Factors modifying the course of spinal muscular atrophy 5q

Cover Page

Cite item

Full Text

Abstract

Proximal spinal muscular atrophy 5q (SMA 5q) is a severe autosomal recessive neuromuscular disease characterized by progressive symptoms of flaccid paralysis and muscular atrophy due to degeneration of α-motor neurons of the anterior horns of the spinal cord. To date, the main modifying factor of spinal muscular atrophy is considered to be the number of copies of the SMN2 gene. However, a sufficient number of other genetic and non-genetic modifiers of the course of SMA have been described.
Advanced neonatal screening, which started in the Russian Federation in 2023, allows detecting SMA 5q before the onset of clinical manifestations. However, to start therapy and select the right drug, it is important to know not only the main modifying factor (the number of copies of SMN2), but also other genetic causes that may affect the age of the disease manifestation or the effectiveness of therapy.

About the authors

M. A. Akhkiamova

Research Centre for Medical Genetics

Author for correspondence.
Email: albmasha@gmail.com
ORCID iD: 0000-0002-7244-9654

1 Moskvorechye St., Moscow 115522

Russian Federation

O. A. Shchagina

Research Centre for Medical Genetics

Email: fake@neicon.ru
ORCID iD: 0000-0003-4905-1303

1 Moskvorechye St., Moscow 115522

Russian Federation

A. V. Polyakov

Research Centre for Medical Genetics

Email: fake@neicon.ru
ORCID iD: 0000-0002-0105-1833

Moskvorechye St., Moscow 115522

Russian Federation

References

  1. Tisdale S., Pellizzoni L. Disease mechanisms and therapeutic approaches in spinal muscular atrophy. J Neurosci 2015;35(23):8691–700. doi: 10.1523/JNEUROSCI.0417-15.2015
  2. Ogino S., Leonard D.G., Rennert H. et al. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet 2002;110:301–7. doi: 10.1002/ajmg.10425
  3. Prior T.W., Snyder P.J., Rink B.D. et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A 2010; 152A:1605–7. doi: 10.1002/ajmg.a.33474
  4. Zabnenkova V.V., Dadali E.L., Spiridonova M.G. et al. Spinal muscular atrophy carrier frequency in Russian Federation. ASHG 2016;2476. doi: 10.13140/RG.2.2.16245.60642
  5. Sugarman E.A., Nagan N., Zhu H. et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72400 specimens. Eur J Hum Genet 2012;20:27–32. doi: 10.1038/ejhg.2011.134
  6. Chaytow H., Huang YT., Gillingwater T.H., Faller K.M.E. The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci 2018;75:3877–94. doi: 10.1007/s00018-018-2849-1
  7. Singh R.N., Howell M.D., Ottesen E.W. Singh N.N. Diverse role of survival motor neuron protein. Biochim Biophys Acta 2017;1860(3):299–315. doi: 10.1016/j.bbagrm.2016.12.008
  8. Lefebvre S., Bürglen,L., Reboullet S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80(1):155–65. doi: 10.1016/0092-8674(95)90460-3
  9. Butchbach M.E.R. Genomic variability in the survival motor neuron genes (SMN1 and SMN2): Implications for spinal muscular atrophy phenotype and therapeutics development. Int J Mol Sci 2021;22(15):7896. doi: 10.3390/ijms22157896
  10. Ogino S., Wilson R.B. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn 2004;4(1):15–29. doi: 10.1586/14737159.4.1.15
  11. Ruhno C., McGovern V.L., Avenarius M.R. et al. Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Hum Gen 2019;138(3):241–56. doi: 10.1007/s00439-019-01983-0
  12. Dil A.V., Nazarov V.D., Sidorenko D.V. et al. Characteristics of genetic changes in the SMN1 gene in spinal muscular atrophy 5q. Nervno-myshechnye bolezni = Neuromuscular Diseases 2022;12(3): 36–44. (In Russ.). doi: 10.17650/22228721-2022-12-3-36-44
  13. Wu X., Wang S.H., Sun J. et al. A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum Mol Genet 2017;26(14):2768–80. doi: 10.1093/hmg/ddx166
  14. Wirth B., Herz M., Wetter A. et al. Quantitative analysis of survival motor neuron copies: Identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation and implications for genetic counseling. Am J Hum Gene 1999;64(5):1340–56. doi: 10.1086/302369
  15. Jedličková I., Přistoupilová A., Nosková L. et al. Spinal muscular atrophy caused by a novel Alu-mediated deletion of exons 2a–5 in SMN1 undetectable with routine genetic testing. Mol Genet Genomic Med 2020;8(7):8(7):e1238. doi: 10.1002/mgg3.1238
  16. Thauvin-Robinet C., Drunat S., Saugier Veber P. et al. Homozygous SMN1 exons 1–6 deletion: Pitfalls in genetic counseling and general recommendations for spinal muscular atrophy molecular diagnosis. Am J Med Genet 2012;158A(7):1735–41. doi: 10.1002/ajmg.a.35402
  17. Gambardella A., Mazzei R., Toscano A. et al. Spinal muscular atrophy due to an isolated deletion of exon 8 of the telomeric survival motor neuron gene. Ann Neurol 1998;44(5):836–9. doi: 10.1002/ana.410440522
  18. Mercer J.M. Unequal crossing over. Ref Mod Life Sci 2017. doi: 10.1016/B978-0-12-809633-8.07324-6
  19. Wirth B., Brichta L., Schrank B. et al. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet 2006;119(4):422–8. doi: 10.1007/s00439-006-0156-7
  20. Crawford T.O., Paushkin S., Kobayashi D.T. et al. Evaluation of SMN protein, transcript and copy number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLoS One 2012;7(4):33572. doi: 10.1371/journal.pone.0033572
  21. Zhang Y., He J., Zhang Y. et al. The analysis of the association between the copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein genes and the clinical phenotypes in 40 patients with spinal muscular atrophy. Observational study. Medicine 2020;99(3):e18809. doi: 10.1097/MD.0000000000018809
  22. Calucho M., Bernal S., Alías L. et al. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord 2018;28(3):208–15. doi: 10.1016/j.nmd.2018.01.003
  23. Wirth B., Mendoza-Ferreira N., Torres-Benito L. Spinal muscular atrophy disease modifiers. Spinal Muscular Atrophy Disease Mechanisms and Therapy 2020:191–210. doi: 10.1016/B978-0-12-803685-3.00012-4
  24. Wadman R., Jansen M., Stam M. et al. Intragenic and structural variation in the SMN locus and clinical variability in spinal muscular atrophy. Brain Communications 2020;2(2):fcaa075. doi: 10.1093/braincomms/fcaa075
  25. Prior T.W., Krainer A.R., Hua, Y. et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009;85(3):408–13. doi: 10.1016/j.ajhg.2009.08.002
  26. Vezain M., Saukkonen A.M., Goina, E. et al. A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. Hum Mutat 2010;31(1):1110–E1125. doi: 10.1002/humu.21173
  27. Bernal S., Alías L., Barceló M.J. et al. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J Med Genet 2010;47(9):640–2. doi: 10.1136/jmg.2010.079004
  28. Blasco-Pérez L., Costa-Roger M., Leno-Colorado J. Deep molecular characterization of milder spinal muscular atrophy patients carrying the c.859G>C variant in SMN2. Int J Mol Sci 2022;23(15):82–9. doi: 10.3390/ijms23158289
  29. Qu Y.-J.., Bai J.-L., Cao Y.-Y. et al. A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy. Eur J Hum Gen 2016;24(6):864–70. doi: 10.1038/ejhg.2015.213
  30. Garbes L., Riessland M., Wirth B. Histone acetylation as a potential therapeutic target in motor neuron degenerative diseases. Curr Pharm Des 2013;19(28):5094–104. doi: 10.2174/13816128113199990356
  31. Nasim M., Chernova T.K., Chowdhury H.M. et al. HnRNP G and Tra2β: opposite effects on splicing matched by antagonism in RNA binding, Hum Mol Gen 2003;12(11):1337–48. doi: 10.1093/hmg/ddg136
  32. Kashima T., Rao N., David C.J., Manley J.L. hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing, Hum Mol Gen 2007;16(24):3149–59. doi: 10.1093/hmg/ddm276
  33. Majumder S., Varadharaj S., Ghoshal K. et al. Identification of a novel cyclic AMP-response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene. J Biol Chem 2004;279(15):14803–11. doi: 10.1074/jbc.M308225200
  34. Baron-Delage S., Abadie A., Echaniz-Laguna A. et al. Interferons and IRF-1 induce expression of the survival motor neuron (SMN) genes. Mol Med 2000;6(11):957–68.
  35. Ting C.H., Lin C.W., Wen S.L. et al. Stat5 constitutive activation rescues defects in spinal muscular atrophy. Hum Mol Genet 2007;16(5):499–514. doi: 10.1093/hmg/ddl482
  36. Markham K., Schuurmans C., Weiss S. STAT5A/B activity is required in the developing forebrain and spinal cord. Mol Cell Neurosci 2007;35(2):272–82. doi: 10.1016/j.mcn.2007.03.001
  37. Workman E., Veith A., Battle D.J. U1A regulates 3 processing of the survival motor neuron mRNA. J Biol Chem 2014;289(6):3703–12. doi: 10.1074/jbc.M113.538264
  38. Kaida D., Berg M.G., Younis I. et al. U1 snRNP protects premRNAs from premature cleavage and polyadenylation. Nature 2010;468(7324):664–8. doi: 10.1038/nature09479
  39. Farooq F., Balabanian S., Liu X. et al. Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum Mol Genet 2009;18(21):4035–45. doi: 10.1093/hmg/ddp352
  40. Burnett B.G., Munoz E., Tandon A. et al. Regulation of SMN protein stability. Mol Cell Biol 2009; 29(5):1107–15. doi: 10.1128/MCB.01262-08
  41. Makhortova N.R., Hayhurst M., Cerqueira A. et al. A screen for regulators of survival of motor neuron protein levels. Nat Chem Biol Nat Chem Biol 2011;7(8):544–52. doi: 10.1038/nchembio.595
  42. Chen P.C., Gaisina I.N., El-Khodor B.F. et al. Identification of a maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitor, BIP-135, that prolongs the median survival time of Δ7 SMA KO mouse model of spinal muscular atrophy. ACS Chem Neurosci 2012;3(1):5–11. doi: 10.1021/cn200085z
  43. Sahashi K. Hua Y. Ling K.K. et al. TSUNAMI: an antisense method to phenocopy splicing-associated diseases in animals. Genes Dev 2012;26(16):1874–84. doi: 10.1101/gad.197418.112
  44. Bebee T.W., Dominguez C.E., Samadzadeh-Tarighat S. et al. Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model. Hum Mol Genet 2012;21(19):4301–13. doi: 10.1093/hmg/dds263
  45. Zhang Z., Lotti F., Dittmar K. et al. SMN deficiency causes tissue specific perturbations in the repertoire of snRNAs and wide spread defects in splicing. Cell 2008;133(4):585–600. DOI: 10.1016/j. cell.2008.03.031
  46. Wan L., Ottinger E., Cho S., Dreyfuss G. Inactivation of the SMN complex by oxidative stress. Mol Cell 2008;31(2):244–54. DOI: 0.1016/j.molcel.2008.06.004
  47. Hosseinibarkooie S., Peters M. Torres-Benitо L. The Power of human protective modifiers: PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype. Am J Hum Genet 2016;99(3):647–65. doi: 10.1016/j.ajhg.2016.07.014
  48. Oprea G.E., Krober S., McWhorter M.L. et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008;320(5875):524–7. doi: 10.1126/science.1155085
  49. Dimitriadi M., Sleigh J.N., Walker A. et al. Conserved genes act as modifiers of invertebrate SMN loss of function defects. PLoS Genet 2010;6(10): e1001172. doi: 10.1371/journal.pgen.1001172
  50. Hao L.T., Wolman M., Granato M., Beattie C.E. Survival motor neuron affects plastin 3 protein levels leading to motor defects. J Neurosci 2012;32(15):5074–84. doi: 10.1523/JNEUROSCI.5808-11.2012
  51. Kremerskothen J., Plaas C., Kindler S. et al. Synaptopodin, a molecule involved in the formation of the dendritic spine apparatus, is a dual actin/alpha-actinin binding protein. J Neurochem 2005;92(3):597–606. doi: 10.1111/j.1471-4159.2004.02888.x
  52. Schulz T.W., Nakagawa T., Licznerski P. et al. Actin/alpha actinindependent transport of AMPA receptors in dendritic spines: role of the PDZ-LIM protein RIL. J Neurosci 2004;24(39):8584–94. doi: 10.1523/JNEUROSCI.2100-04.2004
  53. Dobbins G.C., Luo S., Yang Z. et al. Alpha-actinin interacts with rapsyn in agrin-stimulated AChR clustering. Mol Brain 2008;1:18. doi: 10.1186/1756-6606-1-18
  54. Hall D.D., Dai S., Tseng P.Y. et al. Competition between α-actinin and Ca2+-calmodulin controls surface retention of the L-type Ca2+ channel CaV1.2. Neuron 2013;78(3):483–97. doi: 10.1016/j.neuron.2013.02.032
  55. Torres-Benito L., Schneider S., Rombo R., Ling K.K. NCALD antisense oligonucleotide therapy in addition to nusinersen further ameliorates spinal muscular atrophy in mice. Am J Hum Genet 2019;105(1):221–30. doi: 10.1016/j.ajhg.2019.05.008
  56. Janzen E., Mendoza-Ferreira N., Hosseinibarkooie S. et al. CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis. Brain. 2018;141(8):2343–61. doi: 10.1093/brain/awy167
  57. Zheleznyakova Yu.G., Nilsson E.K., Kiselev A.V. et al. Methylation levels of SLC23A2 and NCOR2 genes correlate with spinal muscular atrophy severity. PLoS One 2015;10(3): e0121964. doi: 10.1371/journal.pone.0121964
  58. Maretina M., Egorova A., Baranov V., Kiselev A. DYNC1H1 gene methylation correlates with severity of spinal muscular atrophy. Ann Hum Genet 2019;83(2):73–81. doi: 10.1111/ahg.12288
  59. Zhuri D., Gurkan H., Eker D. et al. Investigation on the effects of modifying genes on the spinal muscular atrophy phenotype. Glob Med Genet 2022; 9(3):226–36. doi: 10.1055/s-0042-1751302
  60. Karasu N., Acer H., Akalin H. Molecular analysis of SMN2, NAIP and GTF2H2 gene deletions and relation with clinical subtypes of spinal muscular atrophy. 2022. doi: 10.21203/rs.3.rs-1442537/v1
  61. Jiang J., Huang J., Gu J. et al. Genomic analysis of a spinal muscular atrophy (SMA) discordant family identifies a novel mutation in TLL2, an activator of growth differentiation factor 8 (myostatin): a case report. BMC Med Genet 2019;20. doi: 10.1186/s12881-019-0935-3
  62. Bharucha-Goebel D., Kaufmann P. Treatment advances in spinal muscular atrophy. Curr Neurol Neurosci Rep 2017;17(11):91. doi: 10.1007/s11910-017-0798-y
  63. Farooq F., Abadía-Molina F., MacKenzie D. Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation. Hum Mol Gen 2013;22(17):3415–24. doi: 10.1093/hmg/ddt191

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Akhkiamova M.A., Shchagina O.A., Polyakov A.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ЭЛ № ФС 77 - 85909 от  25.08.2023.