Correct Splicing: The Desolation of SMA Spinal Muscular Atrophy and the Survival Motor Neuron Complex (LB94)

Spinal muscular atrophy (SMA) is a genetic disorder leading to death before age two. This is caused by degeneration of motor neurons in the spine and affects one in six thousand babies yearly (Families of SMA, 2013). It is unknown why a point mutation or deletion of the SMN1 gene, which produces survival motor neuron (SMN) protein, causes degeneration. The SMN complex is made of SMN and smaller units called Gemin proteins. In a normally functioning system, the SMN1 gene codes for SMN proteins that are part of the SMN complex that forms small nuclear ribonucleoproteins (snRNPs) from SM proteins and sRNA. The SMN protein binds to Gemin‐2 which holds five of the seven SM proteins, smaller units in snRNPs, in place until the target snRNA sequence is located. The final SM proteins are added when the N‐terminus of Gemin‐2 is moved. The snRNPs have many functions in cells, and five of them are involved in RNA splicing. Knowledge available on normal interactions of SMN and Gemin‐2 allow modeling of these proteins to be completed through 3D printing by the Hartford Union SMART (Students Modeling a Research Topic) Team. In children with SMA, the SMN protein cannot to bind to Gemin‐2 because Asp44 is replaced by valine, causing a break in the ionic bond holding the helices together. While this situation still produces normally operating snRNPs, there are too few to correctly splice the pre‐mRNA, leading to SMA. Grant Funding Source : Supported by a grant from NIH‐CTSA.