Deletion of the App-Runx1 region in mice models human partial monosomy 21.

Thomas Arbogast,Arnaud Duchon,Claire Chevalier,Yann Herault,Valérie Nalesso,Hugues Jacobs,Michel Roux,Doulaye Dembele,Olivia Wendling,Matthieu Raveau

doi:10.1242/dmm.017814

Abstract

ABSTRACTPartial monosomy 21 (PM21) is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21). The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage-sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf). Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21.

Highlights

Segmental aneuploidy, which is defined as an abnormal copy number of a genomic region, is a common cause of human genetic disorders and often leads to intellectual disabilities
In this study, the authors characterize the Ms5Yah mouse model, which is deleted for the App-Runx1 region
Histological analysis revealed that the Ms5Yah foetuses that were unable to breathe appeared essentially normal compared to their wild-type littermates, with the exception of the lungs

Summary

Introduction

Segmental aneuploidy, which is defined as an abnormal copy number of a genomic region, is a common cause of human genetic disorders and often leads to intellectual disabilities. Human chromosome 21 (Homo sapiens 21, Hsa21) aneuploidies are associated with trisomy 21 or Down syndrome, which is the principal genetic cause of intellectual disabilities. Modern techniques have confirmed that the complete monosomy of Hsa without any translocation to another chromosome is incompatible with life (Burgess et al, 2014; Toral-Lopez et al, 2012). Depending on their size and location on Hsa, partial deletions are associated with a large heterogeneity of clinical phenotypes. The most common features of PM21 include intellectual disability, craniofacial malformations, short stature, and muscular and cardiac defects (Chettouh et al, 1995; Lindstrand et al, 2010; Lyle et al, 2009; Roberson et al, 2011; Theodoropoulos et al, 1995; Valero et al, 1999)

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