DISSECTING THE PATHOMOLECULAR MECHANISMS OF PRR12 GENE LOSS LEADING TO NEURODEVELOPMENTAL AND EYE ABNORMALITIES

PRR12 (Proline rich 12) gene is encoding for a nuclear protein but its function remains elusive. In humans, heterozygous loss-of-function mutations cause Neurocular syndrome. So far, the etiopathogenic mechanisms underlying the disorder remain unknown, moreover, neither in vitro nor in vivo models are currently available, and the biological function of PRR12 is poorly characterized.
To address this gap, we established a set of isogenic hESC (human embryonic stem cells) lines carrying heterozygous or homozygous mutations in the PRR12 gene, through the CRISPR/Cas9 system. Next, we differentiated these lines into neural progenitors (NPCs) and cortical neurons. In parallel, we generated a transgenic mouse line carrying a Prr12 floxed allele, by flanking exon 6 with loxP sequences through homologous recombination in ES cells.
Prr12 mutant neural progenitor cells displayed increased proliferation together with defective neuronal differentiation and maturation, while mutant neurons showed abnormal morphology and reduced neurite outgrowth. Transcriptomic profiling of PRR12 knockout neurons confirmed neuronal differentiation impairment. In vivo, ubiquitous deletion of Prr12 caused perinatal lethality, with rare survivors exhibiting growth deficits. By contrast, Prr12 loss-of-function mice survived but showed impaired motor performance, reduced visual acuity, and altered social dominance behavior associated with increased aggression, highlighting critical roles in neurodevelopment and behavior.
Together, these findings identify PRR12 as a critical regulator of neurodevelopment and genomic integrity. Furthermore, this work establishes robust in vitro and in vivo models for future studies.