Down Syndrome: Molecular Prospects

One and a half centuries after the discovery of Down syndrome, interesting prospects are opening up for its treatment at the molecular level.

150 years ago, the English doctor J. L. Down discovered the syndrome to which he would eventually give his name. Numerous studies have been done since then to analyze and treat the syndrome, although practically nowhere has it been studied from the molecular level. We are today seeing some new and interesting prospects for its treatment at the gene and even chromosome level.

Dr. John Langdon Haydon Down / Imagen: Langdon Down Centre

Dr. John Langdon Haydon Down / Image: Langdon Down Centre 

The chromosome and gene basis of the syndrome

In 1959 a group of French researchers (Lejeune, Gautier and Turpin) published an article showing that people with this syndrome had an additional chromosome compared to the standard karyotype for our species: instead of 46 chromosomes –that is, 23 pairs-, they had 47. The extra chromosome was very small, and was thought at the time to be the second smallest chromosome. This was therefore proof that Down syndrome was caused by the trisomy of chromosome 21 (1), which is in fact another name for this syndrome.

Cariotipo de trisomía 21 (síndrome de Down) / Imágenes: pixabay / Departamento de Energía de los EE.UU. Programa Genoma Humano .

Trisomy 21 karyotype (Down syndrome) / Images: Pixabay (left) / U.S. Department of Energy. Human Genome Program.

Today one of the controversies arising from the discovery that the syndrome was due to the presence of a small additional chromosome has been clarified. In the early 1960s, it was established that to analyze our chromosomes they needed to be ordered by size, as seen under the microscope. The small chromosome implicated in Down syndrome was therefore assigned to 21st place, as most researchers thought it was larger than another small chromosome in our karyotype, which was labeled with number 22. Pair 23 was reserved for the sex chromosomes X and Y. Today it has been demonstrated that chromosome 22 contains more DNA than chromosome 21 –some 4 million more nucleotide base pairs out of a total of 50; in other words, although for historical reasons the 21st is maintained as the smallest chromosome, strictly speaking it should be the 22nd.

There is also a debate today as to the possible existence of a critical gene region for the syndrome within chromosome 21 itself. This chromosome is composed of a short arm and a long arm, and on the long arm there are several hundred genes that can synthesize proteins, in addition to others that are only transcribed in RNA and fragments of non-functional genes. On the short arm of chromosome 21 there is only DNA to synthesize ribosomal RNA and repetitive DNA, presumably nonfunctional. What occurs in people with Down syndrome is that due to the increase in the dose (from two to three copies) of the genes on the long arm of chromosome 21, different molecular processes take place in both the chromosome itself and in the rest of the genome: increased expression of some genes (that is, producing more RNA and/or proteins than expected), decreased expression in others, changes in the zones where particular genes are expressed, and so on. These molecular modifications account for the anatomical-physiognomic manifestations of Down syndrome (2).

According to some researchers, these alterations are caused by modifications in the expression of many of the genes on the long arm of chromosome 21. Other specialists claim it is the alterations in certain genes –around thirty of them– in what is known as the region 21q22 (3) that give rise to the molecular modifications that form the basis of the syndrome. So genetically speaking, is there a critical region for the syndrome? For the time being the jury is still out.

New treatment prospects

The application of novel molecular techniques on one of the genes in this presumed critical region is starting to open up interesting prospects for treatment of the syndrome at the gene level. This is gene DYRKA1A, which is particularly implicated in brain development. Specifically, in work being done by a group of U.S. researchers led by Dr. J. Lawrence from Worcester, the Xist gene is inserted in one of the DYRKA1A genes in pluripotent cells in a culture obtained from people with trisomy 21 (4). The Xist gene is a gene in the human X chromosome which normally inactivates one of the two X chromosomes carried by women. What happens in this case is that an RNA is synthesized from the gene of one of a woman’s two X chromosomes, which “sticks” to the whole of chromosome 21, preventing it from becoming functional. After inserting the Xist gene in the DYRKA1A gene of one of the three chromosomes 21 in the stem cells obtained from people with trisomy, the normal level of gene expression can be seen to be restored in many of the altered genes in the syndrome.

Los puntos amarillos pequeños representan la expresión del gen Xist. Finalmente, el cromosoma X inactivo se representa en gris.

The small yellow dots represent the expression of the Xist gene. Finally, the inactive X chromosome is shown in gray /Image: University of Navarre

Still more radical is the strategy pursued by a team at Johns Hopkins University and headed by Dr. T. Amano, whose goal is to eliminate the extra chromosome 21 outright from people with the syndrome (5). In this case, they are inserting the gene ZSCAN4 into  pluripotent stem cells, having previously verified that this gene serves to restore the normal chromosome configuration in cells with extra chromosomes. The result of this treatment is that in in vitro stem cell cultures for chromosome 21 there are a large number of cells in which one chromosome 21 is eliminated, and the normal expression of the genes in this chromosome is restored.

4.Esquema donde se ilustra cómo a partir de células pluripotentes trisómicas se puede eliminar el cromosoma 21 adicional - a la izquierda-o cómo se puede silenciar tal cromosoma- a la derecha. ZSCAN4 y XIST son los genes que se introducen en las células trisómicas para conseguir estos objetivos-véase texto

Diagram showing how the extra chromosome 21 (left) can be eliminated from pluripotent stem cells or how this chromosome can be silenced (right) / Source: ncib

These two experiments have so far only taken place in vitro, but they offer new prospects for their application in living organisms in the long or medium term. It would be interesting for example to analyze first what occurs in mouse models of human trisomy 21. Could we then envisage modifying Down syndrome from its genetic source?


  1. Lejeune, J., Gautier, M., Turpin, R. 1959. Stude des chromosomes somatiques de neuf enfants mongoliens. Compt.Rend. Acad. Sci. Paris, 248: 1721-1722.
  2. Olson, L.E. Et al.2004. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science Oct. 22, 306: 687-690.
  3. Pelleri, M. C. et al. 2016. Systematic reanalysis of partial trisomy 21 with or without Down syndrome suggest a small region on 21q.22.18 as critical to the phenotype. Hum. Mol. Genet. Jun 15, 25 (12): 2525-2538.
  4. Jiang, J. et al. 2013. Translating dosage compensation to trisomy 21. Nature, Aug.15, 500 (7462): 296-300.
  5. Amano, T. et al. 2015. Correction of Down syndrome and Edwards syndrome aneuploidies in human cell cultures. DNA Research, Oct 22 (5): 331-342.

Manuel Ruíz Rejón

Granada University, Autonomous University of Madrid