ADNP Exhibits Methyltransferase Activity in Overexpression Systems and Modulates DNA and Histone Methylation / Claudio Peter D'INCAL in Autism Research, 18-11 (November 2025)  

Public ISBD [article]  inAutism Research > 18-11 (November 2025) . - p.2174-2191 Titre : ADNP Exhibits Methyltransferase Activity in Overexpression Systems and Modulates DNA and Histone Methylation Type de document : texte imprimé Auteurs : Claudio Peter D'INCAL, Auteur ; Kirsten Esther VAN ROSSEM, Auteur ; Elisa CAPPUYNS, Auteur ; Anke VAN DIJCK, Auteur ; Ellen ELINCK, Auteur ; Kevin DE MAN, Auteur ; Ayu SCOTT, Auteur ; Anthony KONINGS, Auteur ; Dale John ANNEAR, Auteur ; R. Frank KOOY, Auteur Article en page(s) : p.2174-2191 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : ABSTRACT Activity-Dependent Neuroprotective Protein (ADNP) is a putative transcription factor that differentially interacts with proteins involved in chromatin remodeling, thereby controlling neuronal differentiation. The protein contains nine zinc fingers, a bipartite nuclear localization signal (NLS), and a homeobox domain with a heterochromatin protein 1 interaction motif, ensuring nuclear association with DNA and chromatin. De novo variants in ADNP cause autism comorbid with intellectual disability in the Helsmoortel?Van der Aa syndrome. ADNP interacts with components of the SWI/SNF in HEK293T cells but has also been reported as part of the repressive ChAHP complex in mouse embryonic stem cells. Although converging evidence suggests a role in chromatin remodeling, Hi-C experiments failed to detect major alterations in 3D chromatin structure. We therefore investigated ADNP's role in epigenetic regulation and identified the chromatin scaffolding protein WDR5 and HDAC2 as interaction partners. Structural modeling revealed two N-terminal methyltransferase domains, suggesting catalytic activity via SAM to SAH conversion. Immunoprecipitated fractions containing wild-type ADNP exhibited methyltransferase activity, which was reduced by nonsense variants. ADNP was expressed in histone-enriched cerebellar fractions in mice and a Helsmoortel?Van der Aa autopsy case, with male-specific reduction of the H3K79me1 modification. At the DNA level, wild-type ADNP induced CpG hypermethylation. However, most variants caused CpG hypomethylation, supporting a loss-of-function mechanism, while NLS variants showed additional hypermethylation, suggesting a gain-of-function effect linked to apoptosis and microtubule transport. Taken together, we identified an ADNP-WDR5-HDAC2 protein complex involved in epigenetic regulation, with ADNP exhibiting methyltransferase activity in overexpression systems. En ligne : https://doi.org/10.1002/aur.70132 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=571 [article] ADNP Exhibits Methyltransferase Activity in Overexpression Systems and Modulates DNA and Histone Methylation [texte imprimé] / Claudio Peter D'INCAL, Auteur ; Kirsten Esther VAN ROSSEM, Auteur ; Elisa CAPPUYNS, Auteur ; Anke VAN DIJCK, Auteur ; Ellen ELINCK, Auteur ; Kevin DE MAN, Auteur ; Ayu SCOTT, Auteur ; Anthony KONINGS, Auteur ; Dale John ANNEAR, Auteur ; R. Frank KOOY, Auteur . - p.2174-2191. Langues : Anglais (eng) in Autism Research > 18-11 (November 2025) . - p.2174-2191 Index. décimale : PER Périodiques Résumé : ABSTRACT Activity-Dependent Neuroprotective Protein (ADNP) is a putative transcription factor that differentially interacts with proteins involved in chromatin remodeling, thereby controlling neuronal differentiation. The protein contains nine zinc fingers, a bipartite nuclear localization signal (NLS), and a homeobox domain with a heterochromatin protein 1 interaction motif, ensuring nuclear association with DNA and chromatin. De novo variants in ADNP cause autism comorbid with intellectual disability in the Helsmoortel?Van der Aa syndrome. ADNP interacts with components of the SWI/SNF in HEK293T cells but has also been reported as part of the repressive ChAHP complex in mouse embryonic stem cells. Although converging evidence suggests a role in chromatin remodeling, Hi-C experiments failed to detect major alterations in 3D chromatin structure. We therefore investigated ADNP's role in epigenetic regulation and identified the chromatin scaffolding protein WDR5 and HDAC2 as interaction partners. Structural modeling revealed two N-terminal methyltransferase domains, suggesting catalytic activity via SAM to SAH conversion. Immunoprecipitated fractions containing wild-type ADNP exhibited methyltransferase activity, which was reduced by nonsense variants. ADNP was expressed in histone-enriched cerebellar fractions in mice and a Helsmoortel?Van der Aa autopsy case, with male-specific reduction of the H3K79me1 modification. At the DNA level, wild-type ADNP induced CpG hypermethylation. However, most variants caused CpG hypomethylation, supporting a loss-of-function mechanism, while NLS variants showed additional hypermethylation, suggesting a gain-of-function effect linked to apoptosis and microtubule transport. Taken together, we identified an ADNP-WDR5-HDAC2 protein complex involved in epigenetic regulation, with ADNP exhibiting methyltransferase activity in overexpression systems. En ligne : https://doi.org/10.1002/aur.70132 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=571

A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome / Andrew LIGSAY in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.26 Titre : A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome Type de document : texte imprimé Auteurs : Andrew LIGSAY, Auteur ; Anke VAN DIJCK, Auteur ; Danh V. NGUYEN, Auteur ; Reymundo LOZANO, Auteur ; Yanjun CHEN, Auteur ; Erika BICKEL, Auteur ; David HESSL, Auteur ; Andrea SCHNEIDER, Auteur ; Kathleen ANGKUSTSIRI, Auteur ; Flora TASSONE, Auteur ; Berten CEULEMANS, Auteur ; R. Frank KOOY, Auteur ; Randi J. HAGERMAN, Auteur Année de publication : 2017 Article en page(s) : p.26 Langues : Anglais (eng) Mots-clés : Adolescents  Children  Clinical trial  Fragile X syndrome  Ganaxolone Index. décimale : PER Périodiques Résumé : BACKGROUND: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. METHODS: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. RESULTS: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. CONCLUSIONS: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01725152. En ligne : http://dx.doi.org/10.1186/s11689-017-9207-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350 [article] A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome [texte imprimé] / Andrew LIGSAY, Auteur ; Anke VAN DIJCK, Auteur ; Danh V. NGUYEN, Auteur ; Reymundo LOZANO, Auteur ; Yanjun CHEN, Auteur ; Erika BICKEL, Auteur ; David HESSL, Auteur ; Andrea SCHNEIDER, Auteur ; Kathleen ANGKUSTSIRI, Auteur ; Flora TASSONE, Auteur ; Berten CEULEMANS, Auteur ; R. Frank KOOY, Auteur ; Randi J. HAGERMAN, Auteur . - 2017 . - p.26. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.26 Mots-clés : Adolescents  Children  Clinical trial  Fragile X syndrome  Ganaxolone Index. décimale : PER Périodiques Résumé : BACKGROUND: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. METHODS: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. RESULTS: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. CONCLUSIONS: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01725152. En ligne : http://dx.doi.org/10.1186/s11689-017-9207-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350

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