Molecular basis of spinal muscular atrophy; RNA processing; gene therapy.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1:6,000 live births. The gene responsible for SMA is called survival motor neuron-1 (SMN1). Interestingly, a human-specific copy gene is present on the same region of chromosome 5q called SMN2. SMN2 is nearly identical to SMN1, however, mutations in SMN2 have no clinical consequence if SMN1 is retained. The reason why SMN2 cannot prevent disease development in the absence of SMN1 is that the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated protein that lacks the 16 amino acids encoded by SMN exon 7 (normally the last coding exon). A single non-polymorphic nucleotide difference (C6T) between SMN1 and SMN2 is responsible for the alternative splicing of the SMN transcripts, however, this is a silent mutation that does not alter the overlapping protein coding capacity of SMN2. Numerous studies have shown that the SMN2-derived protein product (called SMN D 7) is unstable and dysfunctional, further demonstrating the critical nature of the SMN exon 7 splice site decision.
471G Bond Life Sciences Center
Columbia, MO 65211
- Molecular basis of spinal muscular atrophy
- RNA processing
- Gene therapy
Areas of Expertise
- Virology and Molecular Therapies
- Developmental Biology
- Gene Expression
- Gene Therapy
- Neuromuscular biology
- RNA Biology
Education & Training
1997, PhD, University of Missouri - Columbia
In the News
- Rindt H, Z. Feng, C. Mazzasette, J.J. Glascock, D. Valdivia, N. Pyles, T.O. Crawford, K.J., Swoboda, T.N. Patitucci, A.D. Ebert, C.J. Sumner, C.P. Ko, and C.L. Lorson. 2015. Astrocytes influence the severity of spinal muscular atrophy. Hum Mol Genet. 2015 Jul 15;24(14):4094-102. doi: 10.1093/hmg/ddv148. Epub 2015 Apr 24.
- Seng, C.O., C. Magee, P.J. Young, C.L. Lorson and J.P. Allen. 2015. The SMN structure reveals its crucial role in snRNP assembly. Hum Mol Genet. 2015 Apr 15;24(8):2138-46. doi: 10.1093/hmg/ddu734. Epub 2015 Jan 5.
- Osman E.Y., M.R. Miller, K.L. Robbins, A.M. Lombardi, A.K. Atkinson, A.J. Brehm, and C.L. Lorson. Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models. Hum Mol Genet. 2014 Apr 29. pii: ddu198. [Epub ahead of print]
- Robbins, K.L., J.J. Glascock, E.Y. Osman, M.R. Miller, and C.L. Lorson. Defining the therapeutic window in a severe animal model of Spinal Muscular Atrophy. Hum Mol Genet. 2014 Apr 9. [Epub ahead of print]
- Shababi, M., C.L. Lorson, and S.S. Rudnik-Schöneborn. 2013. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2013 Jul 22. doi: 10.1111/joa.12083 [Epub ahead of print]
- Cherry, J.J., E.Y. Osman, M.C. Evans, S. Choi, X. Xing, G.D. Cury, M.A. Glicksman, C.L. Lorson, and E.J. Androphy. 2013. Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds. EMBO Mol Med. 2013 Jul;5(7):1103-18. doi: 10.1002/emmm.201202305. Epub 2013 Jun 5
- Taylor AS, J.J. Glascock, F.F. Rose Jr, C. Lutz, C.L. Lorson. 2013. Restoration of SMN to Emx-1 expressing cortical neurons is not sufficient to provide benefit to a severe mouse model of Spinal Muscular Atrophy. Transgenic Res. 2013 Mar 20. [Epub ahead of print]
- Cobb MS, F.F. Rose, H. Rindt, J.J. Glascock, M. Shababi, M.R. Miller, E.Y. Osman, P.F. Yen, M.L. Garcia, B.R. Martin, M.J. Wetz, C. Mazzasette, Z. Feng, C.P. Ko, C.L. Lorson. 2013. Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy. Hum Mol Genet. 2013 May 1;22(9):1843-55. doi: 10.1093/hmg/ddt037. Epub 2013 Feb 5.