Spinal muscular atrophy (SMA) is a disease that affects the motor nerve cells in the spinal cord that control voluntary muscle movement. It is the most common cause of death in children under the age of two from a genetic disease. SMA is caused by the homozygous loss of the SMN1 gene. This gene contains nine exons that code for the survival motor neuron (SMN) protein. This protein is essential to the maintenance of motor neurons, and without functional SMN, the nerve cells can die, leading to fatal muscle weakness. There are children who lack the SMN1 gene, yet they are still surviving. Their DNA was analyzed and it was found that they carry an amplification of the number of copies of the SMN2 gene. The more copies of SMN2 that an individual had, their severity of SMA symptoms diminished.
Figure 1-Splicing diagram of SMN1 and SMN2
Figure 2-Gel electrophoresis results from RT-PCR
Figure 3-Sequence alignment of the lower band. The top line is the sequence of SMN2 transcript and the bottom line is the sequence of the 326 base pair PCR product
Figure 4-Sequence alignment of the upper band. The top line is the sequence of SMN2 transcript and the bottom line is the sequence of the 380 base pair PCR product
Spinal muscular atrophy (SMA) is a devastating disease that affects the motor nerve cells in the spinal cord that control voluntary muscle movement, compromising one’s ability to walk, eat, and breathe. Approximately 1/6,000 children are born each year with this disease. SMA is caused by the homozygous loss of the SMN1 gene, which codes for the survival motor neuron (SMN) protein. Lacking this functional protein leads to debilitating and potentially fatal muscle weakness. The gene SMN2 has a nearly identical exonic sequence to SMN1, other than a C to T base pair change within exon 8. This SNP doesn’t change the encoded amino acid sequence, but it causes for the majority of the transcripts to lack exon 8 sequence. This transcript that lacks this 54 base pair exon produces a truncated protein that is rapidly degraded. This project aimed to test the ability of various nutraceuticals to modulate the alternative splicing of exon 8. One compound was shown to increase the level of exon 8 inclusion, which could lead to an increase in the production of functional SMN protein, and therefore serve as a potential treatment for spinal muscular atrophy.
I would like to thank Dr. Rubin for providing me the opportunity to participate in this project. I would also like to thank Anthony Evans and Devin Rocks for their support and patience. All of their constant availability, direction, and guidance is greatly appreciated, and without it, this project would not have been possible.
|This document was last modified 05/14/2019.|
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