Novel ADNP syndrome mice reveal dramatic sex-specific peripheral gene expression with brain synaptic and Tau pathologies.

Essential for brain formation and function, activity-dependent neuroprotective protein (ADNP) is a major autism gene. Here, a novel Tyr mouse carrying p.Tyr718* mutation (homologous to the most common ADNP syndrome p.Tyr719*) was generated using CRISPR-Cas9. Adnp p.Tyr718* inhibited early mouse development and showed sex-dependent gait deficits. Delayed speech acquisition was translated to sex-specific mouse syntax abnormalities. Mechanistically, dendritic spine densities/morphologies were significantly decreased in Tyr mice. All mentioned impediments were ameliorated by daily treatments with the ADNP fragment, drug candidate, NAP. Early onset tauopathy was male-specific (hippocampus and visual cortex) mimicking the human condition, paralleled by impaired visual evoked potentials and corrected by acute NAP treatment. RNA-sequencing of spleens revealed a comprehensive effect only on females, with 5 transcripts (SMOX, ARRB1, ADCY6, FOXO3, CPXM1), shared as deregulated by different human patient-derived ADNP mutated lymphoblastoid cell lines. With FOXO3 implicated in apoptosis and steroid synthesis, these changes, converging on AKT1, were further translated to sex-specific microbiota signatures. The Tyr mouse is thus a valid model for the ADNP syndrome, with a human-like pathology. NAP's corrective effects attest to specificity, leading to future drug development with objective biomarkers, including rapidly responsive visual evoked potentials, blood proteomics and microbiota signatures. Overall design: Samples include 14 week-mouse male and female spleens, wild-type or mutated ADNP (p.Tyr718*) and NAP treated or untreated, in triplicates.