Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition
Résumé
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.
Mots clés
Abnormalities
Multiple/*genetics
Animals
Body Weight
Brain/metabolism/ultrastructure
Chromosome Deletion
Chromosome Duplication/*genetics
Chromosome Structures/genetics/metabolism
Chromosomes
Human
Pair 17/genetics
*Cognition
DNA Copy Number Variations
Disease Models
Animal
Epigenesis
Genetic
Female
Gene Deletion
Gene Rearrangement
Hippocampus/metabolism
Intellectual Disability/*genetics
Male
Mice
Inbred C57BL
Knockout
Neuronal Plasticity/genetics
Nuclear Proteins/*genetics/metabolism
Synaptic Transmission/genetics
Up-Regulation
Domaines
GénétiqueOrigine | Fichiers éditeurs autorisés sur une archive ouverte |
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