SPPRS is caused by a mutation in the DNA of a gene called HACE1. This gene encodes the HACE1 enzyme, which functions as a ubiquitin ligase. Ubiquitin ligases control the activity of other proteins and enzymes by helping to tag them with ubiquitin molecules, which function as destruction markers. Proteins tagged with ubiquitin are degraded in cells and become less active. If ubiquitin ligases like HACE1 do not function properly, this disposal process cannot happen as effectively, and some enzymes that should normally be degraded accumulate and become too active.
In the brain, HACE1 enzyme is needed to add ubiquitin to a molecule called RAC1. RAC1 is important for the function, growth, and protection of brain cells. However, if too much RAC1 is active, these cells may become damaged by inflammation and not develop properly. By tagging some RAC1 molecules for destruction, HACE1 normally functions as a controller to balance RAC1 activity. In SPPRS patients, single mutations in the DNA code mean that the HACE1 enzyme is produced incorrectly, with parts missing or not correctly shaped. This mutated HACE1 enzyme cannot effectively tag RAC1 for destruction with ubiquitin, causing RAC1 to be overactive. Scientists suspect that it is this RAC1 overactivity that causes brain cells to develop incorrectly, leading to the variety of symptoms seen in SPPRS.
HACE1