Illana Gozes - Academia.edu (original) (raw)

Papers by Illana Gozes

Regulatory Peptides, 2002

Peptides, 1999

The current study explored whether the neuroprotective effects of vasoactive intestinal peptide (... more The current study explored whether the neuroprotective effects of vasoactive intestinal peptide (VIP) and its analog Stearyl-Nle 17-VIP (SNV) were mediated through cGMP. SNV, was previously found to be 100-fold more potent than VIP in providing neuroprotection. Neuronal survival was assessed in rat cerebral cortical cultures. A cGMP antagonist (RP-8-pCPT-cGMPS, 10 Ϫ12-10 Ϫ9 M) reduced the number of surviving neurons (40-60%), this decline was spared in the presence of SNV (10 Ϫ13 M). A cGMP agonist (Sp-8-pCPT-cGMPS, 10 Ϫ14-10 Ϫ8 M) and SNV (10 Ϫ16-10 Ϫ8 M) both provided significant neuroprotection against 10 Ϫ12 M of the cGMP antagonist. Immunoassays indicated that SNV induced increases in cGMP (two-threefold) in these cultures, whereas VIP was 1000-fold less potent. These results implicate cGMP as a second messenger for VIP/SNV-mediated effects on neuronal survival.

IUPHAR/BPS Guide to Pharmacology CITE, 2019

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) re... more Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [64, 65]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [29]. PG 99-465 [115] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [35]. The selective PAC1 receptor agonis...

Alzheimer's & Dementia, 2010

Translational Psychiatry

Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-m... more Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females (r = 0.74, P = 2.36–9), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 (P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progr...

Journal of Molecular Neuroscience, Jan 20, 2018

Journal of Clinical Investigation, Nov 1, 1994

Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis... more Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis, neuronal survival, and neurodifferentiation in cell culture. VIP can also produce dramatic growth in postimplantation mouse embryos in vitro, characterized by large increases in cell number. The goal of the present study was to assess the role of VIP on early nervous system development in vivo. Pregnant mice were treated with a specific antagonist to VIP. Prenatal administration of the antagonist early in development (E9-Ell) produced severe microcephaly characterized by decreased embryonic brain weight with reduced DNA and protein content. The retardation of growth was disproportionally manifested in the brain compared with the body and was prevented by co-treatment with VIP. Identical treatment with the antagonist later in gestation had no detectable effect on embryonic growth. VIP receptors, which were restricted to the central nervous system during this stage of embryonic development, were increased in the neuroepithelium of antagonist-treated embryos while the number of cells in S-phase was significantly decreased. Thus, VIP regulates brain growth in vivo and inhibition of its action provides new insight into a molecular mechanism for microcephaly. (

Journal of Molecular Neuroscience

Literature Review Dementia is a progressive and devastating disease characterized by the gradual ... more Literature Review Dementia is a progressive and devastating disease characterized by the gradual loss of cognitive function. Dementia affects an individual's quality of life and increases a society's burden of care. The risk of developing dementia increases with age. As of 2020, 41.27 M people across the world suffer from AD (9.5 M in China and 0.16 M in Israel). The latest prevalence study found that about 10% of older adults in Hong Kong suffered from dementia (Lam et al. 2008), predicting that the number of local populations suffering from dementia may triple from 100,000 in 2009 to over 300,000 in 2039 (Yu et al. 2012). Neurodegeneration is the main outcome of dementia, of which Alzheimer's disease (AD) is the most prevalent form and a leading cause of mortality across the elderly. Unfortunately, the underlying pathogenesis and mechanism of most neurodegenerative diseases remain poorly understood. To date, diagnosis of neurodegenerative diseases prior to clinical manifestation remains challenging. While a number of cognitive, behavioral, and neuroimaging

Background: This paper investigates the statistical relationship between bilingualism and the Ons... more Background: This paper investigates the statistical relationship between bilingualism and the Onset Age (OA) of AD and MCI across a clinical sample, consisting of 580 Alzheimer's Disease (AD) subjects and 1264 Mild Cognitive Impairment (MCI) subjects, via a statistical analysis conducted on the sample retrieved from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Method: To investigate whether bilingualism has any correlation with the OAs of AD or MCI subjects, our study leverages the full potential of the ADNI dataset, a dataset that covers both the OA and the bilingualism status of both the AD and MCI subjects. Prior to performing any meaningful statistical analysis, a regression model and a probabilistic model were developed in parallel to fill in the missing OA and bilingualism values. A simple least-square regression model that consists of an independent variable of registered age for Mini-Mental State Examination (MMSE) score was used to estimate the OA...

Experimentation with mouse and rat models has become a central strategy for discovering mammalian... more Experimentation with mouse and rat models has become a central strategy for discovering mammalian gene function, and for preclinical testing of pharmacological treatments, yet the utility of any findings critically depends on their replicability in other laboratories. In previous publications we proposed a statistical approach for estimating the inter-laboratory replicability of novel discoveries made in a single laboratory. We demonstrated that previous phenotyping results from multi-lab databases can be used to derive a Genotype-by-Lab (GxL) adjustment factor to greatly enhance the replicability of the single-lab findings, for similarly measured phenotypes, even before making the effort of replicating these finding in additional laboratories.This demonstration, however, still raised several important questions that could only be answered by an additional large-scale prospective experiment: 1) Does GxL-adjustment work in single-lab experiments that were not intended to be standardi...

Scientific Reports, 2021

This study investigates thoroughly whether acute exposure to outdoor PM2.5 concentration, P, modi... more This study investigates thoroughly whether acute exposure to outdoor PM2.5 concentration, P, modifies the rate of change in the daily number of COVID-19 infections (R) across 18 high infection provincial capitals in China, including Wuhan. A best-fit multiple linear regression model was constructed to model the relationship between P and R, from 1 January to 20 March 2020, after accounting for meteorology, net move-in mobility (NM), time trend (T), co-morbidity (CM), and the time-lag effects. Regression analysis shows that P (β = 0.4309, p < 0.001) is the most significant determinant of R. In addition, T (β = −0.3870, p < 0.001), absolute humidity (AH) (β = 0.2476, p = 0.002), P × AH (β = −0.2237, p < 0.001), and NM (β = 0.1383, p = 0.003) are more significant determinants of R, as compared to GDP per capita (β = 0.1115, p = 0.015) and CM (Asthma) (β = 0.1273, p = 0.005). A matching technique was adopted to demonstrate a possible causal relationship between P and R across 1...

Frontiers in Cellular Neuroscience, 2021

Journal of Molecular Neuroscience, 2020

Frontiers in Neurology, 2020

Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa ... more Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Original data showed that Adnp+/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome.

Background: Motivated by the findings that exposure to daily outdoor PM2.5 (P) may increase the r... more Background: Motivated by the findings that exposure to daily outdoor PM2.5 (P) may increase the risk of influenza infection, our study examines if immediate exposure to outdoor P will modify the rate of change in the daily number of COVID-19 infections (R), for (1) 31 Chinese provincial capital cities and (2) Wuhan, China, using regression modelling. Effective public health measures for reducing R are recommended. Method: A multiple linear regression model was constructed to model the statistical relationship between P and R in China and in Wuhan, from 1 January to 20 March 2020. We carefully accounted for potential key confounders and addressed collinearity. The causal relationship between P and R, and the interaction effect between key variables were investigated. Finding: A causal relationship between P and R across 31 provincial capital cities in China was established via matching. A higher P resulted in a higher R in China. A 10 μg/m3 increase in P gave a 0.9% increase in R (p ...

Journal of Neuroscience Methods, 2019

Methods for single-cells neuronal diversity in human stem cell-derived brain tissue and organoid ... more Methods for single-cells neuronal diversity in human stem cell-derived brain tissue and organoid models. J. Neurosci. Methods 325, 108350.

Scientific Reports, 2019

Mutations in ADNP have been recently associated with intellectual disability and autism spectrum ... more Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy contr...

International Journal of Oncology, 2019

Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic str... more Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, while providing vital information on the diagnosis and management of patients with cancer and stroke. Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections. Cancer treatment

Regulatory Peptides, 2002

Peptides, 1999

The current study explored whether the neuroprotective effects of vasoactive intestinal peptide (... more The current study explored whether the neuroprotective effects of vasoactive intestinal peptide (VIP) and its analog Stearyl-Nle 17-VIP (SNV) were mediated through cGMP. SNV, was previously found to be 100-fold more potent than VIP in providing neuroprotection. Neuronal survival was assessed in rat cerebral cortical cultures. A cGMP antagonist (RP-8-pCPT-cGMPS, 10 Ϫ12-10 Ϫ9 M) reduced the number of surviving neurons (40-60%), this decline was spared in the presence of SNV (10 Ϫ13 M). A cGMP agonist (Sp-8-pCPT-cGMPS, 10 Ϫ14-10 Ϫ8 M) and SNV (10 Ϫ16-10 Ϫ8 M) both provided significant neuroprotection against 10 Ϫ12 M of the cGMP antagonist. Immunoassays indicated that SNV induced increases in cGMP (two-threefold) in these cultures, whereas VIP was 1000-fold less potent. These results implicate cGMP as a second messenger for VIP/SNV-mediated effects on neuronal survival.

IUPHAR/BPS Guide to Pharmacology CITE, 2019

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) re... more Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [64, 65]) are activated by the endogenous peptides VIP, PACAP-38, PACAP-27, peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM) and peptide histidine valine (PHV). VPAC1 and VPAC2 receptors display comparable affinity for the PACAP peptides, PACAP-27 and PACAP-38, and VIP, whereas PACAP-27 and PACAP-38 are >100 fold more potent than VIP as agonists of most isoforms of the PAC1 receptor. However, one splice variant of the human PAC1 receptor has been reported to respond to PACAP-38, PACAP-27 and VIP with comparable affinity [29]. PG 99-465 [115] has been used as a selective VPAC2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC1 and PAC1 receptors [35]. The selective PAC1 receptor agonis...

Alzheimer's & Dementia, 2010

Translational Psychiatry

Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-m... more Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females (r = 0.74, P = 2.36–9), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 (P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progr...

Journal of Molecular Neuroscience, Jan 20, 2018

Journal of Clinical Investigation, Nov 1, 1994

Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis... more Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis, neuronal survival, and neurodifferentiation in cell culture. VIP can also produce dramatic growth in postimplantation mouse embryos in vitro, characterized by large increases in cell number. The goal of the present study was to assess the role of VIP on early nervous system development in vivo. Pregnant mice were treated with a specific antagonist to VIP. Prenatal administration of the antagonist early in development (E9-Ell) produced severe microcephaly characterized by decreased embryonic brain weight with reduced DNA and protein content. The retardation of growth was disproportionally manifested in the brain compared with the body and was prevented by co-treatment with VIP. Identical treatment with the antagonist later in gestation had no detectable effect on embryonic growth. VIP receptors, which were restricted to the central nervous system during this stage of embryonic development, were increased in the neuroepithelium of antagonist-treated embryos while the number of cells in S-phase was significantly decreased. Thus, VIP regulates brain growth in vivo and inhibition of its action provides new insight into a molecular mechanism for microcephaly. (

Journal of Molecular Neuroscience

Literature Review Dementia is a progressive and devastating disease characterized by the gradual ... more Literature Review Dementia is a progressive and devastating disease characterized by the gradual loss of cognitive function. Dementia affects an individual's quality of life and increases a society's burden of care. The risk of developing dementia increases with age. As of 2020, 41.27 M people across the world suffer from AD (9.5 M in China and 0.16 M in Israel). The latest prevalence study found that about 10% of older adults in Hong Kong suffered from dementia (Lam et al. 2008), predicting that the number of local populations suffering from dementia may triple from 100,000 in 2009 to over 300,000 in 2039 (Yu et al. 2012). Neurodegeneration is the main outcome of dementia, of which Alzheimer's disease (AD) is the most prevalent form and a leading cause of mortality across the elderly. Unfortunately, the underlying pathogenesis and mechanism of most neurodegenerative diseases remain poorly understood. To date, diagnosis of neurodegenerative diseases prior to clinical manifestation remains challenging. While a number of cognitive, behavioral, and neuroimaging

Background: This paper investigates the statistical relationship between bilingualism and the Ons... more Background: This paper investigates the statistical relationship between bilingualism and the Onset Age (OA) of AD and MCI across a clinical sample, consisting of 580 Alzheimer's Disease (AD) subjects and 1264 Mild Cognitive Impairment (MCI) subjects, via a statistical analysis conducted on the sample retrieved from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Method: To investigate whether bilingualism has any correlation with the OAs of AD or MCI subjects, our study leverages the full potential of the ADNI dataset, a dataset that covers both the OA and the bilingualism status of both the AD and MCI subjects. Prior to performing any meaningful statistical analysis, a regression model and a probabilistic model were developed in parallel to fill in the missing OA and bilingualism values. A simple least-square regression model that consists of an independent variable of registered age for Mini-Mental State Examination (MMSE) score was used to estimate the OA...

Experimentation with mouse and rat models has become a central strategy for discovering mammalian... more Experimentation with mouse and rat models has become a central strategy for discovering mammalian gene function, and for preclinical testing of pharmacological treatments, yet the utility of any findings critically depends on their replicability in other laboratories. In previous publications we proposed a statistical approach for estimating the inter-laboratory replicability of novel discoveries made in a single laboratory. We demonstrated that previous phenotyping results from multi-lab databases can be used to derive a Genotype-by-Lab (GxL) adjustment factor to greatly enhance the replicability of the single-lab findings, for similarly measured phenotypes, even before making the effort of replicating these finding in additional laboratories.This demonstration, however, still raised several important questions that could only be answered by an additional large-scale prospective experiment: 1) Does GxL-adjustment work in single-lab experiments that were not intended to be standardi...

Scientific Reports, 2021

This study investigates thoroughly whether acute exposure to outdoor PM2.5 concentration, P, modi... more This study investigates thoroughly whether acute exposure to outdoor PM2.5 concentration, P, modifies the rate of change in the daily number of COVID-19 infections (R) across 18 high infection provincial capitals in China, including Wuhan. A best-fit multiple linear regression model was constructed to model the relationship between P and R, from 1 January to 20 March 2020, after accounting for meteorology, net move-in mobility (NM), time trend (T), co-morbidity (CM), and the time-lag effects. Regression analysis shows that P (β = 0.4309, p < 0.001) is the most significant determinant of R. In addition, T (β = −0.3870, p < 0.001), absolute humidity (AH) (β = 0.2476, p = 0.002), P × AH (β = −0.2237, p < 0.001), and NM (β = 0.1383, p = 0.003) are more significant determinants of R, as compared to GDP per capita (β = 0.1115, p = 0.015) and CM (Asthma) (β = 0.1273, p = 0.005). A matching technique was adopted to demonstrate a possible causal relationship between P and R across 1...

Frontiers in Cellular Neuroscience, 2021

Journal of Molecular Neuroscience, 2020

Frontiers in Neurology, 2020

Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa ... more Activity-dependent neuroprotective protein (ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Original data showed that Adnp+/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome.

Background: Motivated by the findings that exposure to daily outdoor PM2.5 (P) may increase the r... more Background: Motivated by the findings that exposure to daily outdoor PM2.5 (P) may increase the risk of influenza infection, our study examines if immediate exposure to outdoor P will modify the rate of change in the daily number of COVID-19 infections (R), for (1) 31 Chinese provincial capital cities and (2) Wuhan, China, using regression modelling. Effective public health measures for reducing R are recommended. Method: A multiple linear regression model was constructed to model the statistical relationship between P and R in China and in Wuhan, from 1 January to 20 March 2020. We carefully accounted for potential key confounders and addressed collinearity. The causal relationship between P and R, and the interaction effect between key variables were investigated. Finding: A causal relationship between P and R across 31 provincial capital cities in China was established via matching. A higher P resulted in a higher R in China. A 10 μg/m3 increase in P gave a 0.9% increase in R (p ...

Journal of Neuroscience Methods, 2019

Methods for single-cells neuronal diversity in human stem cell-derived brain tissue and organoid ... more Methods for single-cells neuronal diversity in human stem cell-derived brain tissue and organoid models. J. Neurosci. Methods 325, 108350.

Scientific Reports, 2019

Mutations in ADNP have been recently associated with intellectual disability and autism spectrum ... more Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy contr...

International Journal of Oncology, 2019

Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic str... more Numerous types of cancer have been shown to be associated with either ischemic or hemorrhagic stroke. In this review, the epidemiology and pathophysiology of stroke in cancer patients is discussed, while providing vital information on the diagnosis and management of patients with cancer and stroke. Cancer may mediate stroke pathophysiology either directly or via coagulation disorders that establish a state of hypercoagulation, as well as via infections. Cancer treatment

A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent n... more A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent neuroprotective protein (ADNP) is a most frequent de novo mutated ASD-related gene. Functionally, ADNP protects nerve cells against electrical blockade. In mice, complete Adnp deficiency results in dysregulation of over 400 genes and failure to form a brain. Adnp haploinsufficiency results in cognitive and social deficiencies coupled to sex-and age-dependent deficits in the key microtubule and ion channel pathways. Here, collaborating with parents/caregivers globally, we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. Looking at Adnp-deficient mice, by computed tomography, showed significantly smaller dental sacs and tooth buds at 5 days of age in the deficient mice compared to littermate controls. There was only trending at 2 days, implicating age-dependent dysregulation of teething in Adnp-deficient mice. Allen Atlas analysis showed Adnp expression in the jaw area. RNA sequencing (RNAseq) and gene array analysis of human ADNP-mutated lymphoblastoids, whole-mouse embryos and mouse brains identified dysregulation of bone/ nervous system-controlling genes resulting from ADNP mutation/deficiency (for example, BMP1 and BMP4). AKAP6, discovered here as a major gene regulated by ADNP, also links cognition and bone maintenance. To the best of our knowledge, this is the first time that early primary (deciduous) teething is related to the ADNP syndrome, providing for early/simple diagnosis and paving the path to early intervention/specialized treatment plan.