Principal Investigator: Prof. Antonio Adamo & Prof. Stefan Arold
Poster Presenter: Kelly J. Cardona Londoño
Lab: STEMD laboratory and StruBE laboratory
Sex chromosome aneuploidies (SCAs) are characterized by an atypical number of X chromosomes. The karyotype 47,XXY is the most prevalent (1:600 males), although higher-grade aneuploidies (HGA) such as 48,XXXY, and 49,XXXXY karyotypes could also occur (1:85000 males). SCAs are associated with a variety of clinical features, including neurocognitive and metabolic disorders, with HGAs displaying a more severe phenotype compared with the 47,XXY. Importantly, the molecular mechanisms bridging X overdosage to the neurodevelopmental defects remain elusive. In this study, we investigated the impact of X chromosome overdosage on two key transcriptional events: alternative splicing (AS) and transcript isoform switching (IS), whose dysregulation has been associated with multiple neurodevelopmental and neuropsychiatric disorders. Using a unique cohort of iPSCs, neural stem cells (NSCs), and neurons derived from SCA patients, we identified a transcriptional switch involving the two major isoforms (S and F) of the ACP1 gene encoding the low molecular weight phosphotyrosine phosphatase (LMW-PTP). HGA-derived iPSCs and NSCs showed higher expression of the alternative isoform S. In contrast, 47,XXY, and 46, XY controls expressed mainly the canonical isoform F. Additionally, we identified a set of genes involved in synapsis switching from protein-coding isoforms to noncoding/NMD isoforms in SCAs. Altogether, our findings provide insights into the molecular mechanisms driving the functional dysregulation associated with SCAs and open avenues for identifying novel genes implicated in its neuropathology.