMN levels and modify transcription are tissue-specific [ 44 ].…”

Section: Mechanisms Of Smn2 Splicing Regulation Targeted By Therapeuticsmentioning

confidence: 99%

Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

Lejman

Zieliński

Gawda

et al. 2021

Genes

View full text Add to dashboard Cite

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.

show abstract

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

102

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

show abstract

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

Cited by 8 publications

References 193 publications

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Contact Info

Product

Resources

About