For the past decade the lab of Gideon Dreyfuss, PhD, the Isaac Norris professor of biochemistry and biophysics at Penn and a Howard Hughes Medical Institute investigator, has centered on the mechanisms of how the genetic code is translated, via messenger RNA (mRNA), to correctly construct proteins that orchestrate the human body. This very basic work has turned out to have profound clinical implications for understanding two genetic conditions -- fragile X syndrome, the most common cause of hereditary mental retardation; and spinal muscular atrophy (SMA), the leading genetic cause of infant death. Specifically, the Penn group has focused on a group of 20 RNA-binding proteins called hnRNPs, which are important in the formation of mRNA.
"In terms of clinical relevance, perhaps the most important area that we now work on is spinal muscular atrophy," notes Dreyfuss. Reduced levels or mutations in a protein called SMN leads to this disease, which is characterized by degeneration of motor nerve cells in the spinal cord. SMN (survival of motor neurons) interacts with one type of hnRNP.
Essentially, these two proteins must work in concert so that motor neurons can function properly. When SMN is mutated the capacity of the cell to produce mRNA is impaired, leading to motor neuron death. Most recently, Dreyfuss and his team found that the SMN protein was concentrated in newly found cell-nuclei structures they dubbed Gemini coiled bodies, or gems, because they resembled companion structures in other cells. Their function still remains a mystery, but is somehow related to the genesis of mRNA. Interestingly, in the most severe type of spinal muscle atrophy, gems are almost completely absent. In both SMA and fragile X syndrome, Dreyfuss hopes that understanding the role of nuclear proteins and their interactions with other proteins will lead to therapies and a better understanding of the pathogenesis of each condition.