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Genetics of Spinal Muscular Atrophy
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Genetics of Spinal Muscular Atrophy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 37296

Special Issue Editor

Dr. Nikolai Naryshkin

E-Mail Website
Guest Editor
PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA
Interests: SMA Therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Spinal muscular atrophy (SMA) represents a remarkable case illustrating the power of modern genetics in solving complex biological and medical questions. In the 25 years since the discovery of the genetic basis of SMA, great progress has been achieved in our understanding of the molecular etiology of the disease. It has been clearly established that SMA is caused by the deletion or mutation of the SMN1 gene and the reduced expression of the SMN protein from the paralogous SMN2 gene due to alternative splicing. This understanding has provided the foundation for an extraordinary success story in modern drug development, resulting in three approved disease-modifying therapies for the treatment of SMA. However, gaps and key questions remain open and need solutions. For instance, we are still trying to understand why motor neurons are particularly sensitive to reduced SMN levels, how the same number of SMN2 copies results in different degrees of SMA severity, the role of epigenetic regulation in SMN expression, and how therapeutics interplay with SMA genetics.

With such open questions in mind, the goal of this Special Issue is to collect submissions, both literature reviews and original research articles, that will present the current conceptual framework to understand SMA and help advance the field to the next level.

The topics we would like to cover include but are not limited to:

  • Genetics of SMA
    • The nature of SMN2, unique to humans. Insight into molecular evolution
    • The functional linkage of SMN2 gene dosage to SMA phenotypic spectrum and features
    • Modifier genes and their functional relationship to SMN and SMA
    • Epigenetic regulation and control of SMN expression
  • SMN expression and function
    • Why motor neurons are the most affected cells in SMA
    • The role of SMN protein in extraneuronal tissues and organs
    • Tissue-specific differences in SMN2 pre-mRNA splicing and SMN protein levels
    • The temporal dynamics of SMN expression pre- and postnatally.
  • The utility and challenges of using animal models to understand the genetics of SMA
  • Insights from SMA genetics as guiding principles for the discovery of drugs against SMA
  • The lessons from SMA therapeutic development for the discovery of drugs against genetic disorders
  • The development and evolution of newborn screening and molecular diagnosis of SMA using classical and next-generation sequencing approaches

Dr. Nikolai Naryshkin
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Spinal muscular atrophy
  • Human molecular genetics
  • SMN protein
  • Drug discovery and development
  • pre-mRNA splicing
  • Gene expression regulation

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Related Special Issue

Published Papers (7 papers)

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Research

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13 pages, 1277 KiB  
Article
Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2
by Laura Blasco-Pérez, Mar Costa-Roger, Jordi Leno-Colorado, Sara Bernal, Laura Alias, Marta Codina-Solà, Desirée Martínez-Cruz, Claudia Castiglioni, Enrico Bertini, Lorena Travaglini, José M. Millán, Elena Aller, Javier Sotoca, Raúl Juntas, Christina Engel Hoei-Hansen, Antonio Moreno-Escribano, Encarna Guillén-Navarro, Laura Costa-Comellas, Francina Munell, Susana Boronat, Ricardo Rojas-García, Mónica Povedano, Ivon Cuscó and Eduardo F. Tizzanoadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(15), 8289; https://doi.org/10.3390/ijms23158289 - 27 Jul 2022
Cited by 12 | Viewed by 2617
Abstract
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount [...] Read more.
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype–phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype–phenotype correlations and improve prognostic outcomes. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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14 pages, 4833 KiB  
Article
Targeted-Deletion of a Tiny Sequence via Prime Editing to Restore SMN Expression
by Miaojin Zhou, Shuqing Tang, Nannan Duan, Mi Xie, Zhuo Li, Mai Feng, Lingqian Wu, Zhiqing Hu and Desheng Liang
Int. J. Mol. Sci. 2022, 23(14), 7941; https://doi.org/10.3390/ijms23147941 - 19 Jul 2022
Cited by 15 | Viewed by 2564
Abstract
Spinal muscular atrophy (SMA) is a devastating autosomal recessive motor neuron disease associated with mutations in the survival motor neuron 1 (SMN1) gene, the leading genetic cause of infant mortality. A nearly identical copy gene (SMN2) is retained in [...] Read more.
Spinal muscular atrophy (SMA) is a devastating autosomal recessive motor neuron disease associated with mutations in the survival motor neuron 1 (SMN1) gene, the leading genetic cause of infant mortality. A nearly identical copy gene (SMN2) is retained in almost all patients with SMA. However, SMN2 fails to prevent disease development because of its alternative splicing, leading to a lack of exon 7 in the majority of SMN2 transcripts and yielding an unstable truncated protein. Several splicing regulatory elements, including intronic splicing silencer-N1 (ISS-N1) of SMN2 have been described. In this study, targeted-deletion of ISS-N1 was achieved using prime editing (PE) in SMA patient-specific induced pluripotent stem cells (SMA-iPSCs) with a high efficiency of 7/24. FL-SMN expression was restored in the targeted-deletion iPS clones and their derived motor neurons (iMNs). Notably, the apoptosis of the iMNs, caused by the loss of SMN protein that leads to the hyperactivity of endoplasmic reticulum (ER) stress, was alleviated in targeted-deletion iPSCs derived-iMNs. Thus, this is the first study to demonstrate that the targeted-deletion of ISS-N1 via PE for restoring FL-SMN expression holds therapeutic promise for SMA. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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33 pages, 15459 KiB  
Article
High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome
by Eric William Ottesen, Diou Luo, Natalia Nikolaevna Singh and Ravindra Narayan Singh
Int. J. Mol. Sci. 2021, 22(16), 8378; https://doi.org/10.3390/ijms22168378 - 4 Aug 2021
Cited by 12 | Viewed by 4247
Abstract
Intronic splicing silencer N1 (ISS-N1) located within Survival Motor Neuron 2 (SMN2) intron 7 is the target of a therapeutic antisense oligonucleotide (ASO), nusinersen (Spinraza), which is currently being used for the treatment of spinal muscular atrophy (SMA), a leading genetic [...] Read more.
Intronic splicing silencer N1 (ISS-N1) located within Survival Motor Neuron 2 (SMN2) intron 7 is the target of a therapeutic antisense oligonucleotide (ASO), nusinersen (Spinraza), which is currently being used for the treatment of spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. The discovery of ISS-N1 as a promising therapeutic target was enabled in part by Anti-N1, a 20-mer ASO that restored SMN2 exon 7 inclusion by annealing to ISS-N1. Here, we analyzed the transcriptome of SMA patient cells treated with 100 nM of Anti-N1 for 30 h. Such concentrations are routinely used to demonstrate the efficacy of an ASO. While 100 nM of Anti-N1 substantially stimulated SMN2 exon 7 inclusion, it also caused massive perturbations in the transcriptome and triggered widespread aberrant splicing, affecting expression of essential genes associated with multiple cellular processes such as transcription, splicing, translation, cell signaling, cell cycle, macromolecular trafficking, cytoskeletal dynamics, and innate immunity. We validated our findings with quantitative and semiquantitative PCR of 39 candidate genes associated with diverse pathways. We also showed a substantial reduction in off-target effects with shorter ISS-N1-targeting ASOs. Our findings are significant for implementing better ASO design and dosing regimens of ASO-based drugs. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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13 pages, 3573 KiB  
Article
Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)
by Zhihua Feng, Steven Lam, Elena-Marie Sandino Tenn, Arundhati Sengupta Ghosh, Sarah Cantor, Wei Zhang, Pei-Fen Yen, Karen S. Chen, Steven Burden, Sergey Paushkin, Gai Ayalon and Chien-Ping Ko
Int. J. Mol. Sci. 2021, 22(15), 8015; https://doi.org/10.3390/ijms22158015 - 27 Jul 2021
Cited by 12 | Viewed by 3821
Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of [...] Read more.
Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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Review

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22 pages, 1571 KiB  
Review
Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development
by Matthew E. R. Butchbach
Int. J. Mol. Sci. 2021, 22(15), 7896; https://doi.org/10.3390/ijms22157896 - 23 Jul 2021
Cited by 46 | Viewed by 11663
Abstract
Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but [...] Read more.
Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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29 pages, 1279 KiB  
Review
Metabolic Dysfunction in Spinal Muscular Atrophy
by Marc-Olivier Deguise, Lucia Chehade and Rashmi Kothary
Int. J. Mol. Sci. 2021, 22(11), 5913; https://doi.org/10.3390/ijms22115913 - 31 May 2021
Cited by 24 | Viewed by 6577
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once [...] Read more.
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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Other

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24 pages, 1734 KiB  
Perspective
What Genetics Has Told Us and How It Can Inform Future Experiments for Spinal Muscular Atrophy, a Perspective
by Anton J. Blatnik III, Vicki L. McGovern and Arthur H. M. Burghes
Int. J. Mol. Sci. 2021, 22(16), 8494; https://doi.org/10.3390/ijms22168494 - 6 Aug 2021
Cited by 8 | Viewed by 4443
Abstract
Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential survival motor neuron (SMN) protein, canonically responsible for the assembly of the spliceosomal [...] Read more.
Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential survival motor neuron (SMN) protein, canonically responsible for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed at increasing SMN protein levels are efficacious in treating SMA. However, it remains unknown how deficiency of SMN results in motor neuron loss, resulting in many reported cellular functions of SMN and pathways affected in SMA. Herein is a perspective detailing what genetics and biochemistry have told us about SMA and SMN, from identifying the SMA determinant region of the genome, to the development of therapeutics. Furthermore, we will discuss how genetics and biochemistry have been used to understand SMN function and how we can determine which of these are critical to SMA moving forward. Full article
(This article belongs to the Special Issue Genetics of Spinal Muscular Atrophy)
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