Abstract
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.
Highlights
Intellectual disability (ID, formerly known as mental retardation) is a generalised neurodevelopmental disorder occurring in 1–3% of the general population (Maulik et al, 2011)
We report the behavioural characterization of a Zdhhc9 mutant mouse line, which uncovered several deficits broadly consistent with phenotypes reported for other mouse models with mutations in ID genes (Peier et al, 2000; Altafaj et al, 2001; Nielsen et al, 2002; Zang et al, 2009)
The Zdhhc9 mutant mice show corpus callosum changes similar to that observed in humans with ZDHHC9 mutations (Baker et al, 2015). These findings suggest that this Zdhhc9 mutant mouse line may provide an excellent model system to dissect the underlying neurodevelopmental changes that lead to ID and other impairments in humans with disruptive ZDHHC9 mutations
Summary
Intellectual disability (ID, formerly known as mental retardation) is a generalised neurodevelopmental disorder occurring in 1–3% of the general population (Maulik et al, 2011). Mutations in the ZDHHC9 gene, located on the X chromosome, lead to mild-to-moderate ID (Raymond et al, 2007), and are associated with seizures sharing features with Rolandic Epilepsy, speech and language problems and deficits in inhibitory control of attention (Baker et al, 2015). These mutations cause hypoplasia of the corpus callosum, volume reductions in sub-cortical areas such as the thalamus and striatum, and thinning of the cortex (Masurel-Paulet et al, 2014; Baker et al, 2015; Bathelt et al, 2016). The enzyme is present in a variety of tissues including brain where it is highly expressed, at least at the mRNA level (Swarthout et al, 2005)
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