@article{7e9b9fd68a5e4b63a83e6cab49a651d9,
title = "A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity-dependent neuroprotective protein (ADNP) causes a mild developmental syndrome",
abstract = "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.",
keywords = "(AL-108), ADNP syndrome, CP201, NAP (davunetide), eating disorders, in silico models, muscle development, social interactions",
author = "Illana Gozes and Shula Shazman",
note = "Publisher Copyright: {\textcopyright} 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.",
year = "2023",
month = jul,
doi = "10.1111/ejn.15920",
language = "אנגלית",
volume = "58",
pages = "2641--2652",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "John Wiley and Sons Inc.",
number = "2",
}