Spinal Muscular Atrophy (SMA)


Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disease characterized by loss of alpha motor neurons, which results in muscle atrophy and weakness.1,2 Nearly 95% of SMA cases result from homozygous deletions in the survival motor neuron 1 (SMN1) gene.2  Point mutations of SMN1 also can occur3 and are responsible for SMA development. The SMN1 gene encodes for the survival motor neuron (SMN) protein.4 The abnormalities observed in SMN1 gene, either deletions or mutations, result in a decreased expression of the fully functional SMN protein.

Mutations in genes other than SMN1 can also be regarded as causing SMA.5  In fact, more than 10 pathogenic variants have been identified as potentially responsible for leading to SMA.6  

SMN1 and SMN2 Genes

Two SMN genes expressing SMN protein were identified in humans in 1995.5 The SMN1 gene is the telomeric form composed of 9 exons, and the SMN2 gene is the centromeric homologous gene; both are located in a genomic unstable region1,7 on chromosome 5q. SMN1 and SMN2 genes differ in 5 nucleotides,8 with one of these differences being a nucleotide located in the coding region for the SMN protein.9 C in exon 7 of SMN1 is substituted by T in SMN2 gene,7 and as the region encoded by exon 7 is a key player in protein function, as this single base change is consequently sufficient to perturb mRNA splicing.9

In SMN1, splicing results in a full-length mRNA that will lead to a functional protein.10 In contrast, exon 7 is skipped from SMN2 mRNA production.10 An unstable and truncated form of the SMN protein is then formed — SMNΔ7.2. This protein is easily and quickly degraded by cells and is also less efficient intracellularly. The molecular mechanism leading to this shortened version of the SMN protein represents the molecular basis that contributed to the development of drugs capable of upregulating SMN cellular levels, such as nusinersen.11

The SMN2 gene has no relevance in healthy individuals, but does have clinical significance in SMA patients since it is solely responsible for SMN protein production in these patients. Nearly 10% of the SMN protein expressed via SMN2 is fully active.12 This means that a high copy number of SMN2 might partially compensate for the lack of SMN protein production21 and ease the severity of the disease. SMA patients carry at least one SMN2 copy, with this number of copies being variable among the SMA types. Milder SMA phenotypes have been associated with a greater number of SMN2 copies,2,5 however, this correlation is not absolute and other factors might be contributing to the disease severity.13

Other genetic independent modifiers have also been deemed responsible for the SMA phenotypic diversity, particularly when patients present the same SMN2 copy number. These include plastin-3 and neurocalcin delta.15 A complete absence of SMN protein is lethal for patients.16

SMN Protein as SMA Cause

The SMN protein is a highly conserved polypeptide with 294 amino acid residues and 32kDa.10,17 This protein is ubiquitously expressed in multimeric complexes in the cytoplasm and nucleus of eukaryotic cells.18,19 SMN protein is involved in diversified physiological activities, interacting with small nuclear ribonucleoproteins (snRNP) and forming multiprotein complexes with impact on transcription, translation, and mRNA metabolism.18,20 A functional SMN protein self-associates into the SMN complex while an unstable protein self-associates in a lower extent. The result is a low level of the fully functional SMN complex21 and consequent defects in many cellular pathways and events such as splicing of genes. This molecular mechanism has been depicted as causative of SMA disease.22,23

SMN protein also plays a vital role in the survival of lower motor neurons of the spinal cord, especially in early stages of development. It has been shown that the level of SMN protein in the spinal cord of humans declines from during the fetal period to 3 months after birth.2 Reduced levels of SMN protein lead to motor neuron death and consequently motor dysfunction.1 SMN protein is a key element in the transport of mRNA in neurons. Low levels of this protein would compromise mRNA transport and facilitate SMA development.2 

Additionally, other effects have been observed at the synapse, dendrite, and neuromuscular junction (NMJ) level. While splicing changes translate to effects in later stages of the disease, other studies correlate morphological and functional changes on the NMJ with a negative impact on muscle development and enervation in earlier SMA pathogenesis.26,27

The lack of SMN protein is also shown to affect different organs, such as the heart, pancreas, and liver.25,26 These observations have raised the possibility of envisioning SMA as a multisystemic disease.20,27,28

Reviewed by Michael Sapko, MD on 7/1/2021

References

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2. Schorling DC, Pechmann A, Kirschner J. Advances in treatment of spinal muscular atrophy – new phenotypes, new challenges, new implications for care. J Neuromuscul Dis. 2020;7(1):1-13. doi:10.3233/JND-190424 

3. Hahnen E, Forkert R, Marke C, et al. Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum Mol Genet. 1995;4:1927-33. doi:10.1093/hmg/4.10.1927 

4. Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. 2004. Expert Rev Mol Diagn. 2004;4(1):15-29. doi:10.1586/14737159.4.1.15

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8. Seo J, Singh NN, Ottesen EW, Lee BM, Singh RN. A novel human-specific splice isoform alters the critical c-terminus of survival motor neuron protein. Sci Rep. 2016;6:30778. doi:10.1038/srep30778 

9. Wirth B, Karakaya M, Kye MJ, et al. Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next. Annu Rev Genomics Hum Genet. 2020;21:231-261. doi:10.1146/annurev-genom-102319-103602

10. Groen EJN, Talbot K, Gillingwater TH. Advances in therapy for spinal muscular atrophy: promises and challenges. Nat Rev Neurol. 2018;14(4):214-224. doi:10.1038/nrneurol.2018.4 

11. Singh NN, Howell MD, Androphy EJ, Singh RN. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 2017;24(9):520-526. doi:10.1038/gt.2017.34

12. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 1999;96(11):6307-6311. doi:10.1073/pnas.96.11.6307 

13. Jędrzejowska M, Milewski M, Zimowski J, et. al. Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease. Acta Biochim Pol. 2009;56(1):103-108. doi:10.18388/abp.2009_2521

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16. Monani UR, Sendtner M, Coovert DD, et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet. 2000;12;9(3):333-339. doi:10.1093/hmg/9.3.333 

17. d’Ydewalle C, Sumner CJ. Spinal muscular atrophy therapeutics: where do we stand? Neurotherapeutics. 2015;12(2):303-316. doi:10.1007/s13311-015-0337-y

18. Giavazzi A, Setola V, Simonati A, Battaglia G. Neuronal-specific roles of the survival motor neuron protein: evidence from survival motor neuron expression patterns in the developing human central nervous system. J Neuropathol Exp Neurol. 2006;65(3):267-277. doi:10.1097/01.jnen.0000205144.54457.a3

19. Burghes AHM, Beattie CE. Spinal muscular atrophy: why do low levels of SMN make motor neurons sick? Nat Rev Neurosci. 2009;10(8):597-609. doi:10.1038/nrn2670

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21. Vitte J, Fassier C, et al. Refined characterization of the expression and stability of the SMN gene products. Am J Pathol. 2007;171(4):1269-1280. doi:10.2353/ajpath.2007.070399

22. Eggert C, Chari A, Laggerbauer B, Fischer U. Spinal muscular atrophy: the RNP connection. Trends Mol Med. 2006;12(3):113-121. doi:10.1016/j.molmed.2006.01.005

23. Gabanella F, Butchbach MER, Saieva L, Carissimi C, Burghes AHM, Pellizzoni L. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One. 2007;2(9):e921. doi:10.1371/journal.pone.0000921

24. Ramos DM, d’Ydewalle C, Gabbeta V, et al. Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment. J Clin Invest. 2019;129(11):4817-4831. doi:10.1172/JCI124120 

25. McWhorter ML, Monani UR, Burghes AHM, Beattie CE. Knockdown of the survival motor neuron (smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J Cell Biol. 2003;162(5):919-931. doi:10.1083/jcb.200303168

26. Ling KK, Gibbs RM, Feng Z, Ko CP. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Hum Mol Genet. 2012;21(1):185-195. doi:10.1093/hmg/ddr453

27. Kariya S, Park GH, Maeno-Hikichi Y, et al. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet. 2008;17(16):2552-2569. doi:10.1093/hmg/ddn156

28. Hamilton G, Gillingwater TH. Spinal muscular atrophy: going beyond the motor. J Neurosci. 2013;19(1):40-50. doi:10.1016/j.molmed.2012.11.002

29. Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2014;224(1):15-28. doi:10.1111/joa.12083

30. Bottai D, Adami R. Spinal muscular atrophy: new findings for an old pathology. Brain Pathol. 2013;23(6):613-622. doi:10.1111/bpa.12071. 31. Yeo CJJ, Darras, BT. Overturning the paradigm of spinal muscular atrophy as just a motor neuron disease.Pediatr Neurol. 2020;109:12-19. doi:10.1016/j.pediatrneurol.2020.01.003.

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