Down syndrome pathophysiology: Difference between revisions
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* In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle.<ref name="pmid7833906">{{cite journal |vauthors=Hawley RS, Frazier JA, Rasooly R |title=Separation anxiety: the etiology of nondisjunction in flies and people |journal=Hum. Mol. Genet. |volume=3 |issue=9 |pages=1521–8 |date=September 1994 |pmid=7833906 |doi= |url=}}</ref><ref name="pmid11151672">{{cite journal |vauthors=Wolstenholme J, Angell RR |title=Maternal age and trisomy--a unifying mechanism of formation |journal=Chromosoma |volume=109 |issue=7 |pages=435–8 |date=November 2000 |pmid=11151672 |doi= |url=}}</ref><ref name="pmid8644722">{{cite journal |vauthors=Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D, Flanders WD, Khoury MJ, Hassold TJ |title=Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study |journal=Am. J. Hum. Genet. |volume=58 |issue=3 |pages=628–33 |date=March 1996 |pmid=8644722 |pmc=1914585 |doi= |url=}}</ref> | * In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle.<ref name="pmid7833906">{{cite journal |vauthors=Hawley RS, Frazier JA, Rasooly R |title=Separation anxiety: the etiology of nondisjunction in flies and people |journal=Hum. Mol. Genet. |volume=3 |issue=9 |pages=1521–8 |date=September 1994 |pmid=7833906 |doi= |url=}}</ref><ref name="pmid11151672">{{cite journal |vauthors=Wolstenholme J, Angell RR |title=Maternal age and trisomy--a unifying mechanism of formation |journal=Chromosoma |volume=109 |issue=7 |pages=435–8 |date=November 2000 |pmid=11151672 |doi= |url=}}</ref><ref name="pmid8644722">{{cite journal |vauthors=Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D, Flanders WD, Khoury MJ, Hassold TJ |title=Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study |journal=Am. J. Hum. Genet. |volume=58 |issue=3 |pages=628–33 |date=March 1996 |pmid=8644722 |pmc=1914585 |doi= |url=}}</ref> | ||
* Nondisjoined chromosomes often show recombination in various patterns and for trisomy 21, achiasmate meioses contribute about 45% of maternal meiotic error cases.<ref name="pmid17910090">{{cite journal |vauthors=Sherman SL, Allen EG, Bean LH, Freeman SB |title=Epidemiology of Down syndrome |journal=Ment Retard Dev Disabil Res Rev |volume=13 |issue=3 |pages=221–7 |date=2007 |pmid=17910090 |doi=10.1002/mrdd.20157 |url=}}</ref><ref name="pmid8875256">{{cite journal |vauthors=Koehler KE, Hawley RS, Sherman S, Hassold T |title=Recombination and nondisjunction in humans and flies |journal=Hum. Mol. Genet. |volume=5 Spec No |issue= |pages=1495–504 |date=1996 |pmid=8875256 |doi= |url=}}</ref> | * Nondisjoined chromosomes often show recombination in various patterns and for trisomy 21, achiasmate meioses contribute about 45% of maternal meiotic error cases.<ref name="pmid17910090">{{cite journal |vauthors=Sherman SL, Allen EG, Bean LH, Freeman SB |title=Epidemiology of Down syndrome |journal=Ment Retard Dev Disabil Res Rev |volume=13 |issue=3 |pages=221–7 |date=2007 |pmid=17910090 |doi=10.1002/mrdd.20157 |url=}}</ref><ref name="pmid8875256">{{cite journal |vauthors=Koehler KE, Hawley RS, Sherman S, Hassold T |title=Recombination and nondisjunction in humans and flies |journal=Hum. Mol. Genet. |volume=5 Spec No |issue= |pages=1495–504 |date=1996 |pmid=8875256 |doi= |url=}}</ref> | ||
* Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.<ref name="pmid8944019">{{cite journal |vauthors=Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J, Gu Y, Shen J, Saker D, May KM, Avramopoulos D, Petersen MB, Hallberg A, Mikkelsen M, Hassold TJ, Sherman SL |title=Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II |journal=Nat. Genet. |volume=14 |issue=4 |pages=400–5 |date=December 1996 |pmid=8944019 |doi=10.1038/ng1296-400 |url=}}</ref> | |||
* Exchange of telomeric segments increase the risk for MI error, whereas exchanges in the pericentromeric regions predispose to MII error. A distally placed chiasma probably links the homologue less efficiently to the spindle and leads to suboptimal orientation of the kinetochore towards opposite pole.<ref name="pmid78339062">{{cite journal |vauthors=Hawley RS, Frazier JA, Rasooly R |title=Separation anxiety: the etiology of nondisjunction in flies and people |journal=Hum. Mol. Genet. |volume=3 |issue=9 |pages=1521–8 |date=September 1994 |pmid=7833906 |doi= |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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Down syndrome Microchapters |
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Down syndrome pathophysiology On the Web |
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Risk calculators and risk factors for Down syndrome pathophysiology |
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][5]
Meiotic non-disjunction
- In approximately 95% cases, the extra chromosome occurs as a result of meiotic nondisjunction (NDJ) or abnormal segregation of chromosomes. Of these, in the majority of cases the error occurs during maternal oogenesis, specially during meiosis I.[6][7]
- The process of oogenesis is lengthy and involves meiotic arrest, which makes predisposes the process to inappropriate segregation of chromosomes than spermatogenesis.[8]
- In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle.[9][10][11]
- Nondisjoined chromosomes often show recombination in various patterns and for trisomy 21, achiasmate meioses contribute about 45% of maternal meiotic error cases.[12][13]
- Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.[14]
- Exchange of telomeric segments increase the risk for MI error, whereas exchanges in the pericentromeric regions predispose to MII error. A distally placed chiasma probably links the homologue less efficiently to the spindle and leads to suboptimal orientation of the kinetochore towards opposite pole.[15]
| 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.[17] |
| 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. [18] |
| 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.[19] |
| 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."[20] |
| 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.[17]
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.
- ↑ Lyle R, Béna F, Gagos S, Gehrig C, Lopez G, Schinzel A, Lespinasse J, Bottani A, Dahoun S, Taine L, Doco-Fenzy M, Cornillet-Lefèbvre P, Pelet A, Lyonnet S, Toutain A, Colleaux L, Horst J, Kennerknecht I, Wakamatsu N, Descartes M, Franklin JC, Florentin-Arar L, Kitsiou S, Aït Yahya-Graison E, Costantine M, Sinet PM, Delabar JM, Antonarakis SE (April 2009). "Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21". Eur. J. Hum. Genet. 17 (4): 454–66. doi:10.1038/ejhg.2008.214. PMC 2986205. PMID 19002211.
- ↑ Antonarakis SE (March 1991). "Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group". N. Engl. J. Med. 324 (13): 872–6. doi:10.1056/NEJM199103283241302. PMID 1825697.
- ↑ Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M (March 1992). "The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms". Am. J. Hum. Genet. 50 (3): 544–50. PMC 1684265. PMID 1347192.
- ↑ Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL (March 2008). "New insights into human nondisjunction of chromosome 21 in oocytes". PLoS Genet. 4 (3): e1000033. doi:10.1371/journal.pgen.1000033. PMC 2265487. PMID 18369452.
- ↑ Hawley RS, Frazier JA, Rasooly R (September 1994). "Separation anxiety: the etiology of nondisjunction in flies and people". Hum. Mol. Genet. 3 (9): 1521–8. PMID 7833906.
- ↑ Wolstenholme J, Angell RR (November 2000). "Maternal age and trisomy--a unifying mechanism of formation". Chromosoma. 109 (7): 435–8. PMID 11151672.
- ↑ Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D, Flanders WD, Khoury MJ, Hassold TJ (March 1996). "Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study". Am. J. Hum. Genet. 58 (3): 628–33. PMC 1914585. PMID 8644722.
- ↑ Sherman SL, Allen EG, Bean LH, Freeman SB (2007). "Epidemiology of Down syndrome". Ment Retard Dev Disabil Res Rev. 13 (3): 221–7. doi:10.1002/mrdd.20157. PMID 17910090.
- ↑ Koehler KE, Hawley RS, Sherman S, Hassold T (1996). "Recombination and nondisjunction in humans and flies". Hum. Mol. Genet. 5 Spec No: 1495–504. PMID 8875256.
- ↑ Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J, Gu Y, Shen J, Saker D, May KM, Avramopoulos D, Petersen MB, Hallberg A, Mikkelsen M, Hassold TJ, Sherman SL (December 1996). "Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II". Nat. Genet. 14 (4): 400–5. doi:10.1038/ng1296-400. PMID 8944019.
- ↑ Hawley RS, Frazier JA, Rasooly R (September 1994). "Separation anxiety: the etiology of nondisjunction in flies and people". Hum. Mol. Genet. 3 (9): 1521–8. PMID 7833906.
- ↑ See Leshin, L. (2003). "Trisomy 21: The Story of Down Syndrome". Retrieved 2006-05-21.
- ↑ 17.0 17.1 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.