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Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model

Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the...

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Autores principales: Kouskou, Marianna, Thomson, David M., Brett, Ros R., Wheeler, Lee, Tate, Rothwelle J., Pratt, Judith A., Chamberlain, Luke H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Academic Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104741/
https://www.ncbi.nlm.nih.gov/pubmed/29944857
http://dx.doi.org/10.1016/j.expneurol.2018.06.014
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author Kouskou, Marianna
Thomson, David M.
Brett, Ros R.
Wheeler, Lee
Tate, Rothwelle J.
Pratt, Judith A.
Chamberlain, Luke H.
author_facet Kouskou, Marianna
Thomson, David M.
Brett, Ros R.
Wheeler, Lee
Tate, Rothwelle J.
Pratt, Judith A.
Chamberlain, Luke H.
author_sort Kouskou, Marianna
collection PubMed
description Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population.
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spelling pubmed-61047412018-10-01 Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model Kouskou, Marianna Thomson, David M. Brett, Ros R. Wheeler, Lee Tate, Rothwelle J. Pratt, Judith A. Chamberlain, Luke H. Exp Neurol Article Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population. Academic Press 2018-10 /pmc/articles/PMC6104741/ /pubmed/29944857 http://dx.doi.org/10.1016/j.expneurol.2018.06.014 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kouskou, Marianna
Thomson, David M.
Brett, Ros R.
Wheeler, Lee
Tate, Rothwelle J.
Pratt, Judith A.
Chamberlain, Luke H.
Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
title Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
title_full Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
title_fullStr Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
title_full_unstemmed Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
title_short Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
title_sort disruption of the zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104741/
https://www.ncbi.nlm.nih.gov/pubmed/29944857
http://dx.doi.org/10.1016/j.expneurol.2018.06.014
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