A Prospective, Longitudinal Study of Caregiver-Reported Adaptive Skills and Function of Individuals with HNRNPH2-related Neurodevelopmental Disorder DOI Creative Commons

Thomas J. Davis,

Rachel Salazar,

Sarah Beenders

et al.

Advances in Neurodevelopmental Disorders, Journal Year: 2023, Volume and Issue: 8(3), P. 445 - 456

Published: Aug. 7, 2023

Abstract Objectives This study presents a cohort of individuals in natural history with de novo pathogenic missense variants HNRNPH2 causative -related neurodevelopmental disorder (NDD) to describe individuals’ adaptive functional abilities. Methods We measured function using the Pediatric Evaluation Disability Inventory Computer Adaptive Test (PEDI-CAT) and Vineland Behavior Scale (VABS-III). Results were compared inferential statistics regression analysis. Sixty-seven carried known or likely . Thirty-five participants (2.89–42.04 years, 83% female) caregivers completed PEDI-CAT assessments 25 these completing VABS-III. Sixteen, three two follow-up assessment at one, years respectively. Individuals had mean normative scores less than age-matched peers across all domains on both VABS-III measures, 91% < 5 th percentile PEDI- CAT Verbal ambulatory significantly higher domains, raw data. There was no significant change over 3 years. Conclusions Overall scores, normative, are low NDD do not represent clinical variability, but may be able capture variability. In small sample, longitudinal data from domain demonstrate stability performance Trial Registration : ClinicalTrials.gov NCT03492060.

Language: Английский

Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism DOI Creative Commons
Claudio Peter D’Incal, Kirsten Esther Van Rossem,

Kevin De Man

et al.

Clinical Epigenetics, Journal Year: 2023, Volume and Issue: 15(1)

Published: March 21, 2023

Abstract Background Individuals affected with autism often suffer additional co-morbidities such as intellectual disability. The genes contributing to cluster on a relatively limited number of cellular pathways, including chromatin remodeling. However, information is available how mutations in single can result pleiotropic clinical features individuals. In this review, we summarize one the most frequently mutated syndromic Activity-Dependent Neuroprotective Protein (ADNP). Results Heterozygous and predicted loss-of-function ADNP individuals inevitably presentation Helsmoortel–Van der Aa syndrome, frequent form autism. ADNP, zinc finger DNA-binding protein has role remodeling: associated pericentromeric HP1, SWI/SNF core complex BRG1, other members remodeling and, murine stem cells, chromodomain helicase CHD4 ChAHP complex. recently been shown possess R-loop processing activity. addition, many functions, for instance, association cytoskeletal proteins have linked ADNP. Conclusions We here present an integrated evaluation all current aspects gene function evaluate abnormalities might relate individual“s” syndrome.

Language: Английский

Citations

23
A novel davunetide (NAPVSIPQQ to NAPVSIPQE) point mutation in activity‐dependent neuroprotective protein (ADNP) causes a mild developmental syndrome DOI Creative Commons
Illana Gozes, Shula Shazman

European Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 58(2), P. 2641 - 2652

Published: Jan. 21, 2023

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

Language: Английский

Citations

14
Distinct Impairments Characterizing Different ADNP Mutants Reveal Aberrant Cytoplasmic-Nuclear Crosstalk DOI Creative Commons

Maram Ganaiem,

Gidon Karmon, Yanina Ivashko‐Pachima

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 2994 - 2994

Published: Sept. 26, 2022

(1) Background: Activity-dependent neuroprotective protein (ADNP) is essential for neuronal structure and function. Multiple de novo pathological mutations in ADNP cause the autistic syndrome, they have been further suggested to affect Alzheimer's disease progression a somatic form. Here, we asked if different produce specific neuronal-like phenotypes toward better understanding personalized medicine. (2) Methods: We employed CRISPR/Cas9 genome editing N1E-115 neuroblastoma cells form neuron-like cell lines expressing mutant proteins conjugated GFP. These new were characterized by quantitative morphology, immunocytochemistry live imaging. (3) Results: Our novel lines, constitutively GFP-ADNP p.Pro403 (p.Ser404* human orthologue) p.Tyr718* (p.Tyr719* orthologue), revealed distinct phenotypes. Increased neurite numbers (day 1, culture) increased lengths upon differentiation 7, linked with p.Pro403*. In contrast, decreased 1). discrete associated an expression of both cytoplasm. Reduced nuclear/cytoplasmic boundaries observed ADNP-mutant line, this malformation being corrected ADNP-derived fragment drug candidate NAP. (4) Conclusions: Distinct impairments characterize mutants reveal aberrant cytoplasmic-nuclear crosstalk.

Language: Английский

Citations

19
NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms DOI Creative Commons

Maram Ganaiem,

Nina D. Gildor,

Shula Shazman

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(18), P. 2251 - 2251

Published: Sept. 11, 2023

(1) Background: Recently, we showed aberrant nuclear/cytoplasmic boundaries/activity-dependent neuroprotective protein (ADNP) distribution in ADNP-mutated cells. This malformation was corrected upon neuronal differentiation by the ADNP-derived fragment drug candidate NAP (davunetide). Here, investigated mechanism of nuclear protection. (2) Methods: CRISPR/Cas9 DNA-editing established N1E-115 neuroblastoma cell lines that express two different green fluorescent proteins (GFPs)-labeled mutated ADNP variants (p.Tyr718* and p.Ser403*). Cells were exposed to conjugated Cy5, followed live imaging. further characterized using quantitative morphology/immunocytochemistry/RNA quantifications. (3) Results: rapidly distributed cytoplasm also seen nucleus. Furthermore, reduced microtubule content observed lines. In parallel, disrupting microtubules zinc or nocodazole intoxication mimicked mutation phenotypes resulted nuclear-cytoplasmic boundaries, which treatment. No effects noted on levels. Ketamine, used as a control, ineffective, but both ketamine exhibited direct interactions with ADNP, via silico docking. (4) Conclusions: Through microtubule-linked mechanism, localized cytoplasmic compartments, ameliorating ADNP-related deficiencies. These novel findings explain previously published gene expression results broaden (davunetide) utilization research clinical development.

Language: Английский

Citations

11
Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males DOI

Jospeh Levine,

Alexandra Lobyntseva, Shula Shazman

et al.

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(1)

Published: Jan. 29, 2024

Language: Английский

Citations

4
Clinical impact and in vitro characterization of ADNP variants in pediatric patients DOI Creative Commons

Chuanhui Ge,

Yuxin Tian, Chunchun Hu

et al.

Molecular Autism, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 22, 2024

Helsmoortel-Van der Aa syndrome (HVDAS) is a rare genetic disorder caused by variants in the activity-dependent neuroprotector homeobox (ADNP) gene; hence, it also called ADNP syndrome. multitasking protein with function as transcription factor, playing critical role brain development. Furthermore, have been identified one of most common single-gene causes autism spectrum (ASD) and intellectual disability. We assembled cohort 15 Chinese pediatric patients, 13 coding region gene, evaluated their clinical phenotypes. Additionally, we constructed corresponding performed western blotting immunofluorescence analysis to examine expression subcellular localization human HEK293T SH-SY5Y cells. Our study conducted thorough characterization manifestations children variants, revealed broad symptoms including global developmental delay, disability, ASD, facial abnormalities, other features. In vitro studies were carried out check variants. Two cases presented missense while remainder exhibited nonsense or frameshift leading truncated mutants overexpression systems. Both overexpressed wildtype all different found be confined nuclei cells; however, distinctive pattern nuclear bodies formed was either partially entirely disrupted mutant proteins. Moreover, two p.Y719* on signal (NLS) pattern, predominantly manifesting cytoplasm limited relatively small sample size absence longitudinal framework monitor progression patient conditions over time. lacked vivo evidence further indicate causal implications reported first HVDAS patients population provided systematic presentations laboratory examinations. multiple validated them vitro. findings offered valuable insights into diverse associated HVDAS.

Language: Английский

Citations

3
Protective inherited mutations in activity-dependent neuroprotective protein (ADNP): the good, the bad, and the ugly DOI
Illana Gozes, Shula Shazman, Eliezer Giladi

et al.

Genomic psychiatry :, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 7

Published: Nov. 14, 2024

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

Language: Английский

Citations

3
Characterizing the autism spectrum phenotype in DYRK1A‐related syndrome DOI
Evangeline C. Kurtz‐Nelson, Hannah M. Rea,

Aiva C. Petriceks

et al.

Autism Research, Journal Year: 2023, Volume and Issue: 16(8), P. 1488 - 1500

Published: July 27, 2023

Abstract Likely gene‐disrupting (LGD) variants in DYRK1A are causative of syndrome and associated with autism spectrum disorder (ASD) intellectual disability (ID). While many individuals diagnosed ASD, they may present a unique profile ASD traits. We comprehensive characterization the children young adults LGDs . Individuals LGD ( n = 29) were compared to who had no known genetic cause, either low nonverbal IQ 14) or average above 41). was assessed using ADOS‐2, ADI‐R, SRS‐2, SCQ, RBS‐R. Quantitative score comparisons conducted, as qualitative analyses clinicians' behavioral observations. Diagnosis confirmed 85% ID 89% participants syndrome. showed broadly similar social communication behaviors idiopathic below‐average IQ, specific challenges noted reciprocity communication. Children also high rates sensory‐seeking behaviors. Phenotypic provide additional information on mechanisms contributing co‐occurring contribute identification predictors

Language: Английский

Citations

7
Tau, ADNP, and sex DOI Creative Commons
Illana Gozes

Cytoskeleton, Journal Year: 2023, Volume and Issue: 81(1), P. 16 - 23

Published: Aug. 12, 2023

With 50 years to the original discovery of Tau, I gave here my perspective, looking through prism activity-dependent neuroprotective protein (ADNP), and influence sex. My starting point was vasoactive intestinal peptide (VIP), a regulator ADNP. then moved ADNP its active site, NAP, drug candidate, davunetide. Tau-ADNP-NAP interactions were explained with emphasis on sex future translational medicine.

Language: Английский

Citations

5
To speak may draw on epigenetic writing and reading: Unravelling the complexity of speech and language outcomes across chromatin-related neurodevelopmental disorders DOI Open Access
Miya St John,

Tanya Tripathi,

Angela Morgan

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 152, P. 105293 - 105293

Published: June 22, 2023

Language: Английский

Citations

4