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* Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. | * Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. | ||
* Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome.<ref name="pmid17668376">{{cite journal |vauthors=Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, Gehrig C, Descombes P, Sherman S, Dagna Bricarelli F, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE |title=Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance |journal=Am. J. Hum. Genet. |volume=81 |issue=2 |pages=252–63 |date=August 2007 |pmid=17668376 |pmc=1950802 |doi=10.1086/519248 |url=}}</ref><ref name="pmid17531092">{{cite journal |vauthors=Sultan M, Piccini I, Balzereit D, Herwig R, Saran NG, Lehrach H, Reeves RH, Yaspo ML |title=Gene expression variation in Down's syndrome mice allows prioritization of candidate genes |journal=Genome Biol. |volume=8 |issue=5 |pages=R91 |date=2007 |pmid=17531092 |pmc=1929163 |doi=10.1186/gb-2007-8-5-r91 |url=}}</ref><ref name="pmid17701894">{{cite journal |vauthors=Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Bléhaut H, Robin S, Delabar JM, Potier MC |title=Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes |journal=Am. J. Hum. Genet. |volume=81 |issue=3 |pages=475–91 |date=September 2007 |pmid=17701894 |pmc=1950826 |doi=10.1086/520000 |url=}}</ref> | * Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome.<ref name="pmid17668376">{{cite journal |vauthors=Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, Gehrig C, Descombes P, Sherman S, Dagna Bricarelli F, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE |title=Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance |journal=Am. J. Hum. Genet. |volume=81 |issue=2 |pages=252–63 |date=August 2007 |pmid=17668376 |pmc=1950802 |doi=10.1086/519248 |url=}}</ref><ref name="pmid17531092">{{cite journal |vauthors=Sultan M, Piccini I, Balzereit D, Herwig R, Saran NG, Lehrach H, Reeves RH, Yaspo ML |title=Gene expression variation in Down's syndrome mice allows prioritization of candidate genes |journal=Genome Biol. |volume=8 |issue=5 |pages=R91 |date=2007 |pmid=17531092 |pmc=1929163 |doi=10.1186/gb-2007-8-5-r91 |url=}}</ref><ref name="pmid17701894">{{cite journal |vauthors=Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Bléhaut H, Robin S, Delabar JM, Potier MC |title=Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes |journal=Am. J. Hum. Genet. |volume=81 |issue=3 |pages=475–91 |date=September 2007 |pmid=17701894 |pmc=1950826 |doi=10.1086/520000 |url=}}</ref> | ||
* Recent data points towards a number of ‘susceptibility regions’ located on Hsa21, which are modified by other loci on Hsa21 and other genomic regions, increase the risk of developing specific DS associated phenotypes.<ref name="pmid19597142">{{cite journal |vauthors=Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L, Grubert F, Erdman C, Gao MC, Lange K, Sobel EM, Barlow GM, Aylsworth AS, Carpenter NJ, Clark RD, Cohen MY, Doran E, Falik-Zaccai T, Lewin SO, Lott IT, McGillivray BC, Moeschler JB, Pettenati MJ, Pueschel SM, Rao KW, Shaffer LG, Shohat M, Van Riper AJ, Warburton D, Weissman S, Gerstein MB, Snyder M, Korenberg JR |title=The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=106 |issue=29 |pages=12031–6 |date=July 2009 |pmid=19597142 |pmc=2709665 |doi=10.1073/pnas.0813248106 |url=}}</ref> | |||
{| class="wikitable" | {| 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> | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
- Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability.
- Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome.[1][2][3]
- Recent data points towards a number of ‘susceptibility regions’ located on Hsa21, which are modified by other loci on Hsa21 and other genomic regions, increase the risk of developing specific DS associated phenotypes.[4]
| 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.[6] |
| 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. [7] |
| 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.[8] |
| 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."[9] |
| 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)
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.[6]
Superoxide dismutase (SOD1)
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
- ↑ Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, Gehrig C, Descombes P, Sherman S, Dagna Bricarelli F, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE (August 2007). "Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance". Am. J. Hum. Genet. 81 (2): 252–63. doi:10.1086/519248. PMC 1950802. PMID 17668376.
- ↑ Sultan M, Piccini I, Balzereit D, Herwig R, Saran NG, Lehrach H, Reeves RH, Yaspo ML (2007). "Gene expression variation in Down's syndrome mice allows prioritization of candidate genes". Genome Biol. 8 (5): R91. doi:10.1186/gb-2007-8-5-r91. PMC 1929163. PMID 17531092.
- ↑ Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Bléhaut H, Robin S, Delabar JM, Potier MC (September 2007). "Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes". Am. J. Hum. Genet. 81 (3): 475–91. doi:10.1086/520000. PMC 1950826. PMID 17701894.
- ↑ Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L, Grubert F, Erdman C, Gao MC, Lange K, Sobel EM, Barlow GM, Aylsworth AS, Carpenter NJ, Clark RD, Cohen MY, Doran E, Falik-Zaccai T, Lewin SO, Lott IT, McGillivray BC, Moeschler JB, Pettenati MJ, Pueschel SM, Rao KW, Shaffer LG, Shohat M, Van Riper AJ, Warburton D, Weissman S, Gerstein MB, Snyder M, Korenberg JR (July 2009). "The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies". Proc. Natl. Acad. Sci. U.S.A. 106 (29): 12031–6. doi:10.1073/pnas.0813248106. PMC 2709665. PMID 19597142.
- ↑ See Leshin, L. (2003). "Trisomy 21: The Story of Down Syndrome". Retrieved 2006-05-21.
- ↑ 6.0 6.1 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.