Deciphering the PURA syndrome: loss of PURA alters neural cell fate decisions and impairs neuronal homeostasis

PURA syndrome is a rare neurodevelopmental disorder caused by heterozygous de novo mutations in the PURA gene, leading to intellectual disability, hypotonia, and epilepsy. While the molecular functions of PURA have been partially elucidated, its role in human neural development remains unclear. Here, we used PURA-knockout (KO) human induced pluripotent stem cells (iPSCs) and isogenic controls to generate 2D neural progenitor cultures and 3D cerebral organoids. Transcriptomic profiling identified PURA-regulated RNAs critical for early neuronal development. Importantly, loss of PURA impaired neural progenitor maintenance and early cell fate decisions. In cerebral organoids, these defects resulted in reduced GABAergic neuron maturation alongside an excess of glutamatergic neurons and cortical hem-like cells, indicating imbalanced excitatory-inhibitory development. Our findings demonstrate that PURA is essential for early neuronal specification and neural homeostasis. Developmental mispatterning may underlie reported phenotypes in patients, including seizures. It highlights the limitations for therapeutic strategies aiming to restore PURA function