Title: | Reduced Euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice |
Author(s): | Balemans, M.C.M. ; Ansar, M.; Oudakker, A.R. ; Caam, A.P.M. van; Bakker, B. ; Vitters, E.L. ; Kraan, P.M. van der ; Bruijn, D.R.H. de ; Janssen, S.M.; Kuipers, A.J. ; Huibers, M.M.; Maliepaard, E.M.; Walboomers, X.F. ; Benevento, M.; Nadif Kasri, N. ; Kleefstra, T. ; Zhou, Huiqing ; Zee, C.E.E.M. van der ; Bokhoven, H. van |
Publication year: | 2014 |
Source: | Developmental Biology, vol. 386, iss. 2, (2014), pp. 395-407 |
ISSN: | 0012-1606 |
DOI: | https://doi.org/10.1016/j.ydbio.2013.12.016 |
Publication type: | Article / Letter to editor |
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/136047 ![]() |
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Subject: | Radboudumc 10: Reconstructive and regenerative medicine RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 5: Inflammatory diseases RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience Radboudumc 7: Neurodevelopmental disorders RIMLS: Radboud Institute for Molecular Life Sciences |
Organization: | Human Genetics Cell Biology (UMC) Cognitive Neuroscience Rheumatology Central Animal Laboratory Paediatrics - OUD tm 2017 Laboratory Medicine Laboratory of Genetic, Endocrine and Metabolic Diseases Dentistry |
Journal title: |
Developmental Biology
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Volume: | vol. 386 |
Issue: | iss. 2 |
Page start: | p. 395 |
Page end: | p. 407 |
Abstract: |
Haploinsufficiency of Euchromatin histone methyltransferase 1 (EHMT1), a chromatin modifying enzyme, is the cause of Kleefstra syndrome (KS). KS is an intellectual disability (ID) syndrome, with general developmental delay, hypotonia, and craniofacial dysmorphisms as additional core features. Recent studies have been focused on the role of EHMT1 in learning and memory, linked to the ID phenotype of KS patients. In this study we used the Ehmt1(+/-) mouse model, and investigated whether the core features of KS were mimicked in these mice. When comparing Ehmt1(+/-) mice to wildtype littermates we observed delayed postnatal growth, eye opening, ear opening, and upper incisor eruption, indicating a delayed postnatal development. Furthermore, tests for muscular strength and motor coordination showed features of hypotonia in young Ehmt1(+/-) mice. Lastly, we found that Ehmt1(+/-) mice showed brachycephalic crania, a shorter or bent nose, and hypertelorism, reminiscent of the craniofacial dysmorphisms seen in KS. In addition, gene expression analysis revealed a significant upregulation of the mRNA levels of Runx2 and several other bone tissue related genes in P28 Ehmt1(+/-) mice. Runx2 immunostaining also appeared to be increased. The mRNA upregulation was associated with decreased histone H3 lysine 9 dimethylation (H3K9me2) levels, the epigenetic mark deposited by Ehmt1, in the promoter region of these genes. Together, Ehmt1(+/-) mice indeed recapitulate KS core features and can be used as an animal model for Kleefstra syndrome. The increased expression of bone developmental genes in the Ehmt1(+/-) mice likely contributes to their cranial dysmorphisms and might be explained by diminished Ehmt1-induced H3K9 dimethylation.
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