Investigation of the pathogenic mechanisms and potential therapeutic strategies for Houge-Janssens Syndrome 1 (HJS1)

Houge-Janssens Syndrome 1 (HJS1) is a rare genetic disorder that affects brain development and function, caused by specific mutations in the PPP2R5D gene. This gene produces a part of a protein called PP2A, which is important for many cell activities. To better understand HJS1, we created three mouse models with mutations seen in HJS1 patients (E198K, E200K, and E420K). Our research showed that these mice had key HJS1 symptoms, such as an enlarged head and abnormal facial features. Mice with the E198K and E420K mutations also showed delays in development of physical and motor skills, higher activity, anxiety in certain contexts, and memory problems, while mice with the E200K mutation had only mild memory issues. Further studies showed that two of the mutations (E198K and E420K) caused changes in brain chemistry, specifically reducing certain protein signals linked to learning and memory, which may help explain some of the symptoms. Given these findings, we tested a drug called BPN14770, which is being studied for fragile X syndrome, another genetic neurodevelopmental disorder. We found that this drug can improve some symptoms in our abnormal mice, even 12 weeks after stopping the drug.

Overall, our study provides (1) new insights into how HJS1 develops and (2) shows that drugs like BPN14770 could be promising treatments for managing HJS1 symptoms.