Trisomy of Human Chromosome 21 Orthologs Mapping to Mouse Chromosome 10 Cause Age and Sex-Specific Learning Differences: Relevance to Down Syndrome.

Ross Minter,Katheleen J Gardiner

doi:10.3390/genes12111697

Abstract

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability. The Dp10(1)Yey (Dp10) is a mouse model of DS that is trisomic for orthologs of 25% of the Hsa21 protein-coding genes, the entirety of the Hsa21 syntenic region on mouse chromosome 10. Trisomic genes include several involved in brain development and function, two that modify and regulate the activities of sex hormones, and two that produce sex-specific phenotypes as null mutants. These last four are the only Hsa21 genes with known sexually dimorphic properties. Relatively little is known about the potential contributions to the DS phenotype of segmental trisomy of Mmu10 orthologs. Here, we have tested separate cohorts of female and male Dp10 mice, at 3 and 9 months of age, in an open field elevated zero maze, rotarod, and balance beam, plus the learning and memory tasks, spontaneous alternation, puzzle box, double-H maze, context fear conditioning, and acoustic startle/prepulse inhibition, that depend upon the function of the prefrontal cortex, striatum, hippocampus, and cerebellum. We show that there are age and sex-specific differences in strengths and weaknesses, suggesting that genes within the telomere proximal region of Hsa21 influence the DS phenotype.

Highlights

Accepted: 25 October 2021Human chromosome 21 (Hsa21) encodes ~165 classical protein-coding genes,~50members of the Keratin Associated Protein family (KRTAP), and several hundred other transcribed sequences that may encode functional RNAs, short open reading frames, or merely transcriptional noise [1]
Impairments in executive function, some spatial navigation strategies, and language skills are well documented in Down syndrome (DS) [7,8,9,10,11,12], implicating the prefrontal cortex, hippocampus, and cerebellum, respectively [7,13,14,15,16], there are recent reports of enhanced spatial learning in strategies implicating the striatum [17,18]
The age and sex-dependent learning/memory strengths and weaknesses described here for the Dp10 suggest that trisomy of these orthologous Hsa21 genes contributes to the phenotypic landscape of intellectual disability (ID) in DS

Summary

Introduction

Human chromosome 21 (Hsa21) encodes ~165 classical protein-coding genes,. ~50members of the Keratin Associated Protein family (KRTAP), and several hundred other transcribed sequences that may encode functional RNAs, short open reading frames, or merely transcriptional noise [1]. Some subset of these genes, when present in three copies, contributes to the phenotypic features of Down syndrome (DS), trisomy of Hsa. The full phenotype of DS is complex, highly variable in penetrance and severity, and can affect many organs and organ systems [2,3]. Other neurological features seen in DS include the increased incidence of seizures and autism, and the development of the neuropathology of Alzheimer’s

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