Characterisation of AHDC1 Function and Exploration of SINEUP RNAs as a Targeted Rescue Strategy in Xia-Gibbs Syndrome

Xia-Gibbs syndrome (XGS) is a rare condition caused by changes in a gene called AHDC1. Children and adults with XGS often have developmental delay, speech difficulties, low muscle tone, sleep problems, seizures and a tendency to gain weight. Although AHDC1 is clearly involved, we still do not fully understand what this gene does inside human cells. Our research focuses on the nucleolus, a small structure inside the cell nucleus where ribosomes, the protein factories of the cell are built. Based on recent studies and our own results, we think that AHDC1 helps keeping the nucleolus and nearby DNA regions working properly. When AHDC1 is reduced, we see signs that ribosome production and energy use are disturbed and that important control pathways may be affected. We will study two models: 1) human cells in which AHDC1 is lowered and 2) blood-derived cell lines from three families with XGS. In both models we will measure: how the nucleolus looks and functions; how much ribosomal RNA is produced; how cells handle energy and grow and how the DNA is packaged and organized. These measurements will give us readouts telling whether AHDC1 is working properly. Because forcing cells to make extra AHDC1 is harmful, we will test a gentler approach called SINEUP RNAs. These are specifically designed synthetic molecules that will slightly increase how efficiently the cell translates AHDC1 without pushing the levels too high. Even if it does not fully rescue cell function, a SINEUP functional on AHDC1 will help us learn whether XGS mutations mostly reduce AHDC1 activity (loss of function) or act in a different way (gain of function). We aim to deliver: tests that show when AHDC1 pathways are off track; a clearer picture of how AHDC1 supports the nucleolus and chromosome regions nearby and first evidence on whether a careful boost of AHDC1 can be a promising therapy. These results will guide future studies helping to shape therapeutic ideas for families living with XGS.