Which genes are affected by Trisomy 21?

Which Genes are Affected by Trisomy 21?

Intense efforts are being made to identify which triplicated genes are having the most profound effects on the presentation of Trisomy 21 and in particular which ones are affecting the brain and cognition.

This makes it possible to specifically target these genes (usually by inhibition) and therefore counteract their negative effects. The large number of triplicated genes in T21 makes the search for the “culprits” very challenging.

Brain and Neurology in Trisomy 21

  • Cognitive impairment in individuals with DS represents the major concern for families and society.
  • The IQ of individuals with DS ranges between 45 and 71 in children and worsens with age; this, in most cases, is not compatible with an autonomous life (10).
  • A patent feature of DS (10) is a brain size reduction that is particularly prominent in some regions such as the;
      • cerebellum – coordination, balance, muscle activity
      • the frontal cortex – Thinking, planning, decision making
      • the hippocampus – Learning, memory
  • Regarding the causes of brain hypotrophy in DS, evidence in fetal material and mouse models of DS (the most widely-used of which is the Ts65Dn mouse) suggests that in the DS brain neurogenesis is impaired starting from the beginning of brain development (embryonic/fetal life stages)(11).
  • Brain abnormalities in DS were thought to be irreversible, but during the last decade several preclinical studies have shown that in mouse models of DS it is possible to improve or even rescue the major neurodevelopmental alterations of the trisomic brain (12-14). There have also been some promising studies done and young adults with DS where improvements occurred (7, 11).
  • In the neocortex of the DS brain, the density of neurons is markedly reduced, whereas that of astrocytes is increased (9). Suggesting the cell division and differentiation process is flawed, producing too many astrocytes and not enough neurons. Neurons are essential for sensory transmission, sending and receiving information, where as astrocytes are an important component of the blood brain barrier.
  • The genes DYRK1A and DSCR1, contribute to suppressed neuronal differentiation of progenitors in the Ts1Cje mouse model of DS (9).


DYRK1A – Dual-specificity tyrosine phosphorylation-regulated kinase 1A

Over expressed 1.5 fold

Responsible for;

  • Cell differentiation (1)
  • Cell cycle regulation (1)
  • Cell proliferation and apoptosis (1)

DYRK1A Overexpression is suspected to be linked to;

  • DS symptoms such as cognitive disability and reduced brain size (2-3).
  • One of the reasons for the early onset of Alzheimers Disease-like neurodegeneration in DS individuals (3-5).
  • Suppressed neuron production and over production of astrocytes (9)
  • Decreased bone mineralization, bone growth and bone maintenance (6).

Inhibitors of DYRK1A

The most promising substance for inhibition of DYRK1A has been found to be Green tea flavonol epigallocatechin-gallate (EGCG). Numerous studies on DS mouse models,  and promising studies on young adults with DS  have found that consumption of EGCG suppresses DYRK1A activity and thus;

  • reverse cognitive deficits in young adults (7)
  • restore hippocampal neurogenesis (15)
  • rescue defective long-term potentiation in the prefrontal cortex (8)
  • correct brain morphogenesis alterations (16)
  • Restoration of hippocampal neurogenesis (9)
  • Rescues defective long-term potentiation in the prefrontal cortex(17).
  • Restores components of GABAergic and glutamatergic pathways in the cortex and hippocampus, and improves behavioral deficits (18).
  • Rescue mitochondrial function and promote mitochondrial biogenesis (19) study initially done in mice and then with a 10 year old boy with DS.
  • Improved bone mineralisation and bone density (6)
  • In a study, young adults with DS (29 subjects) aged 14–29 years were treated with either green tea extracts in capsule form EGCG (mean EGCG oral dose of 9 mg/kg/day) or a placebo for three months (7). The effects of treatment on indices of neuropsychological performance were examined after 3 months of treatment and 3 months after treatment discontinuation. After 3 months of treatment, EGCG-treated individuals showed a significantly higher percentage of correct answers in visual memory recognition compared with those who had been given the placebo. Three months after treatment discontinuation this effect declined, and treated subjects had a performance that returned to baseline measures.
  • In a subsequent study, (11) with 84 adults, examined the effect of cognitive training alone or cognitive training plus green tea extract for a 12 month period.  The supplement was in capsule form containing 45% EGCG.  Subjects were tested with a battery of neuropsychological tests periodically during treatment, at 12 months (i.e., immediately following treatment cessation) and at 6 months after treatment discontinuation. At 12 months, there were significant differences between the two groups in two of the 15 tests developed for testing cognitive performance and in one of the nine adaptive skills. Subjects that received cognitive training plus EGCG had a better performance in these three tests in comparison with the group that received cognitive training only. Some of these effects persisted in the cognitive training plus EGCG group.

It is worth noting that EGCG can cross the blood-brain and placental barriers (20), pregnant mothers of a baby with DS in utero could supplement.


The use of ECGC as an inhibitor of DYRK1A and therefore improvements in cell differentiation within the brain is very promising.

Down Syndrome is a genetic condition and any supplementation will be ongoing. It is a commitment for life, but any opportunity at improving your child’s cognitive abilities is surely an incredible gift.



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2. Park, J.; Song, W.-J.; Chung, K.C. Function and regulation of Dyrk1A: Towards understanding Down syndrome. Cell. Mol. Life Sci. 2009, 66, 3235–3240. [CrossRef] [PubMed]

3. Yabut, O.; Domogauer, J.; D’Arcangelo, G. Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. J. Neurosci. 2010, 30, 4004–4014. [CrossRef] [PubMed]

4. Tejedor, F.J.; Hämmerle, B. MNB/DYRK1A as a multiple regulator of neuronal development. FEBS J. 2011, 278, 223–235. [CrossRef] [PubMed]

5.  Abbassi, R.; Johns, T.G.; Kassiou, M.; Munoz, L. DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications. Pharmacol. Ther. 2015, 151, 87–98. [CrossRef] [PubMed]

6. Joshua D. Blazek, Irushi Abeysekera, Jiliang Li, Randall J. Roper; Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a, Human Molecular Genetics, Volume 24, Issue 20, 15 October 2015, Pages 5687–5696, https://doi.org/10.1093/hmg/ddv284

7. De la Torre, R., De Sola, S., Pons, M., Duchon, A., de Lagran, M. M., Farré, M., Fitó, M., Benejam, B., Langohr, K., Rodriguez, J., Pujadas, M., Bizot, J. C., Cuenca, A., Janel, N., Catuara, S., Covas, M. I., Blehaut, H., Herault, Y., Delabar, J. M. and Dierssen, M. (2014), Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol. Nutr. Food Res., 58: 278–288.

8. Thomazeau A, Lassalle O, Iafrati J, Souchet B, Guedj F, Janel N, Chavis P, Delabar J, Manzoni OJ.. Prefrontal deficits in a murine model overexpressing the Down syndrome candidate gene dyrk1a. J Neurosci 2014; 34:1138-47; PMID:24453307; http://dx.doi.org/10.1523/JNEUROSCI.2852-13.2014 [PMC free article] [PubMed] [Cross Ref

9. Kurabayashi N1, Sanada K1. Molecular Mechanism Underlying Abnormal Differentiation of Neural Progenitor Cells in the Developing Down Syndrome Brain. Vol 137 (2017) Issue 7 p. 795-800 (article in Japanese).

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11. De la Torre R, de Sola S, Hernandez G, Farre M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, et al. Safety and efficacy of cognitive training plus epigallocatechin-3 gallate in young adults with Down’s syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15:801-10; PMID:27302362; http://dx.doi.org/10.1016/S1474-4422(16)30034-5 [PubMed] [Cross Ref]

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