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Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 1-4

Genetics of down syndrome: Recent advances

Department of Paediatrics, Fr. Muller Medical College, Kankanady, Mangalore, Karnataka, India

Date of Web Publication15-Mar-2014

Correspondence Address:
K Varadaraj Shenoy
Department of Paediatrics, Fr. Muller Medical College, Kankanady, Mangalore - 570 06, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-9727.128928

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How to cite this article:
Shenoy K V. Genetics of down syndrome: Recent advances. Muller J Med Sci Res 2014;5:1-4

How to cite this URL:
Shenoy K V. Genetics of down syndrome: Recent advances. Muller J Med Sci Res [serial online] 2014 [cited 2023 May 30];5:1-4. Available from: https://www.mjmsr.net/text.asp?2014/5/1/1/128928

Ever since the first description of the disease by John Langdon Down in 1870, research on Down syndrome (DS) focused mainly on the antenatal screening procedures, understanding the genetic etiology and elucidating the clinical features and complications. It is only recently that a clearer picture has started emerging about the molecular genetics of the different phenotypic manifestations of DS. Although at the present time cure is still a far way off in the future, still many newer drugs are being tried to ameliorate the cognitive deficits in children with DS. All this has come about due to advances made in the molecular genetic technologies and availability of DS mouse models. One of the better outcomes of research in DS has been the survival of patients. In the 1930's, the average life expectancy for patients with DS in the developed countries was 9 years but this has increased to more than 60 years now. [1]

The exact number of chromosomes in a human cell was confirmed only in 1956 by Tijo and Levan. The presence of an extra chromosome was first described by Le Jeune in 1958. The first gene to be isolated was superoxide dismutase 1 from chromosome 21 in 1974. With the human genome project starting off in 1993 the entire sequence of chromosome 21 was known by 2000. Human chromosome 21 is an acrocentric chromosome. Its long arm is about 33.6 Mb in length, which represents about 1% of the entire genome. The approximately 400 genes on the long arm are involved in 81 different molecular functions and are localized in 26 different cellular components. The most frequent molecular function is deoxyribonucleic acid (DNA) binding and transcription factor activity and the most frequent biological process involved is signal transduction. Hence, it is natural that abnormalities of chromosome 21 could affect many biological processes in different tissues leading to multiple defects. [2]

It is one thing to ascribe the phenotypic manifestations in DS to the presence of an extra chromosome but another to explain how the presence of the extra chromosome causes the phenotype of DS or in other words to find the genotypic - phenotypic correlations. The variability of clinical features among the three types (non-dysjunction, translocation and mosaic) and even among those with non-dysjunction leads to the conclusion that there must be specific gene or genes, either acting alone or in combination that are responsible for each of the phenotypic manifestations. [3] It is also possible that genes on other chromosomes might affect the functioning of the chromosome 21 genes. The complexity of gene structure and regulation has made the task of identifying genotype-phenotype correlations difficult. [3],[4],[5]

  Mouse Models of DS Top

Many aspects of development of organs especially the central nervous system (CNS) cannot be studied in human beings with the level of accuracy and detail required. In vitro testing also does not replicate the actual complicated processes involved in development. Hence the need to have anima l models. This is especially true when it comes to studying trisomies because of the disruption of the normal developmental processes. Mouse models for studying DS were available from 1974. Mouse models have been critical to our understanding of the molecular genetics of DS. The various mouse models of trisomy developed over the years have to a large extent mimicked closely the genomic content of human chromosome 21 but there are differences in the content of genetic material in mouse models. It is pertinent to ascertain whether similar genetic content will have the same phenotypic effects as it occurs in human beings and to what extent the genes on other chromosomes in the mouse models will affect the function of the trisomic genes. Nevertheless the results obtained in mouse models have subsequently shown to occur in human trisomy 21 also e.g., the reduced volume of the cerebellum and the hippocampus. [5],[6],[7]

The molecular mechanisms responsible for the phenotype of DS can occur at the level of the gene, in the regulatory elements, in the transcription or post-transcriptional phase. Some of these are: 1. Gene expression variability 2. Transcription factor activity 3. Copy number variation (CNV) 4. Conserved non-coding region (CNG) 5. Micro ribonucleic acid (miRNA) activity 6. RNA editing 7. DNA methylation. [4]

There is a lot of phenotypic variability in children with DS. Cognitive impairment is seen in all children but other features such as congenital heart defects, Hirschsprung disease, duodenal atresia, susceptibility to hematologic malignancy etc., occur in a fraction of affected children. Even the degree of cognitive impairment could vary between individuals. [1],[2],[3],[4],[5]

The presence of an extra chromosome by itself increases the variability of expression of euploid genes thus leading to phenotypic variability. [5] Some of the variability in phenotypic expression could be due to the normal population variation. However, two hypotheses have been put forward to explain this variability. One is the dosage sensitive hypothesis according to which due to the presence of an extra chromosome 21, many genes on this chromosome are over expressed. But this may not always be true because gene expression studies have proved that only some genes are overexpressed while others on chromosome 21 are normally expressed or under expressed. The second hypothesis is the genetic homeostasis hypothesis. This states that the phenotypic features of DS are not the result of specific individual genes but are due to the elevated activity of sets of genes which leads to a decrease in genetic homeostasis. These two hypotheses need not be mutually exclusive. Hence there could two types of genes on 21; those which are dosage sensitive which result in phenotypic effects and those which are dosage insensitive i.e., those which do not contribute to phenotypic effects. [2],[5],[6]

The effect of dosage sensitive genes might be allele specific i.e., certain combinations of alleles might contribute to the phenotype, whereas others may not. Only when the protein level from the transcript of 3 genes reaches a threshold level, only then the phenotype will be manifested. [2]

It is important to realize that it is not merely overexpression of specific genes on 21 but the level and variability of expression, the tissues in which it is overexpressed and the developmental stage when it is over expressed are the deciding factors in the pathogenesis of phenotypic manifestations of DS. [6]

Another aspect of gene expression is how much variation occurs in DS. If the level of variation in expression of a gene is more than 1.5 fold between euploid individuals then that gene is an unlikely candidate for the causation of phenotypic effects in DS. In other words genes which show minimal overlap in expression levels between DS and euploid individuals would be good candidates for having a primary role in the phenotype of DS whereas genes with highly variable expression might play a role in the phenotypic variability seen in DS. [8]

  CNVs Top

Are the regions of the genome, in which there are short sequence repeats the no of which varies from individual to individual. Often these CNV's contain genes and their total length may be more than 12% of the entire genome. On chromosome 21, CNV's constitute about 1.2%. [2] Recent studies present evidence that genes located within CNV's have lower but more variable expression levels than genes located outside CNV's. In addition, they might affect the functioning of genes outside CNVs also. The exact role of CNV's in the pathogenesis of phenotype of DS remains to be elucidated. [8]

  Transcription Factors Top

There are about 25 genes on 21 which directly or indirectly regulate transcription of other genes through the elaboration of transcription factors. Overexpression of the transcription factor regulator genes has been proved to cause skeletal anomalies in experimental mice. [2] Further research is required to elucidate the exact molecular mechanism by which the phenotype is brought about.

  Novel RNA Transcripts Top

Recent research has shown that fusion transcripts that are encoded by two or more genes have been described. This process has also been recognized on chromosome 21. The exact mechanisms by which altered expression of these genes in trisomies is a subject matter for further research. [1]

  CNGs Top

The human genome contains large no of CNGs which are non-repetitive and are not transcribed. These are remarkably conserved in mammals over millions of years strongly indicating that they are functional although their function at the present time remains obscure. Chromosome 21 contains about 2262 such elements constituting about 1% of its entire sequence. [2] The exact mechanism of their effect on the production of the Down phenotype remains to be elucidated. Possible roles for CNGs include roles as cis or trans regulatory regions or as elements required for chromatin or chromosome structure. [8]

  MiRNA Top

Are small RNAs which are not translated but have got regulatory effect on other genes either by degradation or repression of the mRNA product by binding to the 3' untranslated region of mRNA molecules, thus influencing the content of the proteome. Five such miRNA genes have been identified on chromosome 21 and available evidence suggest that they affect t brain development and function. They also affect transcription factor genes and genes that control cell signaling when overexpressed in experimental animals. [6],[7]

  RNA Editing Top

Is a process in which adenosine in mRNA is deaminated to inosine. Inosine acts as guanosine during mRNA translation hence the protein sequence could be altered resulting in a different protein product. RNA editing is apparently required for normal functioning of the CNS. An interesting observation is that RNA editing is carried out by enzymes which are coded by genes on 21. The RNA editing of miRNAs could alter the binding of miRNA to its target RNA. This has been demonstrated in mouse models. [5]

  DNA Methylation Top

Is an epigenetic process regulating gene expression. This is required for long-term silencing of genes. This process could play a role in meiosis, memory formation, cancer and oogenesis. Over expression of the gene on chromosome 21, involved in methylation could lead to alterations in DNA methylation and this process could be dynamic and tissue specific. [5],[8]

  Candidate Genes on 21 Top

Research in the past has focused on finding candidate genes responsible for the phenotype of DS. This resulted from the study of rare patients with partial trisomy of 21 which found certain DS critical regions (DSCR) which harbor such candidate genes. However, the consensus after research in mouse models of DS and detailed analysis of partial trisomy patients suggests that although there might be critical regions on 21 which are responsible for certain phenotypes, they alone cannot account for all the manifestations. [2],[3],[5],[8],[9]

  Cell Adhesion Molecules (CAMs) Top

CAMs might also be responsible for the phenotypic manifestations. For example Hirschsprung disease is thought to be due to the DSCAM gene on chromosome 21, which is responsible for the development of the enteric nervous system. [10] DSCAM is involved in cell signaling in the CNS also and hence can affect many processes during the development of the CNS. [4]

  Cognitive Deficits and Brain Function Top

All children with DS have varying degrees of memory impairment and cognitive deficits. Studies of mouse models have implicated defects in neurogenesis, synaptic transmission and cell signaling pathways as responsible for this phenotype. [7],[9] Studies done on mouse models indicate that several regions of the brain are affected [2] and several genes have been implicated. [2],[9] Some of these genes located in the DSCR are DYRK1A, SIM2, RCAN1, DSCAM, KCNJ. [2],[9] GABA mediated inhibition in DS is thought to be the reason for the memory impairment. [7],[9] Reduced sonic hedgehog signaling, as a result of increased amyloid precursor protein (APP) in Trisomy 21 leads to defective cerebellar neurogenesis which explains the hypotonia and poor fine motor control. [9] Cognitive impairment in DS is probably due to loss of function of a set of neurons called the basal forebrain cholinergic neurons. These are maintained by retrograde transport of a nerve growth factor from the hippocampus. This is inhibited by the APP which is overexpressed in trisomy 21. This is also perhaps the pathogenesis of Alzheimer's disease. [3]

DYRKIA is a priming kinase that facilitates the further phosphorylation of numerous proteins by other kinases. Acting in concert with other genes it could alter the development of many cell types. It has been suggested that this could be the cause of learning impairment and heart defects. [2]

  Heart Defects Top

About 40% of children with DS have congenital heart defects, the most common being atrio ventricular septal defects. Various authors have identified genes such as DSCAM in heart critical region (within the DSCR) on chromosome 21 as being responsible for the congenital heart defects. However, another gene cluster COLA1 and COLA2 located outside the DSCR on chromosome 21 which encodes alpha chain of collagen 6 and a gene CRELD 1 on chromosome 3 which codes for a CAM have also been considered as putative candidates. [4],[9]

  Cranio Facial Alterations Top

Although a discrete region on 21 has not been identified as responsible for the craniofacial alterations nevertheless some mouse models have a trisomic region, which contains some genes responsible for dysmorphic facies. However, there is a complex interplay of genes within and outside critical regions on 21 which ultimately produces the facies.

With the advent of newer molecular investigational tools and with collaborative research efforts, the efforts will be made in the next one decade to generate therapies for some of the features like cognitive deficits and to design better treatments with leukemia in these children. Towards this end some of the possible areas of research could be 1. Defining the functions of all genes on 21 2. Determination of which genes on 2 1 are overexpressed, to what extent and in which tissues and at which developmental stages 3. Definition of the extent and significance of CNVs, CNGs and methylation 4. The relative importance of the genome, transcriptome, proteome and the metabolome.

  References Top

1.Wiseman FK, Alford KA, Tybulewicz VL, Fisher EM. Down syndrome - Recent progress and future prospects. Hum Mol Genet 2009;18:R75-83.  Back to cited text no. 1
2.Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: From genomics to pathophysiology. Nat Rev Genet 2004;5:725-38.  Back to cited text no. 2
3.Reeves RH, Garner CC. A year of unprecedented progress in Down syndrome basic research. Ment Retard Dev Disabil Res Rev 2007;13:215-20.  Back to cited text no. 3
4.Newton RE. Important advances in Down syndrome. In: David TJ, editor. Recent Advances in Pediatrics. Vol. 25. New Delhi: Jaypee Brothers Medical Publishers; 2008;25:77-89.  Back to cited text no. 4
5.Patterson D. Molecular genetic analysis of Down syndrome. Hum Genet 2009;126:195-214.  Back to cited text no. 5
6.Patterson D, Costa AC. Down syndrome and genetics - A case of linked histories. Nat Rev Genet 2005;6:137-47.  Back to cited text no. 6
7.Créau N. Molecular and cellular alterations in Down syndrome: Toward the identification of targets for therapeutics. Neural Plast 2012;2012:171639.  Back to cited text no. 7
8.Patterson D. Genetic mechanisms involved in the phenotype of Down syndrome. Ment Retard Dev Disabil Res Rev 2007;13:199-206.  Back to cited text no. 8
9.Lana-Elola E, Watson-Scales SD, Fisher EM, Tybulewicz VL. Down syndrome: Searching for the genetic culprits. Dis Model Mech 2011;4:586-95.  Back to cited text no. 9
10.Jannot AS, Pelet A, Henrion-Caude A, Chaoui A, Masse-Morel M, Arnold S, et al. Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease. PLoS One 2013;8:e62519.  Back to cited text no. 10

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  In this article
Mouse Models of DS
Transcription Fa...
Novel RNA Transc...
RNA Editing
DNA Methylation
Candidate Genes ...
Cell Adhesion Mo...
Cognitive Defici...
Heart Defects
Cranio Facial Al...

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