Down syndrome (DS) has a prevalence of ∼1 in 800 live births and leads to an array of clinical manifestations, from more broadly recognised features such as intellectual disability, skeletal malformations and sensory impairment to lesser-associated pathologies including leukaemia, diabetes, Alzheimer's disease and heart defects. It is caused by the presence of an additional chromosome 21, known as trisomy 21. There are roughly 230 coding genes in chromosome 21, but it is not fully understood which of these initiate DS pathogenesis with their increased expression.
Victor Tybulewicz, Elizabeth Fisher and colleagues have begun to address this paucity in our knowledge by comprehensively phenotyping a mouse strain with an additional copy of a region of murine chromosome 16 that contains genes orthologous to 63% of human chromosome 21 genes. The authors have investigated the effect of increased dosage of these 148 genes on DS-associated phenotypes. They explored 1800 parameters using 28 different procedures, including physiological and neurological analyses and flow cytometry analyses of haematopoiesis. Compared to WT mice, Dp1Tyb mice harboured significant alterations in 468 of these 1800 parameters from 22 procedures, which were strikingly similar between sexes. Neurological manifestations of DS were recapitulated in Dp1Tyb mice, as they displayed impaired short-term memory, sleep and motor function, the latter of which may be associated with motor neuron loss. Other characteristic DS features were also observed, such as defects in skeletal development and impaired hearing, although Dp1Tyb mice did not present any eye defects. Interestingly, there was a significant decrease in perinatal viability in Dp1Tyb mice, possibly due to congenital heart defects, with heart alterations also apparent in 12-week-old mice. Furthermore, lipid profiling suggested a pre-diabetic state in Dp1Tyb mice, and haematopoiesis data suggested a pre-leukaemic condition, both of which are a higher risk for people with DS.
Intriguingly, there were some key features of DS that were not recapitulated in Dp1Tyb mice. Muscle hypotonia and increased body fat are both apparent in people with DS but were not observed in the mice. Furthermore, higher breathing rates were observed in Dp1Tyb mice, which contrasted with lower cardiorespiratory function in people with DS. These features could be driven by increased dosage of genes found in murine chromosomes 10 and 17 that harbour the remaining human chromosome 21 orthologue genes. By identifying ‘dosage-sensitive’ genes and linking them to a pathological manifestation in DS, we can enhance our understanding of this disease and potentially develop novel treatments. This study will enable further research in this area that dissects these genotype and phenotype relationships in DS.