Cargando…
CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice
Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD cause...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548587/ https://www.ncbi.nlm.nih.gov/pubmed/34702855 http://dx.doi.org/10.1038/s41467-021-26426-1 |
_version_ | 1784590604519342080 |
---|---|
author | Halperin, D. Stavsky, A. Kadir, R. Drabkin, M. Wormser, O. Yogev, Y. Dolgin, V. Proskorovski-Ohayon, R. Perez, Y. Nudelman, H. Stoler, O. Rotblat, B. Lifschytz, T. Lotan, A. Meiri, G. Gitler, D. Birk, O. S. |
author_facet | Halperin, D. Stavsky, A. Kadir, R. Drabkin, M. Wormser, O. Yogev, Y. Dolgin, V. Proskorovski-Ohayon, R. Perez, Y. Nudelman, H. Stoler, O. Rotblat, B. Lifschytz, T. Lotan, A. Meiri, G. Gitler, D. Birk, O. S. |
author_sort | Halperin, D. |
collection | PubMed |
description | Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD. |
format | Online Article Text |
id | pubmed-8548587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85485872021-10-29 CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice Halperin, D. Stavsky, A. Kadir, R. Drabkin, M. Wormser, O. Yogev, Y. Dolgin, V. Proskorovski-Ohayon, R. Perez, Y. Nudelman, H. Stoler, O. Rotblat, B. Lifschytz, T. Lotan, A. Meiri, G. Gitler, D. Birk, O. S. Nat Commun Article Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD. Nature Publishing Group UK 2021-10-26 /pmc/articles/PMC8548587/ /pubmed/34702855 http://dx.doi.org/10.1038/s41467-021-26426-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Halperin, D. Stavsky, A. Kadir, R. Drabkin, M. Wormser, O. Yogev, Y. Dolgin, V. Proskorovski-Ohayon, R. Perez, Y. Nudelman, H. Stoler, O. Rotblat, B. Lifschytz, T. Lotan, A. Meiri, G. Gitler, D. Birk, O. S. CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
title | CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
title_full | CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
title_fullStr | CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
title_full_unstemmed | CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
title_short | CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
title_sort | cdh2 mutation affecting n-cadherin function causes attention-deficit hyperactivity disorder in humans and mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548587/ https://www.ncbi.nlm.nih.gov/pubmed/34702855 http://dx.doi.org/10.1038/s41467-021-26426-1 |
work_keys_str_mv | AT halperind cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT stavskya cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT kadirr cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT drabkinm cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT wormsero cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT yogevy cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT dolginv cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT proskorovskiohayonr cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT perezy cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT nudelmanh cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT stolero cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT rotblatb cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT lifschytzt cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT lotana cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT meirig cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT gitlerd cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice AT birkos cdh2mutationaffectingncadherinfunctioncausesattentiondeficithyperactivitydisorderinhumansandmice |