SMN, profilin IIa and plastin 3: A link between the deregulation of actin dynamics and SMA pathogenesis

Bowerman, Mélissa; Anderson, Carrie L.; Beauvais, Ariane; Boyl, Pietro Pilo; Witke, Walter; Kothary, Rashmi

doi:10.1016/j.mcn.2009.05.009

Cited by 109 publications

(85 citation statements)

References 55 publications

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“…In previous studies, the influence of plastin 3 and profilin IIa proteins level, as well as c.859G4C substitution in the SMN2 gene, on the severity of SMA has been revealed. [11][12][13] However, these findings can only be applied to a limited number of SMA cases.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

et al. 2013

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Spinal muscular atrophy (SMA) is a monogenic disorder that is subdivided into four different types and caused by survival motor neuron gene 1 (SMN1) deletion. Discordant cases of SMA suggest that there exist additional severity modifying factors, apart from the SMN2 gene copy number. Here we performed the first genome-wide methylation profiling of SMA patients and healthy individuals to study the association of DNA methylation status with the severity of the SMA phenotype. We identified strong significant differences in methylation level between SMA patients and healthy controls in CpG sites close to the genes CHML, ARHGAP22, CYTSB, CDK2AP1 and SLC23A2. Interestingly, the CHML and ARHGAP22 genes are associated with the activity of Rab and Rho GTPases, which are important regulators of vesicle formation, actin dynamics, axonogenesis, processes that could be critical for SMA development. We suggest that epigenetic modifications may influence the severity of SMA and that these novel genetic positions could prove to be valuable biomarkers for the understanding of SMA pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

et al. 2013

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“…Patient 2 had a moderate phenotype with a later age of onset and better motor function than patient 1, but both patients had same SMN1 genotype and SMN2-NAIP-P44-H4F5 copy number, and no significant difference in FL-SMN transcript levels. We suggest other factors such as profilin IIa 46,47 and zinc finger protein 48 may also influence SMA phenotype.…”

Section: Discussionmentioning

confidence: 89%

A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy

Bai

Cao

et al. 2015

Eur J Hum Genet

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Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or mutation of SMN1 (survival motor neuron 1). SMN exon 7 splicing is regulated by a number of exonic and intronic regulatory sequences and the trans-factors that bind them. Variants located in or near these regulated regions should be evaluated to determine their effect on splicing. We identified the rare variant c.863G4T (r.835_*3del, p.Gly279Glufs*5) in exon 7 of SMN1 in three patients affected with type I or type II SMA. Most of the SMN1 transcripts exhibited complete loss of exon 7 in vivo. The ex vivo splicing assay demonstrated that the variant disrupts inclusion of exon 7 (~85%) in the SMN1 mRNA; replacement with various bases yielded a variety of splicing effects in SMN1 and SMN2 pre-mRNA. The c.863G4T (r.835_*3del, p.Gly279Glufs*5) variant is located in a region that includes binding sites for multiple splicing factors including Tra2β1. Thus, the variant disrupts Tra2β1 binding, but does not affect binding of hnRNP A1. These findings demonstrate how rare variants influence pre-mRNA splicing of SMN and reveal the functional influence of c.863G4T (r.835_*3del, p.Gly279Glufs*5) variant in patients with SMA.

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“…SMN also has a role in axonal transport through its ability to regulate actin dynamics, forming a complex with β-actin [75,76]. SMN also interacts with profilin (ALS18) to influence indirectly actin filament stability [77,78]. Animal models with SMN depletion are deficient in β-actin mRNA and protein, and numerous disturbances of motor neuron axonal growth and development have been identified [75,79,80].…”

Section: Insights Into Smn1-related Sma Pathogenesismentioning

confidence: 99%

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

2015

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Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

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SMN, profilin IIa and plastin 3: A link between the deregulation of actin dynamics and SMA pathogenesis

Cited by 109 publications

References 55 publications

Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity

A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

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