A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity-dependent neuroprotective protein (ADNP)...

NAP (NAPVSIPQ, drug candidate name, davunetide) is the neuroprotective fragment of activity-dependent neuroprotective protein (ADNP). Recent studies identified NAPVSIP as a Src homology 3 (SH3) domain-ligand association site, responsible for controlling signalling pathways regulating the cytoskeleton. Furthermore, the SIP motif in NAP/ADNP was identified as crucial for direct microtubule end-binding protein interaction facilitating microtubule dynamics and Tau microtubule interaction, at the microtubule end-binding protein site EB1 and EB3. Most de novo ADNP mutations reveal heterozygous STOP or frameshift STOP aberrations, driving the autistic/intellectual disability-related ADNP syndrome. Here, we report for the first time on a de novo missense mutation, resulting in ADNP containing NAPVISPQE instead of NAPVSIPQQ, in a child presenting developmental hypotonia, possibly associated with inflammation affecting food intake in early life coupled with fear of peer interactions and suggestive of a novel case of the ADNP syndrome. In silico modelling showed that the mutation Q (polar side chain) to E (negative side chain) affected the electrostatic characteristics of ADNP (reducing, while scattering the electrostatic positive patch). Comparison with the most prevalent pathogenic ADNP mutation, p.Tyr719*, indicated a further reduction in the electrostatic patch. Previously, exogenous NAP partially ameliorated deficits associated with ADNP p.Tyr719* mutations in transfected cells and in CRISPR/Cas9 genome edited cell and mouse models. These findings stress the importance of the NAP sequence in ADNP and as a future putative therapy for the ADNP syndrome.