Genetic dissection of the Down syndrome critical region

Abstract

Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

“…Kcnj6 plays a crucial role in postsynaptic mechanisms because its channels are coupled with alpha-adrenergic, muscarinic cholinergic and cannabinoid receptors but also with gamma-aminobutyric acid B receptors (Blednov et al 2003 ) that modulates the synaptic transmission in TRS21 mouse models (Kleschevnikov et al 2012 ). Our results are in agreement with recent studies showing that a triple copy of Kcnj6 impairs brain and behavioral traits (Cooper et al 2012 ;Jiang et al 2015 ) but the present results demonstrate that the cognitive impairment is mild. The 285E6 mice are mildly impaired for the novel object recognition task.…”

“…A number of studies have reported interactions between genes or chromosomal fragments syntenic to HSA21 (Jiang et al 2015 ;Zhang et al 2014 ). Proteins encoded by genes located on fragments in the D21S17-ETS2 region interact (Fig.…”

Systematic reanalysis of partial trisomy 21 cases with or without Down syndrome suggests a small region on 21q22.13 as critical to the phenotype

“…Should further analysis demonstrate critical functions for DS in HR-DCSR, this might require a rediscussion of the usefulness of mouse models for confuting the existence of a DSCR in mouse (72) as well as for delimiting it (73). Actually, mouse chromosome band 16C4 presents the same loci that surround human HR-DSCR, and in the same order ( Dyrk1a , Kcnj6 , Kcnj15 , Erg , Ets2 ), but it lacks any relevant homology with the HR-DSCR sequence itself that is located between KCNJ6 and KCNJ15 in humans, and such homology cannot be found in the rest of mouse genome.…”

Mouse-based genetic modeling and analysis of Down syndrome

“…[34][35][36][37][38] To determine if a given relatively small region is necessary for a phenotype, a subtractive strategy can be used by compounding a larger duplication with a deletion of the smaller sub-region. 33,[39][40][41][42] Using different combinations of Dp and Df mutants, the smallest genomic region can be identified for a specific DS phenotype. If this region contains 10 or more Hsa21 gene orthologs, it might be necessary to generate new Dp and/or Df mutants to further dissect the region.…”

“…To determine if the triplication of a specific Hsa21 syntenic region, including an entire Hsa21 sytenic region on a mouse chromosome, is necessary and/or sufficient to cause developmental cognitive deficits, cognitively relevant phenotypes of duplication mutants and/or compound mutants were characterized, which include T-maze test, Morris water maze tests and fear conditioning tests as well as analysis of synaptic plasticity using extracellular recording of hippocampal slices. In parallel with Ts65Dn mice, abnormal cognitively relevant phenotypes were observed in Dp (16) 39,41 The extension of such a subtractive strategy has also led to show that the triplications of some Hsa21 gene orthologs are necessary for cognitively relevant phenotypes, including Dyrk1a.…”