Novel ADNP Syndrome Mice Reveal Dramatic Sex-Specific Peripheral Gene Expression With Brain Synaptic and Tau Pathologies

Gidon Karmon, Shlomo Sragovich, Gal Hacohen-Kleiman, Inbar Ben-Horin-Hazak, Petr Kasparek, Björn Schuster, Radislav Sedlacek, Metsada Pasmanik-Chor, Paschalis Theotokis, Olga Touloumi, Sofia Zoidou, Linxuan Huang, Pei You Wu, Roy Shi, Oxana Kapitansky, Alexandra Lobyntseva, Eliezer Giladi, Guy Shapira, Noam Shomron, Stefan BereswillMarkus M. Heimesaat, Nikolaos Grigoriadis, R. Anne McKinney, Moran Rubinstein, Illana Gozes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Background: ADNP is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation. Methods: Mimicking humans, CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718∗ (Tyr), a paralog of the most common ADNP syndrome mutation. Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment NAPVSIPQ (NAP). Results: RNA sequencing of spleens, representing a peripheral biomarker source, revealed Tyr-specific sex differences (e.g., cell cycle), accentuated in females (with significant effects on antigen processing and cellular senescence) and corrected by NAP. Differentially expressed, NAP-correctable transcripts, including the autophagy and microbiome resilience–linked FOXO3, were also deregulated in human patient-derived ADNP-mutated lymphoblastoid cells. There were also Tyr sex-specific microbiota signatures. Phenotypically, Tyr mice, similar to patients with ADNP syndrome, exhibited delayed development coupled with sex-dependent gait defects. Speech acquisition delays paralleled sex-specific mouse syntax abnormalities. Anatomically, dendritic spine densities/morphologies were decreased with NAP amelioration. These findings were replicated in the Adnp+/− mouse, including Foxo3 deregulation, required for dendritic spine formation. Grooming duration and nociception threshold (autistic traits) were significantly affected only in males. Early-onset tauopathy was accentuated in males (hippocampus and visual cortex), mimicking humans, and was paralleled by impaired visual evoked potentials and correction by acute NAP treatment. Conclusions: Tyr mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3 controls the autophagy initiator LC3 (microtubule-associated protein 1 light chain 3), with known ADNP binding to LC3 augmented by NAP, protecting against tauopathy. NAP amelioration attests to specificity, with potential for drug development targeting accessible biomarkers.

Original languageEnglish
Pages (from-to)81-95
Number of pages15
JournalBiological Psychiatry
Issue number1
StatePublished - 1 Jul 2022


FundersFunder number
Alberto Moscona Nisim Foundation for the Advancement of Science, Art and Culture in Israel
Anne and Alex Cohen
Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University in Vestec
Blindness & Visual DisordersCZ.1.05/2.1.00/19.0395, CZ.1.05/1.1.00/02.0109
Constantiner Institute for Molecular Genetics, The Switzerland Institute of Developmental Biology
Danyel Biotech
Elton Laboratory for Molecular Neuroendocrinology
European Research Area Network Neuron ADNPinMED
German Federal Ministries of Economy and EnergyZF4117904 AJ8
German Federal Ministries of Education and ResearchIP7/ 01KI1725D
Miriam and Sheldon G. Adelson Graduate School of Medicine, Sackler Faculty of Medicine, Tel Aviv UniversityUSWO2017130190A1, CP201, US8618043, 63/165,801, PCT/IL2020/051010, US7960334, 63/165,819
National Science FoundationBSF-NSF 2016746
Naomi Foundation
United States-Israel Binational Science Foundation
Ministerstvo Školství, Mládeže a TělovýchovyLM2018126, LM2015040
Akademie Věd České RepublikyRVO 68378050
Tel Aviv University
Ministry of Science and Technology, Israel
European Regional Development FundGSE167014, GSE72664


    • ADNP
    • Autism
    • Biomarkers
    • CRISPR
    • NAP
    • Tyr Adnpmouse


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