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KMT2C knockout generates ASD-like behaviors in mice

Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 a...

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Autores principales: Brauer, Bastian, Merino-Veliz, Nicolas, Ahumada-Marchant, Constanza, Arriagada, Gloria, Bustos, Fernando J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394233/
https://www.ncbi.nlm.nih.gov/pubmed/37538398
http://dx.doi.org/10.3389/fcell.2023.1227723
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author Brauer, Bastian
Merino-Veliz, Nicolas
Ahumada-Marchant, Constanza
Arriagada, Gloria
Bustos, Fernando J.
author_facet Brauer, Bastian
Merino-Veliz, Nicolas
Ahumada-Marchant, Constanza
Arriagada, Gloria
Bustos, Fernando J.
author_sort Brauer, Bastian
collection PubMed
description Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 and H3K4me3, as being associated with Kleefstra syndrome 2 and autism spectrum disorder (ASD). However, the precise role of KMT2C mutations in brain disorders remains poorly understood. Here we employed CRISPR/Cas9 gene editing to analyze the effects of KMT2C brain specific knockout on animal behavior. Knocking out KMT2C expression in cortical neurons and the mouse brain resulted in decreased KMT2C levels. Importantly, KMT2C brain specific knockout animals exhibited repetitive behaviors, social deficits, and intellectual disability resembling ASD. Our findings shed light on the involvement of KMT2C in neurodevelopmental processes and establish a valuable model for elucidating the cellular and molecular mechanisms underlying KMT2C mutations and their relationship to Kleefstra syndrome 2 and ASD.
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spelling pubmed-103942332023-08-03 KMT2C knockout generates ASD-like behaviors in mice Brauer, Bastian Merino-Veliz, Nicolas Ahumada-Marchant, Constanza Arriagada, Gloria Bustos, Fernando J. Front Cell Dev Biol Cell and Developmental Biology Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 and H3K4me3, as being associated with Kleefstra syndrome 2 and autism spectrum disorder (ASD). However, the precise role of KMT2C mutations in brain disorders remains poorly understood. Here we employed CRISPR/Cas9 gene editing to analyze the effects of KMT2C brain specific knockout on animal behavior. Knocking out KMT2C expression in cortical neurons and the mouse brain resulted in decreased KMT2C levels. Importantly, KMT2C brain specific knockout animals exhibited repetitive behaviors, social deficits, and intellectual disability resembling ASD. Our findings shed light on the involvement of KMT2C in neurodevelopmental processes and establish a valuable model for elucidating the cellular and molecular mechanisms underlying KMT2C mutations and their relationship to Kleefstra syndrome 2 and ASD. Frontiers Media S.A. 2023-07-19 /pmc/articles/PMC10394233/ /pubmed/37538398 http://dx.doi.org/10.3389/fcell.2023.1227723 Text en Copyright © 2023 Brauer, Merino-Veliz, Ahumada-Marchant, Arriagada and Bustos. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Brauer, Bastian
Merino-Veliz, Nicolas
Ahumada-Marchant, Constanza
Arriagada, Gloria
Bustos, Fernando J.
KMT2C knockout generates ASD-like behaviors in mice
title KMT2C knockout generates ASD-like behaviors in mice
title_full KMT2C knockout generates ASD-like behaviors in mice
title_fullStr KMT2C knockout generates ASD-like behaviors in mice
title_full_unstemmed KMT2C knockout generates ASD-like behaviors in mice
title_short KMT2C knockout generates ASD-like behaviors in mice
title_sort kmt2c knockout generates asd-like behaviors in mice
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394233/
https://www.ncbi.nlm.nih.gov/pubmed/37538398
http://dx.doi.org/10.3389/fcell.2023.1227723
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