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Gene Review

SMN2  -  survival of motor neuron 2, centromeric

Homo sapiens

Synonyms: BCD541, C-BCD541, GEMIN1, SMNC, TDRD16B
 
 
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Disease relevance of SMN2

  • Common to all patients with spinal muscular atrophy (SMA) is a functional loss of SMN1 protein due to homozygous deletion, gene conversion or mutation of the SMN1 gene but all patients retain at least one SMN2 copy [1]
  • SMN2 is the major modifier of disease severity of spinal muscular atrophy (SMA). There is a strong inverse correlation between the SMN2 copy number and disease severity. Most type I SMA patients (severe form) have two SMN2 copies whereas patients with type II SMA (intermediate form) and type III SMA (mild form) have three to four SMN2 copies [2].
  • Patients with type IV SMA (adult form) carry four to six SMN2 copies [3].
  • A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy [4].
  • Each SMN2 gene produces only about 10% correctly spliced transcripts whereas 90% lack exon 7. The full-length SMN2 transcripts produces a protein identical to SMN1 [1]
  • Since VPA is a drug highly successfully used in long-term epilepsy therapy, our findings open the exciting perspective for a first causal therapy of an inherited disease by elevating the SMN2 transcription level and restoring its correct splicing [5].
  • We have exploited the existence of a second copy of the human SMN gene (SMN2) to develop a high-throughput screening strategy to identify potential small molecule therapeutics for the genetic disease spinal muscular atrophy (SMA), which is caused by the loss of the SMN1 gene [6].
  • This result suggests that SMN2 deletions could act as a susceptibility factor for sporadic lower motor neuron disease in adults [7].
  • Significant increase in the number of the SMN2 gene copies in an adult-onset Type III spinal muscular atrophy patient with homozygous deletion of the NAIP gene [8].
 

High impact information on SMN2

  • Here we show that the C/T transition functions not to disrupt an exonic splicing enhancer (ESE) in SMN1 (ref. 4), as previously suggested, but rather to create an exonic splicing silencer (ESS) in SMN2 [4].
  • Spinal muscular atrophy results from the lack of functional survival of motor neuron 1 gene (SMN1), even though all affected individuals carry a nearly identical, normal SMN2 gene [9].
  • Our findings explain the basis of defective SMN2 splicing, illustrate the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscore the importance of antagonistic splicing factors and exonic elements in a disease context [10].
  • Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts [11].
  • This discrepancy is because of a single nucleotide difference in SMN2 exon 7, which disrupts an exonic splicing enhancer containing an SF2ASF binding site [11].
 

Chemical compound and disease context of SMN2

 

Biological context of SMN2

  • We show that this ESS functions as a binding site for a known repressor protein, hnRNP A1, which binds to SMN2 but not SMN1 exon 7 RNA [4].
  • Denervation was assessed in 89 spinal muscular atrophy (SMA) 1, 2, and 3 subjects via motor unit number estimation (MUNE) and maximum compound motor action potential amplitude (CMAP) studies, and results correlated with SMN2 copy, age, and function [16].
  • Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information [17].
  • Taken together with our previous data, we may reasonably hypothesize that the SMN2 gene copy number is more critical in determining the severity of the disease compared to the NAIP genotype [8].
  • The two genes undergo alternative splicing with SMN1, producing an abundance of full-length mRNA transcripts, whereas SMN2 predominantly produces exon 7-deleted transcripts [11].
 

Anatomical context of SMN2

  • Homozygous absence of the survival motor neuron gene (SMN1) is the primary cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies [5].
  • We show that in fibroblast cultures derived from SMA patients treated with therapeutic doses (0.5-500 microM) of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold [5].
  • Exon 8 of SMN2 was amplified in 96% of both normal and SMA-affected leukocytes [18].
  • We report that sodium butyrate effectively increases the amount of exon 7-containing SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene [19].
  • Combined treatment with dibutyryl cAMP and forskolin significantly increased the level of both the full-length and exon 7-deleted SMN (exonDelta7SMN) transcript in primary hepatocytes from mice expressing two copies of human SMN2 gene [20].
 

Associations of SMN2 with chemical compounds

 

Physical interactions of SMN2

  • The SR-like trans-acting splicing factor Htra2-beta1 was shown to interact with this ESE and to restore full-length SMN2 expression in vivo in a concentration-dependent manner [23].
 

Regulatory relationships of SMN2

  • RT-PCR studies of SMN transcripts in control and patients with the same SMN2 copy number showed that the full-length/Delta7 ratio is influenced by the SMN1 genotype although it seems independent of the SMN2 copy number [24].
  • Together our results provide strong support for the idea that SMN2 exon 7 splicing is repressed by an hnRNPA1-dependent ESS, but also indicate that creation of such elements is context-dependent [25].
 

Other interactions of SMN2

  • A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2 [26].
  • The SR-like splicing factor Htra2-beta1 facilitates correct splicing of SMN2 exon 7 through direct interaction with an exonic splicing enhancer within exon 7 [27].
  • Analysis of polymerase chain reaction-restriction fragment length polymorphism as well as single-strand conformation polymorphism on exons 7 and 8 of the SMN genes revealed the SMN2-deletion [28].
  • Htra2-beta 1 (SFRS10) stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2) [29].
  • Here we show that such synthetic effectors can mimic the functions of SR proteins and specifically restore wild type splicing when directed to defective BRCA1 or SMN2 pre-mRNA transcripts [30].
 

Analytical, diagnostic and therapeutic context of SMN2

 

References

  1. Identification and characterization of a spinal muscular atrophy-determining gene. Lefebvre, S., Bürglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M. Cell. (1995) [Pubmed]
  2. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Feldkötter, M., Schwarzer, V., Wirth, R., Wienker, T.F., Wirth, B. Am. J. Hum. Genet. (2002) [Pubmed]
  3. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Wirth, B., Brichta, L., Schrank, B., Lochmüller, H., Blick, S., Baasner, A., Heller, R. Hum. Genet. (2006) [Pubmed]
  4. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Kashima, T., Manley, J.L. Nat. Genet. (2003) [Pubmed]
  5. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F.A., Raschke, H., Blumcke, I., Eyupoglu, I.Y., Wirth, B. Hum. Mol. Genet. (2003) [Pubmed]
  6. Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy. Jarecki, J., Chen, X., Bernardino, A., Coovert, D.D., Whitney, M., Burghes, A., Stack, J., Pollok, B.A. Hum. Mol. Genet. (2005) [Pubmed]
  7. Homozygous exon 7 deletion of the SMN centromeric gene (SMN2): a potential susceptibility factor for adult-onset lower motor neuron disease. Echaniz-Laguna, A., Guiraud-Chaumeil, C., Tranchant, C., Reeber, A., Melki, J., Warter, J.M. J. Neurol. (2002) [Pubmed]
  8. Significant increase in the number of the SMN2 gene copies in an adult-onset Type III spinal muscular atrophy patient with homozygous deletion of the NAIP gene. Yamashita, M., Nishio, H., Harada, Y., Matsuo, M., Yamamoto, T. Eur. Neurol. (2004) [Pubmed]
  9. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Cartegni, L., Krainer, A.R. Nat. Genet. (2002) [Pubmed]
  10. Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Cartegni, L., Hastings, M.L., Calarco, J.A., de Stanchina, E., Krainer, A.R. Am. J. Hum. Genet. (2006) [Pubmed]
  11. Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Skordis, L.A., Dunckley, M.G., Yue, B., Eperon, I.C., Muntoni, F. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Grzeschik, S.M., Ganta, M., Prior, T.W., Heavlin, W.D., Wang, C.H. Ann. Neurol. (2005) [Pubmed]
  13. The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Riessland, M., Brichta, L., Hahnen, E., Wirth, B. Hum. Genet. (2006) [Pubmed]
  14. LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate. Garbes, L., Riessland, M., Hölker, I., Heller, R., Hauke, J., Tränkle, C., Coras, R., Blümcke, I., Hahnen, E., Wirth, B. Hum. Mol. Genet. (2009) [Pubmed]
  15. SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy. Riessland, M., Ackermann, B., Förster, A., Jakubik, M., Hauke, J., Garbes, L., Fritzsche, I., Mende, Y., Blumcke, I., Hahnen, E., Wirth, B. Hum. Mol. Genet. (2010) [Pubmed]
  16. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Swoboda, K.J., Prior, T.W., Scott, C.B., McNaught, T.P., Wride, M.C., Reyna, S.P., Bromberg, M.B. Ann. Neurol. (2005) [Pubmed]
  17. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Mailman, M.D., Heinz, J.W., Papp, A.C., Snyder, P.J., Sedra, M.S., Wirth, B., Burghes, A.H., Prior, T.W. Genet. Med. (2002) [Pubmed]
  18. Multiplex nested PCR for preimplantation genetic diagnosis of spinal muscular atrophy. Malcov, M., Schwartz, T., Mei-Raz, N., Yosef, D.B., Amit, A., Lessing, J.B., Shomrat, R., Orr-Urtreger, A., Yaron, Y. Fetal. Diagn. Ther. (2004) [Pubmed]
  19. Treatment of spinal muscular atrophy by sodium butyrate. Chang, J.G., Hsieh-Li, H.M., Jong, Y.J., Wang, N.M., Tsai, C.H., Li, H. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  20. 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. Majumder, S., Varadharaj, S., Ghoshal, K., Monani, U., Burghes, A.H., Jacob, S.T. J. Biol. Chem. (2004) [Pubmed]
  21. Stat5 constitutive activation rescues defects in spinal muscular atrophy. Ting, C.H., Lin, C.W., Wen, S.L., Hsieh-Li, H.M., Li, H. Hum. Mol. Genet. (2007) [Pubmed]
  22. Spinal muscular atrophy: state-of-the-art and therapeutic perspectives. Wirth, B. Amyotroph. Lateral Scler. Other Motor Neuron Disord. (2002) [Pubmed]
  23. Exclusion of Htra2-beta1, an up-regulator of full-length SMN2 transcript, as a modifying gene for spinal muscular atrophy. Helmken, C., Wirth, B. Hum. Genet. (2000) [Pubmed]
  24. A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene. Cuscó, I., López, E., Soler-Botija, C., Jesús Barceló, M., Baiget, M., Tizzano, E.F. Hum. Mutat. (2003) [Pubmed]
  25. hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Kashima, T., Rao, N., David, C.J., Manley, J.L. Hum. Mol. Genet. (2007) [Pubmed]
  26. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Monani, U.R., Lorson, C.L., Parsons, D.W., Prior, T.W., Androphy, E.J., Burghes, A.H., McPherson, J.D. Hum. Mol. Genet. (1999) [Pubmed]
  27. Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1. Helmken, C., Hofmann, Y., Schoenen, F., Oprea, G., Raschke, H., Rudnik-Schöneborn, S., Zerres, K., Wirth, B. Hum. Genet. (2003) [Pubmed]
  28. SMN2-deletion in childhood-onset spinal muscular atrophy. Srivastava, S., Mukherjee, M., Panigrahi, I., Shanker Pandey, G., Pradhan, S., Mittal, B. Am. J. Med. Genet. (2001) [Pubmed]
  29. Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Hofmann, Y., Lorson, C.L., Stamm, S., Androphy, E.J., Wirth, B. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  30. Correction of disease-associated exon skipping by synthetic exon-specific activators. Cartegni, L., Krainer, A.R. Nat. Struct. Biol. (2003) [Pubmed]
  31. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Feldkötter, M., Schwarzer, V., Wirth, R., Wienker, T.F., Wirth, B. Am. J. Hum. Genet. (2002) [Pubmed]
  32. New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations. Ogino, S., Wilson, R.B., Gold, B. Eur. J. Hum. Genet. (2004) [Pubmed]
 
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