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

Thomas Arbogast,Giovanni Iacono,Mohammed Selloum,Nael Nadif Kasri,R Mark Henkelman,David A Koolen,Tania Sorg,Katrin Linda,Xander Houbaert,Nurudeen O Afinowi,Claire Chevalier,Matthijs C Van Eede,Yann Humeau,Marie‐Christine Birling ,Christine Laliberté ,Bert B.a De Vries ,Henk Stunnenberg ,Hamid Méziane ,Maksym V Kopanitsa ,Yann Hérault

doi:10.1371/journal.pgen.1006886

Abstract

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.

Highlights

The Koolen-de Vries syndrome (KdVS) has a prevalence estimated at 1/55,000 based upon CNV studies[1,2,3] and was primary described as a consequence of the 17q21.31 microdeletion
The 17q21.31 deletion syndrome, named Koolen-de Vries syndrome (KdVS), is a rare copy number variants associated in humans with intellectual disability, friendly behavior, congenital malformations
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

Summary

Introduction

The Koolen-de Vries syndrome (KdVS) has a prevalence estimated at 1/55,000 based upon CNV studies[1,2,3] and was primary described as a consequence of the 17q21.31 microdeletion. Patients with KdVS present characteristic facial dysmorphisms[4] and clinical features including intellectual disability, friendly behavior, hypotonia, and several brain anomalies[5,6,7]. Microdeletions and microduplications of genomic fragments in the 17q21.3 region ranging from 400 to 800kb have been found in individuals with intellectual disability[6, 8]; these genomic fragments include five protein-coding genes: CRHR1, SPPL2C, MAPT, STH, and KANSL1. Only eight patients have been described in the literature[8,9,10,11,12]. Two cases out of eight have been diagnosed with autism spectrum disorder (ASD)

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