Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling down syndrome

Abstract

Down syndrome (DS) is the most frequent genetic disorder leading to intellectual disabilities and is caused by three copies of human chromosome 21. Mouse models are widely used to better understand the physiopathology in DS or to test new therapeutic approaches. The older and the most widely used mouse models are the trisomic Ts65Dn and the Ts1Cje mice. They display deficits similar to those observed in DS people, such as those in behavior and cognition or in neuronal abnormalities. The Ts65Dn model is currently used for further therapeutic assessment of candidate drugs. In both models, the trisomy was induced by reciprocal chromosomal translocations that were not further characterized. Using a comparative genomic approach, we have been able to locate precisely the translocation breakpoint in these two models and we took advantage of this finding to derive a new and more efficient Ts65Dn genotyping strategy. Furthermore, we found that the translocations introduce additional aneuploidy in both models, with a monosomy of seven genes in the most telomeric part of mouse chromosome 12 in the Ts1Cje and a trisomy of 60 centromeric genes on mouse chromosome 17 in the Ts65Dn. Finally, we report here the overexpression of the newly found aneuploid genes in the Ts65Dn heart and we discuss their potential impact on the validity of the DS model.

Mouse-based genetic modeling and analysis of Down syndrome

“…12 Ts65Dn mice carry an unbalanced derivative, Ts (17 16 )65Dn, of a balanced translocation, which was randomly induced by irradiation. 12 The Ts (17 16 )65Dn chromosome consists of the entire genomic region distal to Mir155 on Mmu16 and a subcentromeric region on Mmu17, which is not syntenic to Hsa21 13,14 (Supplementary Table S1). The second postnatally viable mouse model of DS is Ts1Cje, which carries an unbalanced derivative, Ts (12 16 ) 1Cje, of a balanced translocation, which was induced by gene-targeting in mouse ES cells.…”

“…Ts (12 16 )1Cje chromosome carries the entire genomic region distal to Sod1 on Mmu16 with Sod1 inactivated 13,15 (Supplementary Table S1). Recent analyses showed a heterozygous deletion on Mmu12 in Ts1Cje mice, which is not syntenic to Hsa21.…”

“…Recent analyses showed a heterozygous deletion on Mmu12 in Ts1Cje mice, which is not syntenic to Hsa21. 13,16 The phenotypes of Ts65Dn and Ts1Cje mice have been extensively characterized and, although these mice are not perfect molecular mimics of human DS, they do show many phenotypic features of the human syndrome [17][18][19][20][21] (Supplementary Table S2). …”

Inheritance of balanced translocation t(17; 22) from a Down syndrome mother to a phenotypically normal daughter

“…Down syndrome is a common genetic disorder, occurring in 1 of 700-800 births, with a gender ratio of three boys to two girls (Duchon et al, 2011). It has been reported that there are more than 217,800 cases a year across the world.…”

“…It has been reported that there are more than 217,800 cases a year across the world. The clinical picture of this syndrome is complex; more than 80 phenotypes have been observed in individuals, including intellectual disabilities with delayed learning and cognition, congenital anomalies such as congenital heart disease and childhood leukemia, and the appearance of an Alzheimer-like disease during aging (Fillon-Emery et al, 2004;Duchon et al, 2011;Wilcock et al, 2013).…”