HACE1encodes HECT domain and ankyrin repeat‐containing ubiquitin ligase 1, which is highly expressed in the brain. As a ubiquitin ligase, the HACE1 enzyme tags proteins for degradation by the 26S proteasome. SPPRS results from different loss-of-function mutations in the HACE1gene, with frameshift and missense mutation being most frequently described.
HACE1 regulates other signalling proteins like NRF2 and RAC1 to reduce reactive oxygen species and cellular stress, and to regulate mitochondrial function. RAC1 is highly indicated in neurodevelopmental disorders, as it regulates neuronal and synapse development and neuroinflammation. In mice and in SPPRS patient-derived cells, reduced expression or functioning of the HACE1 enzyme causes increased expression of RAC1 and an increase in reactive oxygen species. Mice lacking HACE1 show similar symptoms to SPPRS patients, with neurological and motor difficulties and decreased synaptogenesis.
Thus, loss-of-function mutations in the HACE1gene are suspected to cause SPPRS by limiting neuron development and increasing neuroinflammation.
HACE1