Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition
| Autor: | Giovanni Iacono, Katrin Linda, Claire Chevalier, Nael Nadif Kasri, Hamid Meziane, Yann Humeau, Xander Houbaert, Bert B.A. de Vries, Maksym V. Kopanitsa, Thomas Arbogast, Yann Herault, Marie-Christine Birling, R. Mark Henkelman, David A. Koolen, Henk Stunnenberg, Nurudeen O. Afinowi, Tania Sorg, Matthijs C. van Eede, Mohammed Selloum, Christine L. Laliberté |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cancer Research Physiology CNTNAP2 Hippocampus Social Sciences medicine.disease_cause Synaptic Transmission Epigenesis Genetic Mice Cognition Sociology Gene duplication Chromosome Duplication Medicine and Health Sciences Genetics (clinical) Genetics Mammals Genetics & Heredity Gene Rearrangement Mice Knockout Mutation Neuronal Plasticity Animal Behavior DEVELOPMENTAL DELAY ABNORMALITIES Neurogenesis Brain Nuclear Proteins Animal Models Social Discrimination ASSOCIATION ATLAS Phenotype Up-Regulation Experimental Organism Systems Chromosome Structures Animal Sociality Chromosomal region Vertebrates Female Anatomy Chromosome Deletion CLINICAL SPECTRUM Life Sciences & Biomedicine Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] Research Article lcsh:QH426-470 DNA Copy Number Variations Mouse Models Biology Research and Analysis Methods Rodents 03 medical and health sciences Model Organisms Intellectual Disability medicine Animals Abnormalities Multiple Molecular Biology Ecology Evolution Behavior and Systematics Behavior 0604 Genetics Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Science & Technology Biological Locomotion MUTATIONS AUTISM SPECTRUM DISORDER Neurotransmission Body Weight Organisms Biology and Life Sciences Gene rearrangement GENE Mice Inbred C57BL lcsh:Genetics Disease Models Animal 030104 developmental biology dup Amniotes Zoology Gene Deletion Neuroscience Chromosomes Human Pair 17 Developmental Biology |
| Zdroj: | PLoS Genetics Plos Genetics, 13, 7, pp. e1006886 PLoS Genetics, Vol 13, Iss 7, p e1006886 (2017) Plos Genetics, 13, e1006886 |
| ISSN: | 1553-7404 |
| Popis: | 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. Author summary The 17q21.31 deletion syndrome, also named Koolen-de Vries syndrome (KdVS), is a rare copy number variants associated in humans with intellectual disability, friendly behavior, congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 region or by variants in the KANSL1 gene in human. The reciprocal 17q21.31 microduplication syndrome is not so well characterized. To investigate the pathophysiology of the syndromes, we studied the deletion, the duplication of the syntenic region and a heterozygous Kansl1 mutant in the mouse. We found affected morphology and cognition, similar to human condition, with genes controlling chromatin organization, synaptic transmission and neurogenesis dysregulated in the hippocampus of KdVS models. In addition we found that synaptic transmission was altered in KdVS mice. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS and extend substantially our knowledge about altered biological processes. Nevertheless, phenotypic differences between deletion and Kansl1+/- models suggested roles of other genes affected by the 17q21.31 deletion. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|