Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly

Abstract

Activity-dependent neuroprotective protein (ADNP), essential for brain formation/function, reveals multiple cytoplasmic and chromatin interacting sites. Computational modeling, alongside the Vineland Adaptive Behavior Scales, a leading instrument supporting the diagnosis of intellectual/developmental disabilities, now revealed a protective frame shift/stop mutation in ADNP. Thus, a woman with inherited mutation, ADNP_Glu931Glyfs*12 (VB), showed above average Vineland performance. Bioinformatics/in silico protein modeling indicated that while ADNP contains four 14-3-3 protein interaction sites (instrumental for ADNP nuclear/cytoplasmic shuttling), ADNP_Glu931Glyfs*12 contains an additional fifth 14-3-3 interaction site, implicating stronger associations. Furthermore, the endogenous neuroprotective (investigational drug, davunetide) NAPVSIPQ (NAP) site was involved in the ADNP and ADNP_Glu931Glyfs*12-14-3-3 interactions. In this respect, the mutation also enhanced ADNP-SH3 associations (another NAPVISP interaction site 354-361 aa on ADNP, critical for cytoskeletal/cellular signaling). HB, the 8-year-old VB's son, while inheriting the mother's ADNP mutation, further presented a heterozygous pathogenic de novo mutation ADNP, p.Arg730Thrfs*5. However, in comparison to carriers of a similar p.Arg730* mutation (part of the autistic/intellectual disability ADNP syndrome), HB exhibited overall better Vineland 3 standard score of 70–80 for all measures, compared to the nominal score of 20 in a 27-year-old ADNP, p.Arg730* subject and the 100 ± 15 norm, corroborating ADNP_Glu931Glyfs*12 protection.