CHARACTERIZATION OF THE ROLE OF <EM>PURA</EM> IN THE NEURODEVELOPMENTAL PHENOTYPE ASSOCIATED WITH 5Q31 DUPLICATIONS

Purine rich element binding protein A (PURA) encoded by the PURA gene (5q31) is an important transcriptional regulator that binds DNA and RNA and has a key role in neuronal development and differentiation. Haploinsufficiency of this gene has been reported to cause a severe neurodevelopmental syndrome with a wide range of symptoms including intellectual disability, cerebral abnormalities and seizures. Only one large 5q31 duplication of 3.36 Mb involving this gene has been described by Rosenfeld et al. in 2011 in a patient with global developmental delay. However, the consequences of PURA overexpression on neurocognitive development have never been studied. In this project, after demonstrating that gene duplication leads to increased PURA expression at both the transcript and protein levels, we use PURA overexpression models that mimic duplication of this gene. Through a national collaboration, we identified five heterozygous 5q31 duplications in five unrelated patients. Although less severe, these patients exhibit clinical features similar to those observed in cases of PURA mutations or deletions. To understand the impact of these duplications on neuronal development, we performed in vitro functional studies on mouse hippocampal neurons. In young neurons, we demonstrated that overexpression of the PURA protein leads to a significant decrease in proximal dendritic arborization complexity and dendrite number. In mature neurons with increased PURA expression, dendritic spine density is significantly decreased, whereas spine maturation remains unaffected. Our results demonstrate that PURA overexpression affects neuronal development and may contribute to the neurodevelopmental phenotype observed in patients carrying a 5q31 duplication.