We report on the generation and phenotypic characterization of the monosomic Ms1Dja
mouse, a model of Monosomy 21 covering the 1.6 Mb Lipi
region. The deleted interval is syntenic to the centromeric part of the HSA21, and contains 6 genes that are conserved between human and mouse. Homozygous deletion of this region (nullisomy) resulted in mid-gestational embryonic lethality mostly due to neural tube degeneration with evidence of prominent apoptosis, indicating that at least one of the genes in this region is required for development and maintenance of the neural tube. However, as none of the 6 genes in this region have been reported to be involved in neural tube development (and all are normally expressed in the developing brain of the mouse embryo at both E9.5 and E10.5 
, it is hard to speculate which gene (or genes) might be responsible. However, given that homozygous null Samsn1
mice are viable 
, it is unlikely that loss of these genes causes the embryonic lethality observed.
Detailed phenotypic analysis of monosomic Ms1Dja
mice, found them to be viable, fertile, and to display no obvious differences from wildtype littermate controls in terms of morphology, motor skills, gross behavior, and both clinical chemistry and hematological parameters were normal. They did, however, show deficits in long-term memory retention in a socially relevant testing paradigm. Social recognition is hippocampus-dependent 
and has been used for learning and memory testing 
and for assessing cognitive impairment in mice 
. Thus haploinsufficiency of the genes mapped within the deletion may contribute to the intellectual disability of humans with Monosomy 21, but they do not model the other clinical phenotypes commonly seen in Monosomy 21 patients. However, given all currently known Monosomy 21 patients with “centromeric” deletions carry rearrangements spanning much larger regions of HSA21 than represented in our model, we cannot rule out the possibility that genes in the Lipi
region work in synergy contribute to the cognitive phenotype observed in these patients. In addition, there are 2 genes in the 21q11.2-q21.1 region of HSA21 for which there are no mouse orthologs annotated, namely ABCC13
. Our model does not account for the possible roles that these genes may play in Monosomy 21.
Monosomic mice fed a HFD showed significantly increased fat percentage estimates at 8, 14, and 25 weeks of age compared with controls. However, these significantly increased fat percentage estimates over controls were not observed when the monosomic mice were fed a NFD (except at 8 weeks of age, which might be considered as an early phenotype variation). Considering the fact that the overall fat percentage estimate was much higher in both groups of mice on a HFD (containing 21% crude fat) compared to a NFD (containing 9% crude fat), the HFD can be regarded as an environmental factor that increases fat percentage estimates in the mice. Given that monosomic mice showed significantly higher percentage fat estimates than wildtype controls, it is clear that there is also a genetic factor affecting this phenotypic change. However, although the interaction between genetic susceptibility loci
and environmental factors in the development of obesity have been shown in different analyses performed both in humans and mice 
, to our knowledge, this interaction has not been shown before in patients with deletions encompassing the 21q11.2-q21.1 region.
Although four published studies have reported on the presence or absence of obesity in Monosomy 21 patients with deletions encompassing the 21q11.2-q21.1 region 
, only one found a positive correlation; two cases that presented with mild intellectual disability, some facial abnormalities, and obesity 
. Unfortunately, without knowledge of the diet of these individuals, we can only speculate whether the observed obesity in these patients was diet induced.
There are 6 genes that are conserved between human and mouse in the Lipi-Usp25 region: Lipi, Rbm11, Hspa13, Samsn1, Nrip1 and Usp25. To investigate potential molecular mechanisms leading to HFD-induced obesity in monosomic Ms1Dja mice, we performed qRT-PCR analysis on all the genes from the deleted interval in adipocytes from monosomic and wildtype littermates. We found four of them to show a significant down-regulation in monosomic mice relative to controls (Hspa13, Samsn1, Nrip1 and Usp25) and two of them were not expressed in subcutaneous adipose tissue (Lipi and Rbm11). However, as none of the four genes expressed in adipocytes have been reported to be involved in the regulation of adipocyte metabolism, it is hard to speculate if any of the down-regulated genes might be responsible for HFD-induced increase in fat deposition our monosomic mice.
To-date, homozygous null mice for Samsn1
and Nrip1 
and a mouse model carrying a deletion of the exon 10 of the mutant Lipi
) locus 
have been generated. Samsn1
knockout mice were viable and did not show any overt phenotypic abnormalities, but displayed enhanced adaptive immunity 
. However, body weight and resistance to HFD-induced obesity and hepatic steatosis have not been specifically analyzed in either heterozygous or homozygous Samsn1
mice. Homozygous Nrip1
) mice fed a NFD showed a 20% reduction in body weight and remained leaner than controls even when fed a HFD, despite the fact that Nrip1
affects the function of adipose tissue by blocking both mitochondrial respiration and energy uncoupling and prevents expression of key regulatory genes in white adipose tissue (WAT) 
. In addition, Nrip1−/−
mice were resistant to both age-induced hepatic steatosis and HFD-induced fatty changes in the liver (although this could be explained by the increased expression of genes involved in energy expenditure and mitochondrial uncoupling, and the decreased expression of genes encoding lipogenic enzymes) 
. However, body weight and resistance to HFD-induced obesity and hepatic steatosis was only demonstrated in Nrip1−/−
mice and Nrip1+/−
animals have not been studied. Homozygous Lipi
) mice fed on a NFD showed hepatic steatosis and hypertriglyceridemia, while heterozygous Lipi
) mice did not display any of such phenotypic abnormalities 
. No data for body weight or resistance to HFD-induced obesity have been available for either Lipilpd1/Lipilpd1
mice. Interestingly, sequencing of the human LIPI
) gene in 186 individuals with hypertriglyceridemia and 232 controls identified a nonsynonymous coding SNP 164G>A (C55Y) in two patients withhypertriglyceridemia, indicating that this rare missense mutation in the exon 2 of the LIPI
gene might be associated with an elevated triglycerides level 
. To that end, we evaluated the level of triglicerides in monosomic Ms1Dja
and wildtype littermates, but observed no significant differences between monosomic mice and controls. As none of the other 3 genes in the Lipi-Usp25
region are known to be involved in lipid and carbohydrate metabolism or maintenance of energy homeostasis, it is difficult to hypothesize which gene (or genes) is responsible for HFD-induced increase in fat deposition and fatty changes in livers of our monosomic mice. Importantly, although the Ms1Dja
mice were backcrossed to C57BL/6-Tyrc-Brd
for several generations prior to phenotyping, they will retain some ES derived 129P2/OlaHsd DNA linked to the targeted locus that may carry with it variants that contribute to the phenotypes we observe here.
Monosomy 21 is a rare human disease with variable clinical appearances due to differing gene dosage errors on chromosome 21 resulting in phenotypes including intellectual disability, dysmorphology, and cardiac and/or renal abnormalities 
. Attempts to generate genotype-phenotype correlations in this disease have been complicated by both the small number of patients available for study (there is a lack of informative sets of partial Monosomy 21 patients 
) and the fact that some patients with Monosomy 21 also carry anomalies involving other human chromosomes, such as segmental trisomies and deletions 
. We show here that haploinsufficiency of a gene (or genes) in the Lipi-Usp25
region of MMU16, syntenic to human 21q11.2-q21.1, results in a high-fat diet-induced increase in fat deposition and a deficit in memory retention in monosomic mice. Further studies will be required to understand the molecular causes of these phenotypes.