Down syndrome pathophysiology: Difference between revisions

	Down syndrome Microchapters
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Down syndrome from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Sociological and Cultural Aspects
Case Studies
Case #1
Down syndrome pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Down syndrome pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Down syndrome pathophysiology
CDC on Down syndrome pathophysiology
Down syndrome pathophysiology in the news
Blogs on Down syndrome pathophysiology
Directions to Hospitals Treating Down syndrome
Risk calculators and risk factors for Down syndrome pathophysiology

← Older edit Newer edit →

VisualWikitext

Revision as of 23:23, 18 March 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pathophysiology

Table 1: Some genes located on the long arm of chromosome 21^[1]
Gene	OMIM Reference	Location	Purported Function
APP	104760	21q21	Amyloid beta A4 precursor protein. Suspected to have a major role in cognitive difficulties. One of the first genes studied with transgenic mice with Down syndrome.^[2]
SOD1	147450	21q22.1	Superoxide dismutase. Possible role in Alzheimer's disease. Anti-oxidant as well as possible affects on the immuno-system.
DYRK	600855	21q22.1	Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A. May have an effect on mental development through abnormal neurogenesis. ^[3]
IFNAR	107450	21q22.1	Interferon, Alpha, Beta, and Omega, Receptor. Responsible for the expression of interferon, which affects the immuno-system.
DSCR1	602917	21q22.1–21q22.2	Down Syndrome Critical Region Gene 1. Possibly part of a signal transduction pathway involving both heart and brain.^[4]
COL6A1	120220	21q22.3	Collagen, type I, alpha 1 gene. May have an effect on heart disease.
ETS2	164740	21q22.3	Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."^[5]
CRYA1	123580	21q22.3	Crystallin, Alpha-A. Involved in the synthesis of Crystallin, a major component of the lens in eyes. May be cause of cataracts.

Specific genes

Amyloid beta (APP)

Location of the APP gene on chromosome 21 in humans.

One chromosome 21 gene that might predispose Down syndrome individuals to develop Alzheimer's pathology is the gene that encodes the precursor of the amyloid protein. Neurofibrillary tangles and amyloid plaques are commonly found in both Down syndrome and Alzheimer's individuals. Layer II of the entorhinal cortex and the subiculum, both critical for memory consolidation, are among the first affected by the damage. A gradual decrease in the number of nerve cells throughout the cortex follows. A few years ago, Johns Hopkins scientists created a genetically engineered mouse called Ts65Dn (segmental trisomy 16 mouse) as an excellent model for studying the Down syndrome. Ts65Dn mouse has genes on chromosomes 16 that are very similar to the human chromosome 21 genes. Recently, researchers have used this transgenic mouse to connect APP to cognitive problems among the mice.^[2]

Superoxide dismutase (SOD1)

Location of the SOD1 gene on chromosome 21 in humans.

Some (but not all) studies have shown that the activity of the superoxide dismutase enzyme is elevated in Down syndrome. SOD converts oxygen radicals to hydrogen peroxide and water. Oxygen radicals produced in cells can be damaging to cellular structures, hence the important role of SOD. However, the hypothesis says that once SOD activity increases disproportionately to enzymes responsible for removal of hydrogen peroxide (e.g., glutathione peroxidase), the cells will suffer from a peroxide damage. Some scientists believe that the treatment of Down syndrome neurons with free radical scavengers can substantially prevent neuronal degeneration. Oxidative damage to neurons results in rapid brain aging similar to that of Alzheimer's disease.

References

↑ See Leshin, L. (2003). "Trisomy 21: The Story of Down Syndrome". Retrieved 2006-05-21.
↑ ^2.0 ^2.1 Chandra Shekhar (6 July 2006). "Down syndrome traced to one gene". The Scientist. Retrieved 2006-07-11. Check date values in: |date= (help)
↑ Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L.; Kurnit, D. M. (1996). "Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome 'critical region". Genomics. 38: 331–339.
↑ Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (1995). "A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart". Hum Mol Genet. 4 (10): 1935–1944.
↑ OMIM, NIH. "V-ETS Avian Erythroblastosis virus E26 Oncogene Homolog 2". Retrieved 2006-06-29.

Template:WH Template:WS

[Leshin-1] See Leshin, L. (2003). "Trisomy 21: The Story of Down Syndrome". Retrieved 2006-05-21.

[Shekhar2006-2] 2.0 ^2.1 Chandra Shekhar (6 July 2006). "Down syndrome traced to one gene". The Scientist. Retrieved 2006-07-11. Check date values in: |date= (help)

[3] Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L.; Kurnit, D. M. (1996). "Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome 'critical region". Genomics. 38: 331–339.

[4] Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (1995). "A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart". Hum Mol Genet. 4 (10): 1935–1944.

[5] OMIM, NIH. "V-ETS Avian Erythroblastosis virus E26 Oncogene Homolog 2". Retrieved 2006-06-29.

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
 <div style="-webkit-user-select: none;">
-{|class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;
+{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
 |-
 | {{#ev:youtube|https://https://www.youtube.com/watch?v=ze_6VWwLtOE|350}}
@@ Line 10: / Line 10: @@
 ==Overview==
 ==Pathophysiology==
-===Genetics===
-[[Image:Human chromosome 21.png|left|thumb|Chromosome 21 from Human Genome Program]][[Image:Karyotype.png|left|thumb|Normal human [[Karyotype]].]]
-'''Down syndrome''' is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the [[Chromosome 21 (human)|21st chromosome]], either in whole ([[Aneuploidy#Trisomy|trisomy]] [[Chromosome 21 (human)|21]]) or part (such as due to [[Chromosomal translocation|translocations]]). The effects of the extra copy varies greatly from individual to individual, depending on the extent of the extra copy, genetic background, environmental factors, and random chance.  Down syndrome can occur in all human populations, and analogous effects have been found in other species, such as chimpanzees and mice.  Recently, researchers have been able to create [[transgenic]] mice with most of human chromosome 21 (in addition to their normal chromosomes).<ref>{{cite web| url=http://news.bbc.co.uk/1/hi/health/4268226.stm| title=Down's syndrome recreated in mice| author=BBC News| accessdate=2006-06-14| date=[[22 September]] [[2005]]}}</ref>
-A normal human [[karyotype]] is shown here.  Every chromosome has two copies.  In the bottom right, there are chromosomal differences between males (XY) and females (XX), which do not concern us.  A normal human karyotype is designated as 46,XX or 46,XY, indicating 46 chromosomes with an XX arrangement for females and 46 chromosomes with an XY arrangement for males.<ref>For a description of human karyotype see {{cite web| author=Mittleman, A. (editor)| year=1995| url=http://www.iscn1995.org/| title=An International System for Human Cytogenetic Nomeclature| accessdate=2006-06-04}}</ref>  For this section, we will use females for the karyotype designation (46,XX).
-The extra chromosomal material can come about in several distinct ways.  These are explained in the following sections.
-====Trisomy 21====
-[[Image:Down Syndrome Karyotype.png|left|thumb|[[Karyotype]] for trisomy Down syndrome.  Notice the three copies of chromosome 21.]]
-Trisomy 21 (47,XX,+21) is caused by a [[Meiosis|meiotic]] [[nondisjunction]] event.<ref>There is a nice animation that shows nondisjunction at {{cite web| url=http://www.screening.nhs.uk/downs/home.htm| title=Meiotic nondisjunction animation| accessdate=2006-07-01}}</ref>  A normal [[gamete]] (either egg or sperm) has one copy of each chromosome (23 total).  When it is combined with a gamete from the other parent during conception, the child has 46 chromosomes.  However, with nondisjunction, a gamete is produced with an extra copy of chromosome 21 (the gamete has 24 chromosomes).  When combined with a normal gamete from the other parent, the child now has 47 chromosomes, with three copies of chromosome 21.  The trisomy 21 karyotype figure shows the chromosomal arrangement, with the prominent extra chromosome 21.
-Trisomy 21 is the cause of approximately 95% of observed Down syndromes, with 88% coming from nondisjunction in the maternal gamete and 8% coming from nondisjunction in the paternal gamete.<ref name=occurrence>{{cite web|url=http://www.nichd.nih.gov/publications/pubs/downsyndrome/down.htm#TheOccurrence|title=Down syndrome occurrence rates (NIH)|accessdate=2006-06-02}}</ref>  [[Mitosis|Mitotic]] nondisjunctions after conception would lead to mosaicism, and is discussed later.
-There has been reported some cases of Down syndrome parents having trisomy 21 children.<ref>For an example of mosaic Down syndrome mother, see {{cite book| author=Karkany, J.| year=1971| title=Congenital Malformations| location=Chicago| publisher=Year Book Medical Publishers, Inc.| pages=319-322| id=ISBN 0-8151-9098-0}}</ref>  In these cases (all from mothers), the ovaries were trisomy 21, leading to a secondary nondisjunction during gametogenesis and a gamete with an extra chromosome 21.  Such Down syndrome trisomies are indistinguishable from Down syndrome trisomies created through meiotic nondisjunction.
-====Robertsonian translocation====
-[[Image:Balanced Translocation.png|left|thumb|150px|Balanced translocation with chromosomes 14 and 21q.]]
-[[Image:Down syndrome translocation.png|left|thumb|Translocation [[karyotype]] for Down syndrome with 14/21 Robertsonian translocation.  Notice the three copies of 21q (the long arm of chromosome 21).]]
-The extra chromosome 21 material that causes Down syndrome may be due to a [[Robertsonian translocation]].  The long arm of [[Chromosome 21 (human)|chromosome 21]] is attached to another chromosome, often [[Chromosome 14 (human)|chromosome 14]] (45,XX,t(14;21q)) or itself (called an [[isochromosome]], 45,XX,t(21q;21q)) as seen in the translocation karyotype figure.
-Translocation Down syndrome can be ''de novo''; that is, not inherited but occurring at the time of an individual's conception, or may be inherited from a parent with a balanced translocation.  The balanced translocation figure shows a 14/21 translocation, where the other chromosomes are not shown.  The individual has two copies of everything on chromosome 14, and two copies of all of the material on the long arm of chromosome 21 (21q).  The individual only has one copy of the material on the short arm of chromosome 21 (21p), but this appears to have no discernable effect.  Individuals with this chromosomal arrangement are phenotypically normal.  During [[meiosis]], the chromosomal arrangement interferes with normal [[disjunction|separation]] of chromosomes.  Possible gametic arrangements are: Normal 14 and normal 21; Translocated 14/21 and normal 21; Translocated 14/21 only; Normal 14 only.  When combined with a normal gamete from the other parent, the last is lethal, leading to [[spontaneous abortion]].  The first, combined with a normal gamete from the other parent, gives rise to a normal child.  The second leads to a translocation Down syndrome child (see translocation karyotype figure).  The third becomes a translocation carrier, like the parent.
-Translocation Down syndrome is often referred to as ''familial Down syndrome''.  It is the cause of 2-3% of the observed Down syndromes.<ref name=occurrence>{{cite web|url=http://www.nichd.nih.gov/publications/pubs/downsyndrome/down.htm#TheOccurrence|title=Down syndrome occurrence rates (NIH)|accessdate=2006-06-02}}</ref>  It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.
-====Mosaicism====
-Mosaic Down syndrome is when some of the cells in the body are normal and some cells have trisomy 21, an arrangement called a [[Mosaic (genetics)|mosaic]] (46,XX/47,XX,+21).<ref>[http://www.mosaicdownsyndrome.com Mosaic Down Syndrome on the Web]</ref>  This can occur in one of two ways:  A [[nondisjunction]] event during an early cell division leads to a fraction of the cells with trisomy 21; or a Down syndrome embryo undergoes [[nondisjunction]] and some of the cells in the embryo revert back to the normal chromosomal arrangement.  There is considerable variability in the fraction of trisomy 21, both as a whole and tissue-by-tissue.  This is the cause of 1–2% of the observed Down syndromes.<ref name=occurrence>{{cite web|url=http://www.nichd.nih.gov/publications/pubs/downsyndrome/down.htm#TheOccurrence|title=Down syndrome occurrence rates (NIH)|accessdate=2006-06-02}}</ref>  There is evidence that mosaic Down syndrome may produce less developmental delay, on average, than full trisomy 21.<ref>{{cite web| author= Leshin, L.| year=2000| url=http://www.ds-health.com/mosaic.htm| title=Mosaic Down Syndrome|accessdate=2006-06-02}}</ref>
-====Duplication of a portion of chromosome 21====
-Rarely, a region of chromosome 21 will undergo a duplication event.  This will lead to extra copies of some, but not all, of the genes on chromosome 21 (46,XX,dup(21q)).  If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics.  This cause is very rare and no rate estimates are possible.
-===Genetic Research===
-Down syndrome is “a developmental abnormality characterized by [[trisomy]] of human [[chromosome 21]] (Nelson 619). The extra copy of chromosome-21 leads to an over expression of certain [[genes]] located on chromosome-21.
-Research by Arron ''et al'' shows that some of the [[phenotypes]] (displayed genetic characteristics), associated with Down Syndrome can be related to the dysregulation of gene-regulating proteins (596). The gene-regulating proteins bind to [[DNA]] and initiate certain segments of DNA to be replicated for the production of a certain protein (Arron ''et al''. 596).   The gene-regulator in interest is called NFATc.   Its activities are controlled by two proteins, DSCR1 and DYRK1A; these genes are located on chromosome-21 (Epstein 582). In people with Down Syndrome, these proteins have 1.5 times greater concentration than normal (Arron ''et al''. 597). The elevated levels of DSCR1 and DYRK1A mean that most of the NFATc is located in the [[cytoplasm]] rather than in the [[nucleus (cell)|nucleus]] promoting [[DNA replication]] which will produce vital proteins (Epstein 583).
-This dysregulation was discovered by testing in [[transgenic]] mice. The mice had segments of their chromosomes duplicated to simulate a human chromosme-21 trisomy (Arron ''et al''. 597).  A common characteristic of Down Syndrome is poor muscle tone, so a test involving the grip strength of the mice showed that the genetically modified mice had a significantly weaker grip (Arron ''et al''. 596). The mice squeezed a probe with a paw; the modified mice displayed a .2 Newton (measurement of force) weaker grip (Arron ''et al''. 596). Down syndrome is also characterized by increased socialization.  Both modified and unmodified mice were observed for social interaction. The modified mice showed as many as 25% more interactions per time period as the unmodified mice (Arron ''et al''. 596).
-The genes that may be responsible for the phenotypes associated may be located proximal to 21q22.3. Testing by Olson et al, in transgenic mice show the duplicated genes presumed to cause the phenotypes are not enough to cause the exact features. While the mice had sections of multiple genes duplicated to approximate a human chromosome-21 triplication, they only showed slight craniofacial abnormalities (688-690). The transgenic mice were compared to mice that had no gene duplication by measuring distances on various points on their skeletal structure and comparing them to the normal mice (Olson ''et al''. 687). The exact characteristics of Down Syndrome were not observed, so more genes involved for Down Syndrome [[phenotypes]] have to be located elsewhere.
-Reeves ''et al'', using 250 clones of chromosme-21 and specific gene markers, were able to map the gene in mutated bacteria. The testing had 99.7% coverage of the gene with 99.9995% accuracy due to multiple redundancies in the mapping techniques. In the study 225 genes were identified (311-313).
-The search for major genes that may be involved in Down syndrome symptoms is normally in the region 21q21–21q22.3. However, studies by Reeves ''et al''. show that 41% of the genes on chromosome-21 of have no functional purpose, and only 54% of functional genes have a known protein sequence. Functionality of genes was determined by a computer using [[exon]] prediction analysis (312). [[Exon]] sequence was obtained by the same procedures of the chromosome-21 mapping.
-Research has led to an understanding that two genes located on chromosome-21, that code for proteins that control gene regulators, DSCR1 and DYRK1A can be responsible for some of the phenotypes associated with [[Down Syndrome]]. DSCR1 and DYRK1A cannot be blamed outright for the symptoms; there are a lot of genes that have no known purpose. And further research is needed in order to treat Down Sydrome more effectively.
-Recent use of [[genetically modified organism|transgenic]] [[mouse|mice]] to study specific genes in the Down syndrome critical region has yielded some results.  [[Amyloid beta|APP]]<ref>{{OMIM|104760}}, gene [[Locus (genetics)|located]] at [[Chromosome 21 (human)|21]][http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l104760 q21]. Retrieved on [[2006-12-05]].</ref> is an [[Amyloid beta]] A4 precursor protein.  It is suspected to have a major role in cognitive difficulties.<ref>{{cite web |title=Down syndrome traced to one gene |publisher=''The Scientist'' |first=Chandra |last= Shekhar |url=http://www.the-scientist.com/news/display/23869/ |date=2006-07-06 |accessdate = 2006-07-11}}</ref> Another gene, ETS2<ref>{{OMIM|164740}}, located at [[Chromosome 21 (human)|21]] [http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l164740 q22.3]. Retrieved on [[2006-12-05]].</ref> is Avian Erythroblastosis Virus E26 Oncogene Homolog 2.  Researchers have "demonstrated that overexpression of ETS2 results in [[apoptosis]]. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."<ref>{{cite web |author=OMIM, NIH |url=http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164740 |title=V-ETS Avian Erythroblastosis virus E26 Oncogene Homolog 2 |accessdate = 2006-06-29}}</ref>
-[[Image:Human chromosome 21.png|right|thumb|Chromosome 21 from Human Genome Program]]
-'''Research of Down syndrome-related genes''' is based on studying the [[gene]]s located on chromosome 21.  In general, this leads to an overexpression of the genes.<ref>{{cite journal| author=R Mao, CL Zielke, HR Zielke, J Pevsner| title=Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain| journal=[[Genomics]]| year=2003| volume=81| issue=5| pages=457-467| url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WG1-487KHTJ-1&_coverDate=05%2F31%2F2003&_alid=422057371&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6809&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9ec6c22133f1645bad48a10a8fb14485}}</ref> <ref>{{cite journal| author=Rong Mao, X Wang, EL Spitznagel, LP Frelin, JC Ting, H Ding, J Kim, I Ruczinski, TJ Downey, J Pevsner| title=Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart| journal=Genome Biology| year=2005| volume=6| issue=13| pages=R107| url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstract&artid=1414106}}</ref>  Understanding the genes involved may help to target medical treatment to individuals with [[Down syndrome]].  It is estimated that chromosome 21 contains 200 to 250 genes.<ref name=Leshin>See {{cite web| author=Leshin, L.| year=2003| url=http://www.ds-health.com/trisomy.htm| title=Trisomy 21: The Story of Down Syndrome| accessdate=2006-05-21}}</ref>  Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome,<ref>{{cite journal| author=Zohra Rahmani, Jean-Louis Blouin, Nicole Créau-Goldberg, Paul C. Watkins, Jean-François Mattei, Marc Poissonnier, Marguerite Prieur, Zoubida Chettouh, Annie Nicole, Alain Aurias, Pierre-Marie Sinet, Jean-Maurice Delabar| title=Down syndrome critical region around D21S55 on proximal 21q22.3| journal=[[American Journal of Medical Genetics]]| year=2005| volume=37| issue=S2| pages=98-103| url=http://www3.interscience.wiley.com/cgi-bin/abstract/110515872/ABSTRACT?CRETRY=1&SRETRY=0}}</ref> located proximal to 21q22.3.  The search for major genes involved in Down syndrome characteristics is normally in the region 21q21–21q22.3.
-Some suspected genes involved in features of Down syndrome are given in the Table 1:
 {| class="wikitable"
-|+ Table 1: Some genes located on the long arm of chromosome 21<ref name=Leshin>See {{cite web| author=Leshin, L.| year=2003| url=http://www.ds-health.com/trisomy.htm| title=Trisomy 21: The Story of Down Syndrome| accessdate=2006-05-21}}</ref>
+|+ Table 1: Some genes located on the long arm of chromosome 21<ref name="Leshin">See {{cite web| author=Leshin, L.| year=2003| url=http://www.ds-health.com/trisomy.htm| title=Trisomy 21: The Story of Down Syndrome| accessdate=2006-05-21}}</ref>
 |-
 !Gene
@@ Line 72: / Line 20: @@
 |-
 ![[Amyloid beta|APP]]
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104760 104760]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104760 104760]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l104760 21q21]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l104760 21q21]
-|[[Amyloid beta]] A4 precursor protein.  Suspected to have a major role in cognitive difficulties.  One of the first genes studied with [[genetically modified organism|transgenic]] [[mouse|mice]] with Down syndrome.<ref name=Shekhar2006>{{cite web|title=Down syndrome traced to one gene| publisher=The Scientist| author=Chandra Shekhar| url=http://www.the-scientist.com/news/display/23869/| date= [[6 July]] [[2006]]|accessdate=2006-07-11}}</ref>
+|[[Amyloid beta]] A4 precursor protein.  Suspected to have a major role in cognitive difficulties.  One of the first genes studied with [[genetically modified organism|transgenic]] [[mouse|mice]] with Down syndrome.<ref name="Shekhar2006">{{cite web|title=Down syndrome traced to one gene| publisher=The Scientist| author=Chandra Shekhar| url=http://www.the-scientist.com/news/display/23869/| date= [[6 July]] [[2006]]|accessdate=2006-07-11}}</ref>
 |-
 ![[Superoxide dismutase|SOD1]]
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147450 147450]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147450 147450]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l147450 21q22.1]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l147450 21q22.1]
 |[[Superoxide dismutase]].  Possible role in [[Alzheimer's disease]].  Anti-oxidant as well as possible affects on the immuno-system.
 |-
 !DYRK
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600855 600855]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600855 600855]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l600855 21q22.1]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l600855 21q22.1]
 |Dual-specificity [[Tyrosine kinase|Tyrosine Phosphorylation-Regulated Kinase 1A]].  May have an effect on mental development through abnormal neurogenesis. <ref>{{cite journal| author=Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L.; Kurnit, D. M.| title=Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome 'critical region| journal=Genomics| volume=38| pages=331-339| year=1996}}</ref>
 |-
 !IFNAR
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107450 107450]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107450 107450]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l107450 21q22.1]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l107450 21q22.1]
 |Interferon, Alpha, Beta, and Omega, Receptor.  Responsible for the expression of [[interferon]], which affects the immuno-system.
 |-
 !DSCR1
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602917 602917]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602917 602917]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l602917 21q22.1–21q22.2]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l602917 21q22.1–21q22.2]
 |Down Syndrome Critical Region Gene 1.  Possibly part of a [[signal transduction]] pathway involving both heart and brain.<ref>{{cite journal| author=Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X| title=A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart| journal=Hum Mol Genet| year=1995| volume=4| issue=10| pages=1935-1944}}</ref>
 |-
 !COL6A1
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120220 120220]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120220 120220]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l120220 21q22.3]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l120220 21q22.3]
 |[[Collagen]], type I, alpha 1 gene.  May have an effect on heart disease.
 |-
 !ETS2
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164740 164740]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164740 164740]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l164740 21q22.3]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l164740 21q22.3]
 |Avian Erythroblastosis Virus E26 Oncogene Homolog 2.  Researchers have "demonstrated that overexpression of ETS2 results in [[apoptosis]]. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."<ref>{{cite web| author=OMIM, NIH|  url=http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164740| title=V-ETS Avian Erythroblastosis virus E26 Oncogene Homolog 2| accessdate=2006-06-29}}</ref>
 |-
 !CRYA1
-|align="center"|[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=123580 123580]
+| align="center" |[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=123580 123580]
-|align="center"|[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l123580 21q22.3]
+| align="center" |[http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l123580 21q22.3]
 |Crystallin, Alpha-A.  Involved in the synthesis of [[Crystallin]], a major component of the lens in eyes.  May be cause of cataracts.
 |}
@@ Line 115: / Line 63: @@
 ===Amyloid beta (APP)===
 [[Image:App location.jpg|right|thumb|Location of the APP gene on chromosome 21 in humans.]]
-One chromosome 21 gene that might predispose Down syndrome individuals to develop Alzheimer's pathology is the gene that encodes the precursor of the [[amyloid protein]]. Neurofibrillary tangles and amyloid plaques are commonly found in both Down syndrome and Alzheimer's individuals. Layer II of the [[entorhinal cortex]] and the subiculum, both critical for [[memory consolidation]], are among the first affected by the damage. A gradual decrease in the number of nerve cells throughout the [[cortex (neuroanatomy)|cortex]] follows. A few years ago, [[Johns Hopkins University|Johns Hopkins]] scientists created a genetically engineered [[mus musculus|mouse]] called Ts65Dn (segmental trisomy 16 mouse) as an excellent model for studying the Down syndrome. Ts65Dn mouse has genes on chromosomes 16 that are very similar to the human chromosome 21 genes. Recently, researchers have used this transgenic mouse to connect APP to cognitive problems among the mice.<ref name=Shekhar2006/>
+One chromosome 21 gene that might predispose Down syndrome individuals to develop Alzheimer's pathology is the gene that encodes the precursor of the [[amyloid protein]]. Neurofibrillary tangles and amyloid plaques are commonly found in both Down syndrome and Alzheimer's individuals. Layer II of the [[entorhinal cortex]] and the subiculum, both critical for [[memory consolidation]], are among the first affected by the damage. A gradual decrease in the number of nerve cells throughout the [[cortex (neuroanatomy)|cortex]] follows. A few years ago, [[Johns Hopkins University|Johns Hopkins]] scientists created a genetically engineered [[mus musculus|mouse]] called Ts65Dn (segmental trisomy 16 mouse) as an excellent model for studying the Down syndrome. Ts65Dn mouse has genes on chromosomes 16 that are very similar to the human chromosome 21 genes. Recently, researchers have used this transgenic mouse to connect APP to cognitive problems among the mice.<ref name="Shekhar2006" />
 ===Superoxide dismutase (SOD1)===
 [[Image:SOD1 Location.gif|left|thumb|Location of the SOD1 gene on chromosome 21 in humans.]]
 Some (but not all) studies have shown that the activity of the [[Superoxide dismutase|superoxide dismutase enzyme]] is elevated in Down syndrome. SOD converts [[oxygen radicals]] to [[hydrogen peroxide]] and [[water]]. Oxygen radicals produced in cells can be damaging to cellular structures, hence the important role of SOD. However, the hypothesis says that once SOD activity increases disproportionately to [[enzyme]]s responsible for removal of hydrogen peroxide (e.g., [[glutathione peroxidase]]), the cells will suffer from a peroxide damage. Some scientists believe that the treatment of Down syndrome [[neuron]]s with [[free radical]] scavengers can substantially prevent neuronal degeneration. Oxidative damage to neurons results in rapid [[human brain|brain]] aging similar to that of [[Alzheimer's disease]].
-==MicroRNA genes==
-Human chromosome 21  contains five [[microRNA]] genes: [[Mir-10 microRNA precursor family|miR-99a]], [[Let-7 microRNA precursor|let-7c]], miR-125b-2, [[mir-155 microRNA|miR-155]], and miR-802. MiR-155 and miR-802  regulate the expression of the methyl-CpG-binding protein ([[MeCP2]]). It has been suggested that the underexpression of MeCP2, secondary to trisomic overexpression of Human chromosome 21 derived miRNAs, may result in  aberrant expression of the [[transcription factor]]s of [[CREB1]] and [[MEF2C]] . This in turn may lead to abnormal brain development through anomalous neuronal gene expression during the critical period of synaptic maturation by alterating [[neurogenesis]], neuronal differentiation, [[myelination]], and [[synaptogenesis]].<ref>{{cite journal | author = Kuhn DE, Nuovo GJ, Terry AV Jr, Martin MM, Malana GE, Sansom SE, Pleister AP, Beck WD, Head E ''et al.'' | year = 2010 | title = Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains | url = | journal = J Biol Chem | volume = 285 | issue = 2| pages = 1529–43 | doi = 10.1074/jbc.M109.033407 | pmid = 19897480 | pmc=2801278}}</ref>
 ==References==