Abstract

Spinal muscular atrophy (SMA) results from loss of both telomeric 5q13 copies of the SMN1 gene. The centromeric 5q13 SMN2 gene encodes an identical protein. While loss of SMN2 does not lead to development of SMA, the presence of SMN2 acts as a disease modifier in a dose-dependent manner. The SMN1 gene produces a full-length transcript while the primary product of SMN2 is an exon-skipped mRNA lacking exon 7. The principal investigator that a single non-polymorphic nucleotide difference between SMN1 and SMN2 is the basis for this alternative splicing. By comparing hybrid SMN genes derived from SMA patients with unaffected relatives, the principal investigator and his group demonstrated that the origin of this nucleotide (SMN1 or SMN2) dictated clinical outcome. Therefore, the clinical evolution of SMA correlates with the splicing of SMN genes. They have also reported that the SMN protein self-associates and the protein translated from the alternative spliced SMN2 RNA have a reduced ability to form oligomers. Furthermore, SMN point mutants from SMA patients show defective oligomerization proportional to their disease severity. These studies have defined the genetic and biochemical basis for development of SMA.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040275-05
Application #
6650868
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Gwinn, Katrina
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$318,000
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Singh, N N; Howell, M D; Androphy, E J et al. (2017) How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther 24:520-526
Singh, Natalia N; Singh, Ravindra N; Androphy, Elliot J (2007) Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res 35:371-89
Singh, Natalia N; Androphy, Elliot J; Singh, Ravindra N (2004) An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. Biochem Biophys Res Commun 315:381-8
Singh, Natalia N; Androphy, Elliot J; Singh, Ravindra N (2004) The regulation and regulatory activities of alternative splicing of the SMN gene. Crit Rev Eukaryot Gene Expr 14:271-85
Singh, Natalia N; Androphy, Elliot J; Singh, Ravindra N (2004) In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes. RNA 10:1291-305
Monani, Umrao R; Pastore, Matthew T; Gavrilina, Tatiana O et al. (2003) 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 160:41-52
Young, Philip J; Francis, Jonathan W; Lince, Diane et al. (2003) The Ewing's sarcoma protein interacts with the Tudor domain of the survival motor neuron protein. Brain Res Mol Brain Res 119:37-49
Young, Philip J; Day, Patricia M; Zhou, Jianhua et al. (2002) A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. J Biol Chem 277:2852-9
Young, Philip J; DiDonato, Christine J; Hu, Diane et al. (2002) SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2 beta 1. Hum Mol Genet 11:577-87
Zhang, M L; Lorson, C L; Androphy, E J et al. (2001) An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA. Gene Ther 8:1532-8

Showing the most recent 10 out of 12 publications