Deficiencies in the region syntenic to human 21q22.3 cause cognitive deficits in mice

Abstract

Copy-number variation in the human genome can be disease-causing or phenotypically neutral. This type of genetic rearrangement associated with human chromosome 21 (Hsa21) underlies partial Monosomy 21 and Trisomy 21. Mental retardation is a major clinical manifestation of partial Monosomy 21. To model this human chromosomal deletion disorder, we have generated novel mouse mutants carrying heterozygous deletions of the 2.3-and 1.1-Mb segments on mouse chromosome 10 (Mmu10) and Mmu17, respectively, which are orthologous to the regions on human 21q22.3, using Cre/loxP-mediated chromosome engineering. Alterations of the transcriptional levels of genes within the deleted intervals reflect gene-dosage effects in the mutant mice. The analysis of cognitive behaviors shows that the mutant mice carrying the deletion on either Mmu10 or Mmu17 are impaired in learning and memory. Therefore, these mutants represent mouse models for Monosomy 21-associated mental retardation, which can serve as a powerful tool to study the molecular mechanism underlying the clinical phenotype and should facilitate efforts to identify the haploinsufficient causative genes.

Unraveling the genetic architecture of copy number variants associated with schizophrenia and other neuropsychiatric disorders

“…Using Cre‐lox, researchers have generated deletions on both mouse chromosome 10 and 17 to model the human CNV, 21q22.3 (monosomy 21). The mouse model displays reduced learning and memory function, consistent with the intellectual deficits in patients (Yu et al, ). Similarly, researchers generated duplications on mouse chromosomes 17, 16, and 10 to model the trisomic regions of DS.…”

The telomeric part of the human chromosome 21 from Cstb to Prmt2 is not necessary for the locomotor and short-term memory deficits observed in the Tc1 mouse model of Down syndrome

“…The Pdxk gene is present 3′ downstream of Cstb on Mmu10 and hence the Df(10)1Yey model is larger than our Ms4Yah model. These models were analysed in the open field, Morris watermaze, contextual and fear conditioning tests [55]. Df(10)1Yey mice showed impairment in spatial and learning reference memory as assessed by the Morris watermaze test and associative memory as assessed by fear conditioning test.…”

Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer's Disease

“…One caveat to translational inferences, however, is that the Ts65Dn murine model is only trisomic for approximately 88/161 orthologs on HSA21, and also includes approximately 50 triplicated encoded genes that are not triplicated in HSA21 [14]. Although select cognitive and morphological changes seen in Ts65Dn mice are similar to that found in human DS, future MCS investigations are warranted employing newly generated trisomic models, including the Dp16 and Dp16/Dp17/Dp10 mouse lines [25, 131, 132]. Each of these trisomic models has its own limitations, but together they will likely shed greater insight into the potential of MCS as a therapy for DS.…”