Investigating DDX3Y compensatory mechanism in DDX3X-related syndrome

DDX3X syndrome is a common genetic cause of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). It is caused by changes (mutations) in the DDX3X gene, which is essential for making proteins in our brain cells. Because DDX3X is located on the X-chromosome, severe mutations are usually lethal for boys. Most affected individuals are girls, who have one working and one changed copy of the gene. Currently, there is no specific treatment for DDX3X syndrome; care is focused only on symptoms. We recently found a very unique young boy with DDX3X syndrome. He has a severe mutation that causes a complete loss of the DDX3X protein, which should have been lethal. However, he also has three copies of a closely related gene called DDX3Y (boys usually have one copy). This extra dose of DDX3Y appears to be rescuing him, leading to a much milder condition than predicted. This strongly suggests that the DDX3Y gene, when boosted, can compensate for the missing DDX3X function. Our project uses this boy's unique cells to understand exactly how this rescue happens. We will grow brain cells (neurons) in the lab from the boy's cells, as well as from specially corrected control cells, to study the condition and the rescue effect directly. We will check if the rescue restores normal cell structure and growth, such as how neurons extend their connections. Using advanced technology, we will create a detailed "protein map" of the cells. This map will show us which specific proteins and cell processes are fixed by the extra DDX3Y. This is critical because the DDX3X protein's main job is controlling how other proteins are made. This information will reveal the exact molecular mechanism of compensation. The specific proteins and pathways that are "fixed" by DDX3Y will become new, targeted drug goals for researchers. Our ultimate aim is to find a way to mimic this natural rescue with a future medication to help all children affected by DDX3X syndrome.