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      Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children

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          Abstract

          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.

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          Systematic and quantitative assessment of the ubiquitin-modified proteome.

          Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the human ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly)-containing isopeptides following trypsin digestion. We identify ~19,000 diGly-modified lysine residues within ~5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition, indicating both a dependence on ongoing translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            A de novo convergence of autism genetics and molecular neuroscience.

            Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with large genetic components, but identification of pathogenic genes has proceeded slowly because hundreds of loci are involved. New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations. Targeted large-scale resequencing studies have confirmed the significance of specific loci, including chromodomain helicase DNA binding protein 8 (CHD8), sodium channel, voltage-gated, type II, alpha subunit (SCN2A), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), and catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1, beta-catenin). We review recent studies and suggest that they have led to a convergence on three functional pathways: (i) chromatin remodeling; (ii) wnt signaling during development; and (iii) synaptic function. These pathways and genes significantly expand the neurobiological targets for study, and suggest a path for future genetic and functional studies. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder.

              Autism spectrum disorder is characterized by patterns of delay and deviance in the development of social, communicative, and cognitive skills that arise in the first years of life. Although frequently associated with intellectual disability, this condition is distinctive in its course, impact, and treatment. Autism spectrum disorder has a wide range of syndrome expression and its management presents particular challenges for clinicians. Individuals with an autism spectrum disorder can present for clinical care at any point in development. The multiple developmental and behavioral problems associated with this condition necessitate multidisciplinary care, coordination of services, and advocacy for individuals and their families. Early, sustained intervention and the use of multiple treatment modalities are indicated.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                February 2017
                21 February 2017
                1 February 2017
                : 7
                : 2
                : e1043
                Affiliations
                [1 ]The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine , Tel Aviv, Israel
                [2 ]Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University , Tel Aviv, Israel
                [3 ]Department of Medical Genetics, University and University Hospital of Antwerp , Antwerp, Belgium
                [4 ]Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University , Tel Aviv, Israel
                [5 ]The Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv, Israel
                [6 ]Monique and Jacques Roboh Department of Genetic, Hadassah Hebrew University Medical Center , Jerusalem, Israel
                [7 ]ADNP Kids Research Foundation , Brush Prairie, WA, USA
                Author notes
                [* ]Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University , Einstein Street, Tel Aviv 6997801, Israel. E-mail: igozes@ 123456post.tau.ac.il
                Article
                tp201727
                10.1038/tp.2017.27
                5438031
                28221363
                bfb09c80-31cc-4457-9b71-0f33b258b03e
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 02 November 2016
                : 20 December 2016
                : 17 January 2017
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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