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Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children
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 dysreg...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438031/ https://www.ncbi.nlm.nih.gov/pubmed/28221363 http://dx.doi.org/10.1038/tp.2017.27 |
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author | Gozes, I Van Dijck, A Hacohen-Kleiman, G Grigg, I Karmon, G Giladi, E Eger, M Gabet, Y Pasmanik-Chor, M Cappuyns, E Elpeleg, O Kooy, R F Bedrosian-Sermone, S |
author_facet | Gozes, I Van Dijck, A Hacohen-Kleiman, G Grigg, I Karmon, G Giladi, E Eger, M Gabet, Y Pasmanik-Chor, M Cappuyns, E Elpeleg, O Kooy, R F Bedrosian-Sermone, S |
author_sort | Gozes, I |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5438031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54380312017-06-01 Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children Gozes, I Van Dijck, A Hacohen-Kleiman, G Grigg, I Karmon, G Giladi, E Eger, M Gabet, Y Pasmanik-Chor, M Cappuyns, E Elpeleg, O Kooy, R F Bedrosian-Sermone, S Transl Psychiatry Original Article 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. Nature Publishing Group 2017-02 2017-02-21 /pmc/articles/PMC5438031/ /pubmed/28221363 http://dx.doi.org/10.1038/tp.2017.27 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ 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/ |
spellingShingle | Original Article Gozes, I Van Dijck, A Hacohen-Kleiman, G Grigg, I Karmon, G Giladi, E Eger, M Gabet, Y Pasmanik-Chor, M Cappuyns, E Elpeleg, O Kooy, R F Bedrosian-Sermone, S Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children |
title | Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children |
title_full | Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children |
title_fullStr | Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children |
title_full_unstemmed | Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children |
title_short | Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children |
title_sort | premature primary tooth eruption in cognitive/motor-delayed adnp-mutated children |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438031/ https://www.ncbi.nlm.nih.gov/pubmed/28221363 http://dx.doi.org/10.1038/tp.2017.27 |
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