Jacob, a child with Down Syndrome, enjoying a family holiday and browsing in shops, like any other 5 year old child wouldJacob looking at books and watching TV at age 6 years - Down Syndrome doesn't stop normal development, but social attitudes do. - Jacob, a baby with Down Syndrome - Jacob at one year of age

Down Syndrome treatments may evolve and involve turning off the extra chomosome and genes in Down Syndrome, trisomy 21, to create higher intelligence, and less abnormalities. Discovering the Genetic Basis of Down Syndrome

Down syndrome, or Trisomy 21, is caused by all or part of an extra human chromosome 21.

Down syndrome is one of the most frequent genetic disorders and the most frequent genetic cause of mental retardation. Down syndrome phenotypes (observable traits) are variable and include heart malformation, gastrointestinal disorders, immune system defects and early-onset Alzheimer’s disease. However, only mental retardation is invariably present in Down syndrome patients.

It’s very likely that the activity of one or more of these extra genes leads to cognitive impairment.

Clinical and molecular analysis of Down syndrome patients allowed the identification of Down Syndrome Chromosomal Region-1 (DCR-1), a 21q22.2 sub-band, responsible for many features of Down syndrome, including mental retardation.

Thus, Down Syndrome treatments directed at reducing the activity of the extra gene(s) in the DCR-1 region might prevent or reverse the deficit.

This article will discuss progress towards discovering the genetic basis of Down syndrome. The Human genome sequencing project delivered the complete DNA sequence of our species. Numerous data mining tools allowed gene identification and precise localization. The availability of these data promises breakthroughs in the understanding of human pathologies, including Down syndrome.


What is Trisomy 21?

Trisomy 21 means that there are 3 (tri) copies of chromosome (somy) 21.

The chromosomes are holders of the genes, those bits of DNA that direct the production of a wide array of materials that the body needs.

This direction by the gene is called the gene’s “expression”.

In trisomy 21, the presence of an extra set of genes leads to overexpression of the involved genes, in all cells of the afflicted individuals, leading to increased production of certain products called proteins.

For most genes, their overexpression has little effect due to the body’s regulating mechanisms of genes and their products. But the genes that cause Down syndrome appear to be exceptions.

The number of the genes involved in the pathogenesis of Down syndrome remains undetermined.

However, extensive efforts have been carried out to construct a map of the DCR-1 region. At least 28 genes are localized in the DCR-1 of which only a few have been studied as candidate genes.


Mental retardation

Mental retardation and abnormal development of the brain are hallmarks of Down syndrome.

The cognitive features of Down syndrome include a progressive decline in IQ, beginning in the first year and reaching an IQ of 25-55 in adulthood.

Consequently, early implementation of special education programs results in improved cognitive abilities in Down syndrome individuals.

Down syndrome patients have relative strengths in visual-spatial function and deficits in auditory short term memory and productive language.

Emphasizing that IQ is not comprised of a single entity or measure, genetic analysis indicates that multiple regions of chromosome 21 may contribute to mental retardation.

The mental retardation in Down syndrome is mainly a consequence of developmental alterations in neurogenesis, dendritogenesis, and synaptogenesis.

The brain of Down syndrome individuals is characterized by pre- and post-natal abnormalities in synaptogenesis leading to retardation of brain growth, such as lower brain weight, with a small cerebellum, and small cerebral cortex.

Children with Down syndrome have delayed brain maturation with fewer neurons, abnormal synaptic connection, decreased number of dendritic spines and defective cortical layering.

Overall these alterations observed in the brain of Down syndrome, in particular those in key regions involved in learning and memory processes, could be the origin of mental retardation in trisomic patients.


Which genes are involved in Down syndrome?

Human chromosome 21 encodes >300 genes.iii However, only a small region of chromosome 21 needs to be triplicated in order to get the most severe Down syndrome features.

This is the so called Down Syndrome Critical Region (DSCRiv,v) which contains only 33 genesvi.

Exactly how these duplicate genes influence development is not well understood, but it’s thought that only a small set of genes in the DSCR including DSCR1, DOPEY2 and DYRK1A, or APPmay eventually be involved in producing many features of Down syndrome, and contribute significantly, but not exclusively to the mental retardation.


Are common features of Down syndrome linked to the overexpression of specific genes?

Yes. The most likely consequence of the presence of three copies of chromosome 21 is the overexpression of its resident genes, a fact which underlies the pathogenesis of the abnormalities that occur in Down syndrome.

According to the “gene dosage effect hypothesis” the particular pathological traits of Down syndrome, that is, the phenotype, is a direct result of the cumulative effects of the imbalance of the individual gene located on the triplicated chromosome.

Consequently the DSCR was defined as a minimal interval of chromosome 21 that carries the dosage-sensitive genes necessary and sufficient for typical features of Down syndrome individuals.

Several features of Down syndrome have been produced in transgenic mice engineered to overexpress the DSCR genes lending support to the “dosage-sensitive gene” hypothesis.

The molecular level of Down Syndrome

To shed light on the understanding of the molecular effect of the genetic overdosage, gene expression studies have crucial importance to quantify expression variations in Down syndrome tissues and cell types compared to normal ones. In this way, several transcriptome studies have been performed by microarrays or Serial Analysis of Gene Expression (SAGE) using human tissues or cells lines and also mouse trisomic model tissues, particularly focused on total brain.

It was found that the majority of trisomic genes showed transcript levels increased of about 1.5-fold in human and mouse trisomic tissues. Other human chromosome 21 trisomic genes showed different transcriptional changes being overexpressed at different ratios than 1.5 or, for a few of them, decreased expression was found.

Single gene approaches remain indispensable to determine a precise gene expression map in different embryonic, fetal, and adult ages, in human and mouse. In addition, identifying brain cell types expressing a particular gene supplies fundamental information that helps our gene function understanding.


The critical Down syndrome genes

Genes that may have input into Down syndrome include:

  • APP – over expression may be associated with plaques and learning deficits
  • COL6A1 – over expression may be the cause of heart defects
  • ETS2 – over expression may be the cause of skeletal abnormalities and increased rate of apoptosis of neurons
  • DSCR1 – over expression modifies synaptic activity; may contribute to mental retardation
  • DYRK1A – over expression may contribute to mental retardation
  • DOPEY2 – over expression may contribute to mental retardation
  • CRYA1– over expression may be the cause of cataracts

No gene has yet been fully linked to any feature associated with Down syndrome. Thus there is no single critical region for mental retardation in Down syndrome. It is more likely that multiple regions may contribute.


DOPEY2 gene

The human Dopey family member 2 gene, DOPEY2, localized in DSCR, is a member of the Dopey family containing leucine zipper-like domains with protein-protein functions. Mammalian DOPEY2 is highly expressed in brain and overexpressed in cerebellum, the hippocampus, and the cortex in Down syndrome brain and trisomic mouse tissues (Lopes et al., 2003; Lyle et al., 2004).

DOPEY2 was also demonstrated to be over expressed in three fetal brain regions that play central roles in learning and memory.vii

The hippocampal formation works as a control center of the memory circuits and storage and the cortex and cerebellum also participate in the elaboration of memory.

In Down syndrome patients all three regions present neuronal alterations.

These findings correlate to several previous expression studies indicating that the level of transcriptional variations for a given gene can change in the different tissues and brain regions in Down syndrome patients and during development stages.

Transgenic mouse models over expressing DOPEY2 show several neurological alterations correlating to Down syndrome phenotypes.

These mice have increased DOPEY2-expressing cortical cell density corresponding to the abnormal cortical lamination in Down syndrome patients.

They also have cerebellar alterations, with an increased length of the vermis.

In addition, these mice show impairment of learning and memory that could be produced by these neurological abnormalities, suggesting that DOPEY2 could be a candidate gene for these phenotypes.


APP gene

Amyloid precursor protein, or APP gene and mental retardation

By using state-of-the-art genomics Korbel et al. (2009)viii found 12 Down syndrome cases with borderline to normal function all of which included three copies of regions containing APP. Taken together with five families that had increased expression of the region with APP and normal cognition, these data suggest that APP may contribute but is not essential for mental retardation in Down syndrome.

Importantly, Korebel et al. (2009) also found new evidence for a region of human chromosome 21 that may contribute to mental retardation. This includes a region called TMEM1, one of two essential subunits comprising the TRAPPII complex involved in the management and intracellular trafficking.


DYRK1A gene

Due to efforts in isolating the gene(s) responsible for cognitive dysfunction in Down syndrome, the DYRK1A gene was identified within the DSCR on human chromosome 21.

The DRYK1A enzyme plays a critical role in neurodevelopment and may contribute to the learning and memory deficit, altered synaptic plasticity and impaired cell cycle regulation in Down syndrome.

Mice over expressing the DYRK1A protein showed significant hippocampal-dependent learning and memory deficits reminiscent of human Down syndrome. They also showed significant beta-amyloid production in the hippocampus which is a hallmark of Alzheimer disease.

This suggests that over expression of DYRK1A may be closely associated with cognitive dysfunction and with the early onset of Alzheimer disease in Down syndrome.ix


The next step – turning genes off

There appears to be abundant evidence for the role of DYRK1A in Down syndrome.

Nevertheless, we’re still a long way from experimental findings to clinical applications.

Two putative DRYK1A inhibitors were recently developed from in vitro high-throughput screening. One of them is a polyphenolic constituent of tea epigallocatechin 3-gallate (ECCG). ECCG is resported to specifically inhibit approximately 90% activity of DYRK1A. The other agent harmine, was shown to inhibit in vitro approximately 95% activity of DYRK1A in the nanomolar range, though it also had an effect on other kinases including DYRK2 and DYRK3.

One of the characteristics of Down syndrome is the wide variety of features and characteristics of people with trisomy 21.

There is a wide range of mental retardation and developmental delay noted among children with Down syndrome.

Some babies are born with heart defects and others aren’t.

Some children have associated illnesses such as epilepsy or celiac disease, and others don’t.

The first possible reason for this difference lies in the difference in the genes that are triplicated.

It’s not a matter of taking a gene and suppressing it 100%, which may not be good for things in the rest of the our body. You’re just over expressing some proteins a little bit.

In addition, this extra gene is affecting a second gene, which is affecting another gene.

The challenge is to turn down several genes just a bit and at the right time depending on the characteristics of the individual.

These types of Down syndrome treatments, will therefore be very specifically made to an individuals trisonomic 21 genetic code – there will not be a single treatment that can just be given to everyone with Down Syndrome.


References used for shutting down genes as a Down Syndrome treatment.

iii Huang X, Gardiner K. Protein coding features and conservation of novel human chr21 transcript, in preparation.

iv Delabar JM et al., Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Hum Genet 1993; 1: 114-124.

v Ronan A, et al. Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. J Med Genet 2007; 44: 448-451.

vi Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC. The Down syndrome critical region is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci 2009; 29: 5938-5948.

vii Rachidi M, Delezoide A-L, Delabar J-M, Lopes C. A quantitative assessment of gene expression reveals differential overexpression of DOPEY2, a candidate gene for mental retardation, in Down syndrome brain regions. Int J Developm Neurosci 2009; 27: 393-398.

viii Korbel JO, Tirosh-Wagner T, Urban AE, Chen X-N, Kasowski M, et al. The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. PNAS 2009; 106: 12031-12036.

ix Liu F, Liang Z, Wegiel J, Hwang YW, Igbal K, Grundke-Igbal I, Ramakrishna N, Gong CX. Overexpression of Dyrk1A contributes to neurofibrillary degeneration Down syndrome. FASEB J 2008; 22: 3224-33.

Researched and written by Dr. Annette Kirchgessner, Phd (Neuroscience), medical university Professor, minor editing by Donald Urquhart (Psychologist).

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