Research provides new molecular clues about a rare neurodevelopmental disorder similar to Angelman syndrome.
Angelman syndrome is a genetic disease that causes developmental delay, impaired speech and balance, intellectual disability, and in some cases, seizures.
Previously detected mutations in the HERC2 gene, which encodes a ubiquitin ligase enzyme that plays a key role in the nervous system, cause an inherited neurodevelopmental disorder that bears similarities to Angelman syndrome.
In all identified cases similar to Angelman syndrome, a total loss of the HERC2 protein or very low levels of the HERC2 protein, encoded by this gene, have been found.
Now, a research group has analyzed the cell signaling pathways affected by the most frequent mutation of the HERC2 gene (c.1781C>T, p.Pro594Leu) in this pathology similar to Angelman syndrome.
A better understanding of how pathogenic variants affect these pathways will be critical to help define future therapies for the disease.
Mutations in genes are involved in Angelman syndrome and in the other disease similar to it that has been investigated in the new study. (Illustration: Amazings/NCYT)
The research is the work of a team led by Professor José Luís Rosa, from the Faculty of Medicine and Health Sciences of the University of Barcelona (UB) and the Bellvitge Biomedical Research Institute (IDIBELL), located in Hospitalet de Llobregat. and which forms part of the CERCA institution of the Generalitat of Catalonia.
The results of the study indicate that cells from patients with this hereditary disorder —or also human cells deficient in the HERC2 protein— have an overactivated cellular response to oxidative stress. This is produced by the activation of an atypical signaling pathway involving the RAF, MKK3 and p38 proteins. “Our results highlight RAF inhibition as a potential therapeutic target for people with this hereditary and neurodevelopmental disorder,” concludes Professor José Luís Rosa.
The study is titled “HERC2 deficiency activates C-RAF/MKK3/p38 signaling pathway altering the cellular response to oxidative stress.” And it has been published in the academic journal Cellular and Molecular Life Sciences: (Source: UB)