Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (129)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lorson, C. L.
Right arrow Articles by Androphy, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lorson, C. L.
Right arrow Articles by Androphy, E. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2000, Vol. 9, No. 2 259-265
© 2000 Oxford University Press

An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN

Christian L. Lorson1 and Elliot J. Androphy1,2,+

1Department of Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA and 2Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA

The survival motor neuron genes, SMN1 and SMN2, encode identical proteins; however, only homo- zygous loss of SMN1 correlates with the development of spinal muscular atrophy (SMA). We have previously shown that a single non-polymorphic nucleotide difference in SMN exon 7 dramatically affects SMN mRNA processing. SMN1 primarily produces a full-length RNA whereas SMN2 expresses dramatically reduced full-length RNA and abundant levels of an aberrantly spliced transcript lacking exon 7. The importance of proper exon 7 processing has been underscored by the identification of several mutations within splice sites adjacent to exon 7. Here we show that an AG-rich exonic splice enhancer (ESE) in the center of SMN exon 7 is required for inclusion of exon 7. This region functioned as an ESE in a heterologous context, supporting efficient in vitro splicing of the Drosophila double-sex gene. Finally, the protein encoded by the exon-skipping event, {Delta}7, was less stable than full-length SMN, providing additional evidence of why SMN2 fails to compensate for the loss of SMN1 and leads to the development of SMA.

+ To whom correspondence should be addressed. Tel: +1 617 636 1493; Fax: +1 617 636 6190; Email: eandroph@opal.tufts.edu


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
E. Workman, L. Saieva, T. L. Carrel, T. O. Crawford, D. Liu, C. Lutz, C. E. Beattie, L. Pellizzoni, and A. H.M. Burghes
A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice
Hum. Mol. Genet., June 15, 2009; 18(12): 2215 - 2229.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
T. D. Baughan, A. Dickson, E. Y. Osman, and C. L. Lorson
Delivery of bifunctional RNAs that target an intronic repressor and increase SMN levels in an animal model of spinal muscular atrophy
Hum. Mol. Genet., May 1, 2009; 18(9): 1600 - 1611.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
B. Renvoise, S. Colasse, P. Burlet, L. Viollet, U. T. Meier, and S. Lefebvre
The loss of the snoRNP chaperone Nopp140 from Cajal bodies of patient fibroblasts correlates with the severity of spinal muscular atrophy
Hum. Mol. Genet., April 1, 2009; 18(7): 1181 - 1189.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. R. Heier and C. J. DiDonato
Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo
Hum. Mol. Genet., April 1, 2009; 18(7): 1310 - 1322.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
B. G. Burnett, E. Munoz, A. Tandon, D. Y. Kwon, C. J. Sumner, and K. H. Fischbeck
Regulation of SMN Protein Stability
Mol. Cell. Biol., March 1, 2009; 29(5): 1107 - 1115.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
H.-H. Chen, J.-G. Chang, R.-M. Lu, T.-Y. Peng, and W.-Y. Tarn
The RNA Binding Protein hnRNP Q Modulates the Utilization of Exon 7 in the Survival Motor Neuron 2 (SMN2) Gene
Mol. Cell. Biol., November 15, 2008; 28(22): 6929 - 6938.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. K. Bose, I.-F. Wang, L. Hung, W.-Y. Tarn, and C.-K. J. Shen
TDP-43 Overexpression Enhances Exon 7 Inclusion during the Survival of Motor Neuron Pre-mRNA Splicing
J. Biol. Chem., October 24, 2008; 283(43): 28852 - 28859.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
E. Goina, N. Skoko, and F. Pagani
Binding of DAZAP1 and hnRNPA1/A2 to an Exonic Splicing Silencer in a Natural BRCA1 Exon 18 Mutant
Mol. Cell. Biol., June 1, 2008; 28(11): 3850 - 3860.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
T. O. Gavrilina, V. L. McGovern, E. Workman, T. O. Crawford, R. G. Gogliotti, C. J. DiDonato, U. R. Monani, G. E. Morris, and A. H.M. Burghes
Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect
Hum. Mol. Genet., April 15, 2008; 17(8): 1063 - 1075.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
O. Biondi, C. Grondard, S. Lecolle, S. Deforges, C. Pariset, P. Lopes, C. Cifuentes-Diaz, H. Li, B. della Gaspera, C. Chanoine, et al.
Exercise-Induced Activation of NMDA Receptor Promotes Motor Unit Development and Survival in a Type 2 Spinal Muscular Atrophy Model Mouse
J. Neurosci., January 23, 2008; 28(4): 953 - 962.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. J. Hertel
Combinatorial Control of Exon Recognition
J. Biol. Chem., January 18, 2008; 283(3): 1211 - 1215.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
R. E. Pyatt, D. C. Mihal, and T. W. Prior
Assessment of Liquid Microbead Arrays for the Screening of Newborns for Spinal Muscular Atrophy
Clin. Chem., November 1, 2007; 53(11): 1879 - 1885.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
J. Vitte, C. Fassier, F. D. Tiziano, C. Dalard, S. Soave, N. Roblot, C. Brahe, P. Saugier-Veber, J. P. Bonnefont, and J. Melki
Refined Characterization of the Expression and Stability of the SMN Gene Products
Am. J. Pathol., October 1, 2007; 171(4): 1269 - 1280.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
T. W. Prior
Spinal Muscular Atrophy Diagnostics
J Child Neurol, August 1, 2007; 22(8): 952 - 956.
[Abstract] [PDF]

Home page
 J Child NeurolHome page
C. J. Sumner
Molecular Mechanisms of Spinal Muscular Atrophy
J Child Neurol, August 1, 2007; 22(8): 979 - 989.
[Abstract] [PDF]

Home page
 J Child NeurolHome page
C. E. Beattie, T. L. Carrel, and M. L. McWhorter
Fishing for a Mechanism: Using Zebrafish to Understand Spinal Muscular Atrophy
J Child Neurol, August 1, 2007; 22(8): 995 - 1003.
[Abstract] [PDF]

Home page
 J Child NeurolHome page
C. R. Heier, R. G. Gogliotti, and C. J. DiDonato
SMN Transcript Stability: Could Modulation of Messenger RNA Degradation Provide a Novel Therapy for Spinal Muscular Atrophy?
J Child Neurol, August 1, 2007; 22(8): 1013 - 1018.
[Abstract] [PDF]

Home page
 Hum Mol GenetHome page
C.-H. Ting, C.-W. Lin, S.-L. Wen, H.-M. Hsieh-Li, and H. Li
Stat5 constitutive activation rescues defects in spinal muscular atrophy
Hum. Mol. Genet., March 1, 2007; 16(5): 499 - 514.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
T. Kashima, N. Rao, and J. L. Manley
An intronic element contributes to splicing repression in spinal muscular atrophy
PNAS, February 27, 2007; 104(9): 3426 - 3431.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. Raponi, F. E. Baralle, and F. Pagani
Reduced splicing efficiency induced by synonymous substitutions may generate a substrate for natural selection of new splicing isoforms: the case of CFTR exon 12
Nucleic Acids Res., January 28, 2007; 35(2): 606 - 613.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
T. L. Carrel, M. L. McWhorter, E. Workman, H. Zhang, E. C. Wolstencroft, C. Lorson, G. J. Bassell, A. H. M. Burghes, and C. E. Beattie
Survival Motor Neuron Function in Motor Axons Is Independent of Functions Required for Small Nuclear Ribonucleoprotein Biogenesis
J. Neurosci., October 25, 2006; 26(43): 11014 - 11022.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. J. Smith, C. Zhang, J. Wang, S. L. Chew, M. Q. Zhang, and A. R. Krainer
An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers
Hum. Mol. Genet., August 15, 2006; 15(16): 2490 - 2508.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
N. K. Singh, N. N. Singh, E. J. Androphy, and R. N. Singh
Splicing of a Critical Exon of Human Survival Motor Neuron Is Regulated by a Unique Silencer Element Located in the Last Intron
Mol. Cell. Biol., February 15, 2006; 26(4): 1333 - 1346.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
C. Winkler, C. Eggert, D. Gradl, G. Meister, M. Giegerich, D. Wedlich, B. Laggerbauer, and U. Fischer
Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy
Genes & Dev., October 1, 2005; 19(19): 2320 - 2330.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. Wang, P. J. Smith, A. R. Krainer, and M. Q. Zhang
Distribution of SR protein exonic splicing enhancer motifs in human protein-coding genes
Nucleic Acids Res., September 7, 2005; 33(16): 5053 - 5062.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. Grondard, O. Biondi, A.-S. Armand, S. Lecolle, B. D. Gaspera, C. Pariset, H. Li, C.-L. Gallien, P.-P. Vidal, C. Chanoine, et al.
Regular Exercise Prolongs Survival in a Type 2 Spinal Muscular Atrophy Model Mouse
J. Neurosci., August 17, 2005; 25(33): 7615 - 7622.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. Jarecki, X. Chen, A. Bernardino, D. D. Coovert, M. Whitney, A. Burghes, J. Stack, and B. A. Pollok
Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy
Hum. Mol. Genet., July 15, 2005; 14(14): 2003 - 2018.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. Pagani, M. Raponi, and F. E. Baralle
Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution
PNAS, May 3, 2005; 102(18): 6368 - 6372.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
T. T. Le, L. T. Pham, M. E.R. Butchbach, H. L. Zhang, U. R. Monani, D. D. Coovert, T. O. Gavrilina, L. Xing, G. J. Bassell, and A. H.M. Burghes
SMN{Delta}7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN
Hum. Mol. Genet., March 15, 2005; 14(6): 845 - 857.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
C. J. Webb, C. M. Romfo, W. J. van Heeckeren, and J. A. Wise
Exonic splicing enhancers in fission yeast: functional conservation demonstrates an early evolutionary origin
Genes & Dev., January 15, 2005; 19(2): 242 - 254.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
N. N. SINGH, E. J. ANDROPHY, and R. N. SINGH
In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes
RNA, August 1, 2004; 10(8): 1291 - 1305.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Majumder, S. Varadharaj, K. Ghoshal, U. Monani, A. H. M. Burghes, and S. T. Jacob
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., April 9, 2004; 279(15): 14803 - 14811.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
M. L. McWhorter, U. R. Monani, A. H.M. Burghes, and C. E. Beattie
Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding
J. Cell Biol., September 1, 2003; 162(5): 919 - 932.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. J. Lam, A. Bakshi, F. Y. Ekinci, J. Webb, B. R. Graveley, and K. J. Hertel
Enhancer-dependent 5'-Splice Site Control of fruitless Pre-mRNA Splicing
J. Biol. Chem., June 13, 2003; 278(25): 22740 - 22747.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Miyaso, M. Okumura, S. Kondo, S. Higashide, H. Miyajima, and K. Imaizumi
An Intronic Splicing Enhancer Element in Survival Motor Neuron (SMN) Pre-mRNA
J. Biol. Chem., April 25, 2003; 278(18): 15825 - 15831.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
U. R. Monani, M. T. Pastore, T. O. Gavrilina, S. Jablonka, T. T. Le, C. Andreassi, J. M. DiCocco, C. Lorson, E. J. Androphy, M. Sendtner, et al.
A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy
J. Cell Biol., January 2, 2003; 160(1): 41 - 52.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Vyas, C. Bechade, B. Riveau, J. Downward, and A. Triller
Involvement of survival motor neuron (SMN) protein in cell death
Hum. Mol. Genet., October 15, 2002; 11(22): 2751 - 2764.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
Y. Hofmann and B. Wirth
hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-{beta}1
Hum. Mol. Genet., August 15, 2002; 11(17): 2037 - 2049.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Miyajima, H. Miyaso, M. Okumura, J. Kurisu, and K. Imaizumi
Identification of a Cis-acting Element for the Regulation of SMN Exon 7 Splicing
J. Biol. Chem., June 21, 2002; 277(26): 23271 - 23277.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. Cifuentes-Diaz, S. Nicole, M. E. Velasco, C. Borra-Cebrian, C. Panozzo, T. Frugier, G. Millet, N. Roblot, V. Joshi, and J. Melki
Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model
Hum. Mol. Genet., June 1, 2002; 11(12): 1439 - 1447.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. J. Young, C. J. DiDonato, D. Hu, R. Kothary, E. J. Androphy, and C. L. Lorson
SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2{beta}1
Hum. Mol. Genet., March 1, 2002; 11(5): 577 - 587.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. T. Moseley, P. E. Mullis, M. A. Prince, and J. A. Phillips III
An Exon Splice Enhancer Mutation Causes Autosomal Dominant GH Deficiency
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 847 - 852.
[Abstract] [Full Text] [PDF]

Home page
 J. Mol. Diagn.Home page
S. Ogino, D. G. B. Leonard, H. Rennert, and R. B. Wilson
Spinal Muscular Atrophy Genetic Testing Experience at an Academic Medical Center
J. Mol. Diagn., February 1, 2002; 4(1): 53 - 58.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
W. Rossoll, A.-K. Kroning, U.-M. Ohndorf, C. Steegborn, S. Jablonka, and M. Sendtner
Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?
Hum. Mol. Genet., January 1, 2002; 11(1): 93 - 105.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. Guth, T. O. Tange, E. Kellenberger, and J. Valcarcel
Dual Function for U2AF35 in AG-Dependent Pre-mRNA Splicing
Mol. Cell. Biol., November 15, 2001; 21(22): 7673 - 7681.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. J. DiDonato, C. L. Lorson, Y. De Repentigny, L. Simard, C. Chartrand, E. J. Androphy, and R. Kothary
Regulation of murine survival motor neuron (Smn) protein levels by modifying Smn exon 7 splicing
Hum. Mol. Genet., November 1, 2001; 10(23): 2727 - 2736.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. Andreassi, J. Jarecki, J. Zhou, D. D. Coovert, U. R. Monani, X. Chen, M. Whitney, B. Pollok, M. Zhang, E. Androphy, et al.
Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients
Hum. Mol. Genet., November 1, 2001; 10(24): 2841 - 2849.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Ferrari, S. Giliani, A. Insalaco, A. Al-Ghonaium, A. R. Soresina, M. Loubser, M. A. Avanzini, M. Marconi, R. Badolato, A. G. Ugazio, et al.
Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM
PNAS, October 23, 2001; 98(22): 12614 - 12619.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J.-G. Chang, H.-M. Hsieh-Li, Y.-J. Jong, N. M. Wang, C.-H. Tsai, and H. Li
Treatment of spinal muscular atrophy by sodium butyrate
PNAS, August 14, 2001; 98(17): 9808 - 9813.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
A. Fedorov, S. Saxonov, L. Fedorova, and I. Daizadeh
Comparison of intron-containing and intron-lacking human genes elucidates putative exonic splicing enhancers
Nucleic Acids Res., April 1, 2001; 29(7): 1464 - 1469.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Jablonka, M. Bandilla, S. Wiese, D. Buhler, B. Wirth, M. Sendtner, and U. Fischer
Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy
Hum. Mol. Genet., March 1, 2001; 10(5): 497 - 505.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
U. R. Monani, D. D. Coovert, and A. H.M. Burghes
Animal models of spinal muscular atrophy
Hum. Mol. Genet., October 1, 2000; 9(16): 2451 - 2457.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
G. Meister, D. Buhler, B. Laggerbauer, M. Zobawa, F. Lottspeich, and U. Fischer
Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins
Hum. Mol. Genet., August 12, 2000; 9(13): 1977 - 1986.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Hofmann, C. L. Lorson, S. Stamm, E. J. Androphy, and B. Wirth
Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2)
PNAS, August 6, 2000; (2000) 160181697.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
S. R. Lim and K. J. Hertel
Modulation of Survival Motor Neuron Pre-mRNA Splicing by Inhibition of Alternative 3' Splice Site Pairing
J. Biol. Chem., November 21, 2001; 276(48): 45476 - 45483.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Hofmann, C. L. Lorson, S. Stamm, E. J. Androphy, and B. Wirth
Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2)
PNAS, August 15, 2000; 97(17): 9618 - 9623.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.