Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype–phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). Approximately 0.45% of human conceptions are trisomic for Hsa21 (1). The incidence of trisomy is influenced by maternal age and differs between populations (between 1 in 319 and 1 in 1000 live births are trisomic for Hsa21) (2–6). Trisomic fetuses are at an elevated risk of miscarriage, and people with DS have an increased risk of developing several medical conditions (7). Recent advances in medical treatment and social inclusion have significantly increased the life expectancy of people with DS. In economically developed countries, the average life span of people who are trisomic for Hsa21 is now greater than 55 years (8). In this review, we will discuss novel findings in the understanding of DS and highlight future important avenues of research.
The additional copy of Hsa21, in people with DS, is proposed to result in the increased expression of many of the genes encoded on this chromosome. The imbalance in expression of Hsa21 and non-Hsa21 genes is hypothesized to result in the many phenotypes that characterize DS. However, only some of the Hsa21 genes are likely to be dosage-sensitive, such that the phenotype they confer is altered by gene-copy number. Thus to understand DS, it is crucial both to understand the genomic content of Hsa21 and to evaluate how the expression levels of these genes are altered by the presence of a third copy of Hsa21. There have been a number of recent advances in genomics relevant to DS. For example, the traditional definition of a gene has been modified (Box 1). A number of fusion transcripts that are encoded by two or more genes previously considered to be separate have been reported, such as the transcript encoded by exons from the Hsa21, DONSON and ATP50 genes (9). Whether these transcripts represent novel genes has yet to be determined. However, the number of genes recognized on Hsa21 is likely to continue to increase from the current count of more than 400 (10). In particular, as algorithms to identify non-coding RNAs (e.g. microRNAs) improve, the number of recognized genes may increase. Five microRNAs have been identified on Hsa21 (11,12). MicroRNAs regulate the expression of other genes (13), and their role in DS is not fully understood. Spatial and temporal mapping of the Hsa21 gene expression is also critical to the understanding of DS. The increase in expression of some Hsa21 genes caused by trisomy of Hsa21 has been recently shown to lie within the range of natural variations in the expression of these genes in the euploid population (14,15). Similar findings have also been reported in the Ts(1716)65Dn (Ts65Dn) mouse model of DS (Fig. 1) (16).
Mouse models of Hsa21 trisomy and monosomy. Hsa21 (orange) is syntenic with regions of mouse chromosomes 16 (Mmu16, blue), 17 (Mmu 17, green) and 10 (Mmu10, grey). The Tc1 mouse model carries a freely segregating copy of Hsa21, which has two deleted regions, such that the model is trisomic for the majority of genes on Hsa21. The Dp1Yu, Ts65Dn, Ts1Cje and Ts1Rhr mouse models contain an additional copy of regions of mouse chromosome 16 that are syntenic with Hsa21, such that they are trisomic for a proportion of Hsa21 genes. The Ms1Rhr mouse model contains a deletion of a region of Mmu16; the Ms1Yah mouse model contains a deletion of a region of Mmu10. Hence, these models are monosomic for the genes in these deleted Hsa21 syntenic segments.
People with Down syndrome are born with three - rather than two - copies of chromosome 21.
People with Down syndrome are born with three - rather than two - copies of chromosome 21. This extra chromosome causes cognitive disability, early-onset Alzheimer's disease, increased risk of leukemia, heart defects and abnormal function in the immune and endocrine systems.
While most research into Down syndrome has focused on understanding the the mechanisms behind its symptoms, Jeanne Lawrence, PhD, from University of Massachusetts Medical School (UMMS), and her team have directly addressed the issue of the third chromosome, known as trisomy 21.
"I never heard anyone even speculate about doing this," Dr. Lawrence told Medical News Today, "but it was natural for me because I have interests/background in clinical human genetics and counseling as well as basic epigenetics."
XIST chromosome therapy
The UMMS team has reported initial success in silencing the additional chromosome in pluripotent stem cells donated by a patient with Down syndrome. They achieved this by inserting an RNA gene into the additional copy of chromosome 21.
This gene, called XIST, plays a role in turning off one of the two X chromosomes in female mammals, and the UMMS researchers found that it was effective at repressing the genes across the extra chromosome in their laboratory stem cells.
- About half of children with Down syndrome are born with heart problems
- A woman's risk of having a child with Down syndrome is significantly higher at age 35 and older
- Most children with Down syndrome never reach their average adult height, as physical development is slower.
Learn more about Down syndrome
Now, Dr. Lawrence told MNT, the team is "working on inserting XIST into a trisomic chromosome of two different mouse models, into embryonic stem cells."
"These are technically challenging experiments," she admitted, "and we have encountered some issues with the embryonic stem cells available." Nevertheless, the team remains hopeful that their XIST therapy can correct Down syndrome-related pathologies in a mouse model, "but it will be some time before we have the full test of that in hand."
"When we first set out to test the feasibility of this in human Down syndrome patient-derived cells, there was a large risk that the effort would take a long time and not be successful," she added. "So one would have to be quite motivated to try this."
If Dr. Lawrence's XIST therapy is proved to be effective, she says that while it would provide "probably not a full cure," the treatment may improve certain aspects of the condition in Down syndrome patients, "but all need to be further developed and tested."
Dr. Lawrence is particularly interested in the associations between Down syndrome and Alzheimer's and leukemia. "Down syndrome is important in itself," she said, "but it will be increasingly important as a form of early-onset Alzheimer's disease, and study of this in Down syndrome will help the broader population, which has a substantial chance to develop Alzheimer's disease with age."
"From my perspective, Dr. Lawrence's and colleagues' research is a very elegant study and a spectacular accomplishment," Dr. Michael M. Harpold, chief scientific officer of the LuMind Foundation, told MNT, adding:
"This research will have a number of important potential research applications to better understand aspects of Down syndrome and will provide very useful new laboratory research tools and cells for molecular and cellular research, including laboratory research relevant to cognition and other areas in Down syndrome. This represents the primary research utility of this research. Any potential human therapeutic approaches and applications based on this research, if any, will be many years away; many significant technical hurdles remain."
Though not involved in the UMMS study, the LuMind Foundation fund research into a wide spectrum of Down syndrome-related research - from sleep and cognition to restoring neuronal pathways.
New drug targets for improving cognitive function in people with Down syndrome
Dr. Harpold identifies one area of research that is yielding particularly exciting results at the moment.
Dr. Jamie Edgin: "Those who work with or love people with Down syndrome must help educate others to overcome some common misperceptions about Down syndrome."
By identifying mechanisms involved in the developmental intellectual disability of Down syndrome - as well as the early-onset Alzheimer's component of the condition - LuMind-associated research has found specific drug targets that Dr. Harpold says "have been shown in the laboratory to mediate improvement in cognitive function and/or ameliorate the Alzheimer's disease associated neurodegeneration in Down syndrome."
This research includes the development of a novel anti-amyloid vaccine to prevent Alzheimer's disease in people with Down syndrome, which is due to begin a clinical trial soon.
In 2011, LuMind also partnered with the pharmaceutical company Roche in bringing a new drug designed to address the cognitive and behavioral deficits of Down syndrome to clinical trial. A large, multi-national phase 2 trial was initiated earlier this year, and Dr. Harpold describes the foundation as being "extremely pleased" with the progress of the "landmark" trials so far.
IQ, sleep apnea and adaptive behavior
"There are significant new studies by Dr. Jamie Edgin and colleagues," Dr. Harpold says, "which represent an important deeper understanding of the correlation between levels of cognitive function and sleep dysfunction, including sleep apnea, in people with Down syndrome."
In her 2014 study published in the journal Developmental Medicine and Child Neurology, Dr. Edgin and colleagues presented results demonstrating that children with Down syndrome who also have sleep apnea average a verbal IQ score nine points lower than those without sleep apnea.
Her previous work - some of which we touched on in yesterday's spotlight feature - has looked at the role "adaptive behavior" plays in "the Down syndrome advantage," where even though people with Down syndrome have lower IQ scores than the general population, this does not necessarily impede their overall well-being.
"IQ and adaptive behavior are two ways of measuring a person's functional level, with IQ having a heavy focus on verbal learning," Dr. Edgin explained to MNT. "Adaptive behavior is a broad functional measure that incorporates a wider set of daily living skills, including social skills, personal living skills and communication."
"People with Down syndrome often have difficulties in expressive language and verbal working memory, two cognitive problems that lower their IQ scores. However, because they often can excel in day to day living tasks, adaptive behavior scores can be higher (on average) than IQ scores. This difference in 'adaptive' behavior may be what people are referring to when they describe the 'easy-going' or 'helpful' nature of their child. It should be noted that the dissociation between IQ and adaptive is a difference that occurs on average when we study groups of people with Down syndrome, but that between individuals there is a wide range of variability."
Dr. Edgin is one researcher who believes that, as important as scientific breakthroughs are, increasing understanding of people with Down syndrome among the general population is equally essential.
"Through education and increased advocacy efforts we can help the community at large understand individuals with Down syndrome and their strengths and weaknesses," she told us.
"They are people first," she emphasized, "and as with all people they have areas in which they excel, are happy and successful, and areas in which they need more support. Those who work with or love people with Down syndrome must help educate others to overcome some common misperceptions about Down syndrome."