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PLoS Genet. 2017 Jul 13;13(7):e1006886. doi: 10.1371/journal.pgen.1006886. eCollection 2017 Jul.

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.

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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
Université de Strasbourg, Illkirch, France.
Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
Synome Ltd, Moneta Building, Babraham Research Campus, Cambridge, United Kingdom.
Interdisciplinary Institute for Neuroscience, CNRS, UMR5297, Bordeaux University, Bordeaux, France.
Mouse Imaging Center (MICe), The Hospital for Sick Children Toronto, Toronto, Ontario, Canada.
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), CNRS, INSERM, University of Strasbourg, Illkirch-Graffenstaden, France.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.


Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.

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