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{{Down syndrome}}
{{Down syndrome}}
{{CMG}}
{{CMG}}; {{AE}}{{HK}}
==Overview==
==Overview==
Down Syndrome (DS) is the consequence of trisomy of human [[Chromosome 21 (human)|chromosome 21]] (Hsa21) and is the most common [[Genetics|genetic]] form of intellectual disability. Additional copy of [[Chromosome 21 (human)|chromosome 21]] results in elevated expression of many of the [[genes]] encoded on this [[chromosome]], leading to variying [[Gene expression|expression of genes]] associated with this [[chromosome]]. Mechanisms leading to trisomy 21 include [[Meiotic nondisjunction|meiotic non-disjunction]] during [[meiosis I]] (majority) and [[meiosis]] II, [[Robertsonian translocation]] and [[mosaicism]] (rare). In addition, increased [[maternal]] age leads to rapid degradation of [[cellular]] [[proteins]] involved in [[Spindle fiber|spindle]] formation, [[Sister chromatids|sister chromatid]] cohesion and [[anaphase]] separation of [[sister chromatids]] in [[oocytes]] during [[cell cycle]]. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in [[non-disjunction]] of [[Chromosome 21 (human)|chromosome 21]].Immaturity of the [[Fetus|feto]]-[[placental]] unit has been proposed as an explanation for the reduced [[maternal]] [[serum]] [[alpha fetoprotein]] ([[Alpha-fetoprotein|AFP]]) and unconjugated [[Estriol|oestriol]] ([[Estriol|UE3]]) levels and increased [[Human chorionic gonadotropin|hCG]] levels in Down’s syndrome pregnancies. Reduced synthesis of [[Alpha-fetoprotein|AFP]] by the [[Fetus|fetal]] [[liver]] is also thought to contribute to low [[Alpha-fetoprotein|AFP]] in Down’s syndrome [[Pregnancy|pregnancies]]. [[Robertsonian translocation]] occurrs when the long arms of 2 [[acrocentric]] [[chromosomes]] ([[chromosomes]] with [[centromeres]] near their ends) fuse at the [[centromeres]] and the 2 short arms are lost. [[Mosaicism]] does not have any [[maternal]] association and it is a post-[[fertilization]] [[mitotic]] error. Disbilities found in Down syndrome patients are thought to arise secondary to varied [[Gene expression|genetic expression]] associated with the presence an extra 21st [[chromosome]].
==Pathophysiology==
==Pathophysiology==
* 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 (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 (human)|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><ref name="pmid19002211">{{cite journal |vauthors=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 |title=Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21 |journal=Eur. J. Hum. Genet. |volume=17 |issue=4 |pages=454–66 |date=April 2009 |pmid=19002211 |pmc=2986205 |doi=10.1038/ejhg.2008.214 |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><ref name="pmid19002211">{{cite journal |vauthors=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 |title=Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21 |journal=Eur. J. Hum. Genet. |volume=17 |issue=4 |pages=454–66 |date=April 2009 |pmid=19002211 |pmc=2986205 |doi=10.1038/ejhg.2008.214 |url=}}</ref>
 
=== Mechanisms of trisomy 21 ===
 
==== Meiotic non-disjunction ====
*  In trisomy 21 the extra [[Chromosome 21 (human)|chromosome 21]] is [[maternal]] in origin in about 95 percent of the cases, and paternal in only about 5 percent.
* 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]].<ref name="pmid1825697">{{cite journal |vauthors=Antonarakis SE |title=Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group |journal=N. Engl. J. Med. |volume=324 |issue=13 |pages=872–6 |date=March 1991 |pmid=1825697 |doi=10.1056/NEJM199103283241302 |url=}}</ref><ref name="pmid1347192">{{cite journal |vauthors=Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M |title=The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms |journal=Am. J. Hum. Genet. |volume=50 |issue=3 |pages=544–50 |date=March 1992 |pmid=1347192 |pmc=1684265 |doi= |url=}}</ref>
* The process of [[oogenesis]] is lengthy and involves [[Meiosis|meiotic]] arrest, which makes predisposes the process to inappropriate segregation of [[chromosomes]] than [[spermatogenesis]].<ref name="pmid18369452">{{cite journal |vauthors=Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL |title=New insights into human nondisjunction of chromosome 21 in oocytes |journal=PLoS Genet. |volume=4 |issue=3 |pages=e1000033 |date=March 2008 |pmid=18369452 |pmc=2265487 |doi=10.1371/journal.pgen.1000033 |url=}}</ref>
* In addition, increased maternal age leads to rapid degradation of [[cellular]] [[proteins]] involved in [[Spindle fibers|spindle]] formation, [[Sister chromatids|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 [[Genetic recombination|recombination]] in various patterns and for trisomy 21, achiasmate [[Meiosis|meioses]] contribute about 45% of [[maternal]] [[Meiosis|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 (human)|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 [[Telomeres|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 [[Homologous|homologue]] less efficiently to the [[Spindle fibers|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>
* Achiasmate [[Meiosis|meioses]] and mono-[[Telomere|telomeric]] exchanges lead to an increased risk of [[Non-disjunction|NDJ]] regardless of [[maternal]] age.<ref name="pmid15551222">{{cite journal |vauthors=Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL |title=Association between maternal age and meiotic recombination for trisomy 21 |journal=Am. J. Hum. Genet. |volume=76 |issue=1 |pages=91–9 |date=January 2005 |pmid=15551222 |pmc=1196437 |doi=10.1086/427266 |url=}}</ref>
* On the other hand, pericentromeric exchange pedispose older mothers to [[Non-disjunction|NDJ]] during [[meiosis]] II.<ref name="pmid155512222">{{cite journal |vauthors=Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL |title=Association between maternal age and meiotic recombination for trisomy 21 |journal=Am. J. Hum. Genet. |volume=76 |issue=1 |pages=91–9 |date=January 2005 |pmid=15551222 |pmc=1196437 |doi=10.1086/427266 |url=}}</ref><ref name="pmid183694522">{{cite journal |vauthors=Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL |title=New insights into human nondisjunction of chromosome 21 in oocytes |journal=PLoS Genet. |volume=4 |issue=3 |pages=e1000033 |date=March 2008 |pmid=18369452 |pmc=2265487 |doi=10.1371/journal.pgen.1000033 |url=}}</ref>
* Immaturity of the [[Fetus|feto]]-[[placental]] unit has been proposed as an explanation for the reduced [[maternal]] [[serum]] [[alpha fetoprotein]] ([[Alpha-fetoprotein|AFP]]) and unconjugated [[Estriol|oestriol]] ([[Estriol|UE3]]) levels and increased [[Human chorionic gonadotropin|hCG]] levels in Down’s syndrome pregnancies. Reduced synthesis of [[Alpha-fetoprotein|AFP]] by the [[Fetus|fetal]] [[liver]] is also thought to contribute to low [[Alpha-fetoprotein|AFP]] in Down’s syndrome [[Pregnancy|pregnancies]].
* In Down’s syndrome pregnancies the normal proportion of [[Syncytiotrophoblast|syncytiotrophoblasts]] to [[Cytotrophoblast|cytotrophoblasts]] is disturbed leading to increased [[Human chorionic gonadotropin|hCG]] levels.
 
==== Robertsonian translocation ====
* Approximately 4 percent cases of DS arise from [[Robertsonian translocation]].
* This involves non-reciprocal [[chromosomal]] translocation that commonly involves [[chromosome]] pairs 13, 14, 15, 21 and 22.
* The event occurrs when the long arms of 2 [[acrocentric]] [[chromosomes]] ([[chromosomes]] with [[centromeres]] near their ends) fuse at the [[centromeres]] and the 2 short arms are lost
* Unbalanced [[translocations]] result in [[miscarriage]], [[stillbirth]] and [[chromosomal]] imbalance (Down's syndrome, [[Patau syndrome]])


=== Meiotic non-disjunction ===
==== Mosaicism ====
*  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.<ref name="pmid1825697">{{cite journal |vauthors=Antonarakis SE |title=Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group |journal=N. Engl. J. Med. |volume=324 |issue=13 |pages=872–6 |date=March 1991 |pmid=1825697 |doi=10.1056/NEJM199103283241302 |url=}}</ref><ref name="pmid1347192">{{cite journal |vauthors=Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M |title=The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms |journal=Am. J. Hum. Genet. |volume=50 |issue=3 |pages=544–50 |date=March 1992 |pmid=1347192 |pmc=1684265 |doi= |url=}}</ref>
* Down syndrome resulting from [[mosaicism]] is very rare and accounts for around 1 percent of cases of DS.
* [[Mosaicism]] does not have any [[maternal]] association and it is a post-[[fertilization]] [[mitotic]] error.
 
=== Effects on increased gene dosage ===
* The [[phenotypical]] characrteristics produced in DS may be attributed to the disturbed [[gene expression]] due to trisomy 21.
 
==== Learning and memory ====
* Patients with DS have [[learning]] and [[memory]] problems and exhibit differences in [[brain]] structure compared to the euploid population.<ref name="pmid16967345">{{cite journal |vauthors=Vicari S, Carlesimo GA |title=Short-term memory deficits are not uniform in Down and Williams syndromes |journal=Neuropsychol Rev |volume=16 |issue=2 |pages=87–94 |date=June 2006 |pmid=16967345 |doi=10.1007/s11065-006-9008-4 |url=}}</ref><ref name="pmid8981379">{{cite journal |vauthors=Carlesimo GA, Marotta L, Vicari S |title=Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down's syndrome |journal=Neuropsychologia |volume=35 |issue=1 |pages=71–9 |date=January 1997 |pmid=8981379 |doi= |url=}}</ref><ref name="pmid10200735">{{cite journal |vauthors=Aylward EH, Li Q, Honeycutt NA, Warren AC, Pulsifer MB, Barta PE, Chan MD, Smith PD, Jerram M, Pearlson GD |title=MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia |journal=Am J Psychiatry |volume=156 |issue=4 |pages=564–8 |date=April 1999 |pmid=10200735 |doi=10.1176/ajp.156.4.564 |url=}}</ref>
* Impaired [[synaptic plasticity]] in the interstriatal [[cholinergic]] system has been though to play a key role in DS-associated [[Motor skill|motor]] and [[Cognition|cognitive]] defects.<ref name="pmid19818432">{{cite journal |vauthors=Di Filippo M, Tozzi A, Ghiglieri V, Picconi B, Costa C, Cipriani S, Tantucci M, Belcastro V, Calabresi P |title=Impaired plasticity at specific subset of striatal synapses in the Ts65Dn mouse model of Down syndrome |journal=Biol. Psychiatry |volume=67 |issue=7 |pages=666–71 |date=April 2010 |pmid=19818432 |doi=10.1016/j.biopsych.2009.08.018 |url=}}</ref>
* [[Murine]] models have allowed to identify [[genes]] thought to affect [[memory]] and [[learning]] in DS patients. The main [[genes]] involved are:<ref name="pmid16455265">{{cite journal |vauthors=Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, Goo JS, Choi SY, Han JS, Ha I, Song WJ |title=DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects |journal=Neurobiol. Dis. |volume=22 |issue=3 |pages=463–72 |date=June 2006 |pmid=16455265 |doi=10.1016/j.nbd.2005.12.006 |url=}}</ref><ref name="pmid19211897">{{cite journal |vauthors=Yu HH, Yang JS, Wang J, Huang Y, Lee T |title=Endodomain diversity in the Drosophila Dscam and its roles in neuronal morphogenesis |journal=J. Neurosci. |volume=29 |issue=6 |pages=1904–14 |date=February 2009 |pmid=19211897 |pmc=2671081 |doi=10.1523/JNEUROSCI.5743-08.2009 |url=}}</ref><ref name="pmid17093127">{{cite journal |vauthors=Best TK, Siarey RJ, Galdzicki Z |title=Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current |journal=J. Neurophysiol. |volume=97 |issue=1 |pages=892–900 |date=January 2007 |pmid=17093127 |doi=10.1152/jn.00626.2006 |url=}}</ref><ref name="pmid10400987">{{cite journal |vauthors=Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, Inokuchi K, Katsuki M, Fujii-Kuriyama Y |title=Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome |journal=Hum. Mol. Genet. |volume=8 |issue=8 |pages=1409–15 |date=August 1999 |pmid=10400987 |doi= |url=}}</ref><ref name="pmid18490108">{{cite journal |vauthors=Best TK, Cho-Clark M, Siarey RJ, Galdzicki Z |title=Speeding of miniature excitatory post-synaptic currents in Ts65Dn cultured hippocampal neurons |journal=Neurosci. Lett. |volume=438 |issue=3 |pages=356–61 |date=June 2008 |pmid=18490108 |doi=10.1016/j.neulet.2008.04.039 |url=}}</ref><ref name="pmid16530433">{{cite journal |vauthors=Meng X, Shi J, Peng B, Zou X, Zhang C |title=Effect of mouse Sim2 gene on the cell cycle of PC12 cells |journal=Cell Biol. Int. |volume=30 |issue=4 |pages=349–53 |date=April 2006 |pmid=16530433 |doi=10.1016/j.cellbi.2005.11.012 |url=}}</ref><ref name="pmid19460634">{{cite journal |vauthors=Rachidi M, Delezoide AL, Delabar JM, Lopes C |title=A quantitative assessment of gene expression (QAGE) reveals differential overexpression of DOPEY2, a candidate gene for mental retardation, in Down syndrome brain regions |journal=Int. J. Dev. Neurosci. |volume=27 |issue=4 |pages=393–8 |date=June 2009 |pmid=19460634 |doi=10.1016/j.ijdevneu.2009.02.001 |url=}}</ref>
** [[DYRK1A]]
** [[Synaptojanin 1]](SYNJ1)
** [[SIM2]]
** [[DOPEY2]]
** [[DSCAM]]
 
==== Neurodevelopment ====
* DS patients have increased rates of neuronal apoptosis related to oxidative stress.<ref name="pmid8524410">{{cite journal |vauthors=Busciglio J, Yankner BA |title=Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro |journal=Nature |volume=378 |issue=6559 |pages=776–9 |date=1995 |pmid=8524410 |doi=10.1038/378776a0 |url=}}</ref>
* Brain size of fetuses carrying trisomy 21 is smaller than euploid fetuses.
* Murine models have suggested that disruption in expression of the following genes may play key roles in affecting neurodevelopment in DS patients:
** PREP1<ref name="pmid20110257">{{cite journal |vauthors=Micali N, Longobardi E, Iotti G, Ferrai C, Castagnaro L, Ricciardi M, Blasi F, Crippa MP |title=Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress |journal=Nucleic Acids Res. |volume=38 |issue=11 |pages=3595–604 |date=June 2010 |pmid=20110257 |pmc=2887940 |doi=10.1093/nar/gkq019 |url=}}</ref>
** [[TTC3|Tetratricopeptide repeat domain 3]] ([[TTC3]])<ref name="pmid20059950">{{cite journal |vauthors=Suizu F, Hiramuki Y, Okumura F, Matsuda M, Okumura AJ, Hirata N, Narita M, Kohno T, Yokota J, Bohgaki M, Obuse C, Hatakeyama S, Obata T, Noguchi M |title=The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt |journal=Dev. Cell |volume=17 |issue=6 |pages=800–10 |date=December 2009 |pmid=20059950 |doi=10.1016/j.devcel.2009.09.007 |url=}}</ref>
** [[DYRK1A]]<ref name="pmid19218269">{{cite journal |vauthors=Lepagnol-Bestel AM, Zvara A, Maussion G, Quignon F, Ngimbous B, Ramoz N, Imbeaud S, Loe-Mie Y, Benihoud K, Agier N, Salin PA, Cardona A, Khung-Savatovsky S, Kallunki P, Delabar JM, Puskas LG, Delacroix H, Aggerbeck L, Delezoide AL, Delattre O, Gorwood P, Moalic JM, Simonneau M |title=DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome |journal=Hum. Mol. Genet. |volume=18 |issue=8 |pages=1405–14 |date=April 2009 |pmid=19218269 |doi=10.1093/hmg/ddp047 |url=}}</ref><ref name="pmid18771760">{{cite journal |vauthors=Canzonetta C, Mulligan C, Deutsch S, Ruf S, O'Doherty A, Lyle R, Borel C, Lin-Marq N, Delom F, Groet J, Schnappauf F, De Vita S, Averill S, Priestley JV, Martin JE, Shipley J, Denyer G, Epstein CJ, Fillat C, Estivill X, Tybulewicz VL, Fisher EM, Antonarakis SE, Nizetic D |title=DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome |journal=Am. J. Hum. Genet. |volume=83 |issue=3 |pages=388–400 |date=September 2008 |pmid=18771760 |pmc=2556438 |doi=10.1016/j.ajhg.2008.08.012 |url=}}</ref> 
** [[MECP2]]<ref name="pmid19897480">{{cite journal |vauthors=Kuhn DE, Nuovo GJ, Terry AV, Martin MM, Malana GE, Sansom SE, Pleister AP, Beck WD, Head E, Feldman DS, Elton TS |title=Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains |journal=J. Biol. Chem. |volume=285 |issue=2 |pages=1529–43 |date=January 2010 |pmid=19897480 |pmc=2801278 |doi=10.1074/jbc.M109.033407 |url=}}</ref>
 
==== Alzheimer's disease ====
* Trisomy 21 leads to increased expression of [[amyloid precursor protein]] ([[Amyloid precursor protein|APP]]), which is suspected to predispose individuals with DS to early-onset [[Alzheimer's disease]] ([[dementia]] by the age of 60).<ref name="pmid16369530">{{cite journal |vauthors=Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D |title=APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy |journal=Nat. Genet. |volume=38 |issue=1 |pages=24–6 |date=January 2006 |pmid=16369530 |doi=10.1038/ng1718 |url=}}</ref><ref name="pmid16959815">{{cite journal |vauthors=Cabrejo L, Guyant-Maréchal L, Laquerrière A, Vercelletto M, De la Fournière F, Thomas-Antérion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D |title=Phenotype associated with APP duplication in five families |journal=Brain |volume=129 |issue=Pt 11 |pages=2966–76 |date=November 2006 |pmid=16959815 |doi=10.1093/brain/awl237 |url=}}</ref>
* Patients with [[Alzheimer's disease]] exhibit [[brain atrophy]], [[extracellular]] [[Beta amyloid|β-amyloid]] (Aβ) deposits and the accumulation of [[Neurofibrillary tangle|neurofibrillary tangles]] (NFTs) that are composed of [[Hyperphosphorylation|hyperphosphorylated]] [[Tau protein|Tau]]. The [[amyloid precursor protein]], ([[Amyloid precursor protein|APP]]), from which Aβ is produced, is encoded on Hsa21.
* Trisomy 21 leads to loss of [[basal forebrain]] [[cholinergic]] [[neurons]] and enlargement of early [[endosomes]].<ref name="pmid16815330">{{cite journal |vauthors=Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC |title=Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration |journal=Neuron |volume=51 |issue=1 |pages=29–42 |date=July 2006 |pmid=16815330 |doi=10.1016/j.neuron.2006.05.022 |url=}}</ref><ref name="pmid15869949">{{cite journal |vauthors=Seo H, Isacson O |title=Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice |journal=Exp. Neurol. |volume=193 |issue=2 |pages=469–80 |date=June 2005 |pmid=15869949 |doi=10.1016/j.expneurol.2004.11.017 |url=}}</ref>
* [[DYRK1A|DYRK1A gene]] (found on [[Chromosome 21 (human)|chromosome 21]]) encodes a [[kinase]] which may contribute to [[phosphorylation]] of [[Tau protein|Tau]] found in patients suffering from [[Alzheimer's disease]].<ref name="pmid17906291">{{cite journal |vauthors=Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH, Ahn YS, Chung SH, Song WJ |title=DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease |journal=J. Biol. Chem. |volume=282 |issue=48 |pages=34850–7 |date=November 2007 |pmid=17906291 |doi=10.1074/jbc.M707358200 |url=}}</ref>
 
==== Cancer and leukemias ====
* DS predisposes individuals to developing [[Myeloproliferative disease|myeloproliferative]] dosorders, as well as acute megakaryocytic leukemia (AMKL) and [[acute lymphoblastic leukemia]] ([[Acute lymphoblastic leukemia|ALL]]).<ref name="pmid12172547">{{cite journal |vauthors=Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD |title=Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome |journal=Nat. Genet. |volume=32 |issue=1 |pages=148–52 |date=September 2002 |pmid=12172547 |doi=10.1038/ng955 |url=}}</ref><ref name="pmid17532652">{{cite journal |vauthors=Izraeli S, Rainis L, Hertzberg L, Smooha G, Birger Y |title=Trisomy of chromosome 21 in leukemogenesis |journal=Blood Cells Mol. Dis. |volume=39 |issue=2 |pages=156–9 |date=2007 |pmid=17532652 |doi=10.1016/j.bcmd.2007.04.004 |url=}}</ref><ref name="pmid17068151">{{cite journal |vauthors=Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K, Macintyre EA, Villeval JL, Vainchenker W, Berger R, Bernard OA, Delabesse E, Penard-Lacronique V |title=Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia |journal=Blood |volume=109 |issue=5 |pages=2202–4 |date=March 2007 |pmid=17068151 |doi=10.1182/blood-2006-09-045963 |url=}}</ref>
*Trisomy 21 lies at the heart of these abnormal [[Cell proliferation|cell proliferations]].
*Varied expression of the following [[genes]] may lead to the development of disorders of [[Cell proliferation|cellular proliferation]]:
**GATA binding protein 1 ([[GATA1]]) [[gene]]- Transient [[Myeloproliferative disease|myeloproliferative disorder]]<ref name="pmid12172547">{{cite journal |vauthors=Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD |title=Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome |journal=Nat. Genet. |volume=32 |issue=1 |pages=148–52 |date=September 2002 |pmid=12172547 |doi=10.1038/ng955 |url=}}</ref><ref name="pmid12747884">{{cite journal |vauthors=Groet J, McElwaine S, Spinelli M, Rinaldi A, Burtscher I, Mulligan C, Mensah A, Cavani S, Dagna-Bricarelli F, Basso G, Cotter FE, Nizetic D |title=Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder |journal=Lancet |volume=361 |issue=9369 |pages=1617–20 |date=May 2003 |pmid=12747884 |doi=10.1016/S0140-6736(03)13266-7 |url=}}</ref><ref name="pmid20108342">{{cite journal |vauthors=Stepensky P, Brooks R, Waldman E, Revel-Vilk S, Izraeli S, Resnick I, Weintraub M |title=A rare case of GATA1 negative chemoresistant acute megakaryocytic leukemia in an 8-month-old infant with trisomy 21 |journal=Pediatr Blood Cancer |volume=54 |issue=7 |pages=1048–9 |date=July 2010 |pmid=20108342 |doi=10.1002/pbc.22331 |url=}}</ref>
**Janus kinase 3 (JAK3)- Acute megakaryocytic leukemia (AMKL)<ref name="pmid17068151">{{cite journal |vauthors=Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K, Macintyre EA, Villeval JL, Vainchenker W, Berger R, Bernard OA, Delabesse E, Penard-Lacronique V |title=Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia |journal=Blood |volume=109 |issue=5 |pages=2202–4 |date=March 2007 |pmid=17068151 |doi=10.1182/blood-2006-09-045963 |url=}}</ref><ref name="pmid18397343">{{cite journal |vauthors=Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E |title=Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome |journal=Br. J. Haematol. |volume=141 |issue=5 |pages=681–8 |date=May 2008 |pmid=18397343 |doi=10.1111/j.1365-2141.2008.07081.x |url=}}</ref><ref name="pmid17456055">{{cite journal |vauthors=De Vita S, Mulligan C, McElwaine S, Dagna-Bricarelli F, Spinelli M, Basso G, Nizetic D, Groet J |title=Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome |journal=Br. J. Haematol. |volume=137 |issue=4 |pages=337–41 |date=May 2007 |pmid=17456055 |doi=10.1111/j.1365-2141.2007.06574.x |url=}}</ref>
**Janus kinase 2 (JAK2) point mutation- [[Acute lymphoblastic leukemia]] ([[Acute lymphoblastic leukemia|ALL]])<ref name="pmid19120350">{{cite journal |vauthors=Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, Plon SE, Basso G, Pession A, Rabin KR |title=Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia |journal=Br. J. Haematol. |volume=144 |issue=6 |pages=930–2 |date=March 2009 |pmid=19120350 |pmc=2724897 |doi=10.1111/j.1365-2141.2008.07552.x |url=}}</ref><ref name="pmid19965641">{{cite journal |vauthors=Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S, Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S |title=Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group |journal=Blood |volume=115 |issue=5 |pages=1006–17 |date=February 2010 |pmid=19965641 |doi=10.1182/blood-2009-08-235408 |url=}}</ref>
 
== Genetics ==
Expression of the following [[genes]] may be disturbed in trisomy 21:
{| 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>
Line 65: Line 128:
|}
|}


==Specific genes==
==Associated Conditions==
===Amyloid beta (APP)===
The following conditions may be associated with Down's syndrome:
[[Image:App location.jpg|right|thumb|Location of the APP gene on chromosome 21 in humans.]]
* Early onset [[Alzheimer's disease]]
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" />
* [[Hypothyroidism]]
* [[Hyperthyroidism]]
* [[Mental retardation]]
* [[Leukemia|Leukemias]]
* [[Infertility]]
* [[Delayed puberty]]
* [[Autoimmune diseases]]:
** [[Diabetes]]
** [[Celiac disease]]
* [[Short stature]]
* [[Congenital heart disease|Congenital heart defects]] ([[Atrioventricular canal defect (patient information)|atrioventricular canal defect]], [[ventricular septal defect]], [[atrial septal defect]], [[patent ductus arteriosus]], [[tetralogy of Fallot]])
* [[Hearing loss]] (related to [[otitis media]] with effusion or [[Sensorineural hearing loss|sensorineural]])
* [[Ophthalmic]] disorders ([[congenital]] [[Cataract|cataracts]], [[glaucoma]], [[strabismus]])
* [[Gastrointestinal tract|Gastrointestinal]] malformations ([[duodenal atresia]], [[Hirschsprung's disease|Hirschsprung disease]])
 
== Gross Pathology ==
There are no [[Gross examination|gross]] pathological findings associated with Down syndrome.


===Superoxide dismutase (SOD1)===
== Microscopic Pathology ==
[[Image:SOD1 Location.gif|left|thumb|Location of the SOD1 gene on chromosome 21 in humans.]]
There are no [[microscopic]] findings associated with Down syndrome.
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]].


==References==
==References==

Latest revision as of 05:15, 21 March 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

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. Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). 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. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.Immaturity of the feto-placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. Reduced synthesis of AFP by the fetal liver is also thought to contribute to low AFP in Down’s syndrome pregnancies. Robertsonian translocation occurrs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromeres and the 2 short arms are lost. Mosaicism does not have any maternal association and it is a post-fertilization mitotic error. Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome.

Pathophysiology

Mechanisms of trisomy 21

Meiotic non-disjunction

Robertsonian translocation

Mosaicism

Effects on increased gene dosage

Learning and memory

Neurodevelopment

  • DS patients have increased rates of neuronal apoptosis related to oxidative stress.[30]
  • Brain size of fetuses carrying trisomy 21 is smaller than euploid fetuses.
  • Murine models have suggested that disruption in expression of the following genes may play key roles in affecting neurodevelopment in DS patients:

Alzheimer's disease

Cancer and leukemias

Genetics

Expression of the following genes may be disturbed in trisomy 21:

Table 1: Some genes located on the long arm of chromosome 21[50]
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.[51]
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. [52]
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.[53]
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."[54]
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.

Associated Conditions

The following conditions may be associated with Down's syndrome:

Gross Pathology

There are no gross pathological findings associated with Down syndrome.

Microscopic Pathology

There are no microscopic findings associated with Down syndrome.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Wolstenholme J, Angell RR (November 2000). "Maternal age and trisomy--a unifying mechanism of formation". Chromosoma. 109 (7): 435–8. PMID 11151672.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL (January 2005). "Association between maternal age and meiotic recombination for trisomy 21". Am. J. Hum. Genet. 76 (1): 91–9. doi:10.1086/427266. PMC 1196437. PMID 15551222.
  17. ↑ Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL (January 2005). "Association between maternal age and meiotic recombination for trisomy 21". Am. J. Hum. Genet. 76 (1): 91–9. doi:10.1086/427266. PMC 1196437. PMID 15551222.
  18. ↑ 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.
  19. ↑ Vicari S, Carlesimo GA (June 2006). "Short-term memory deficits are not uniform in Down and Williams syndromes". Neuropsychol Rev. 16 (2): 87–94. doi:10.1007/s11065-006-9008-4. PMID 16967345.
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  21. ↑ Aylward EH, Li Q, Honeycutt NA, Warren AC, Pulsifer MB, Barta PE, Chan MD, Smith PD, Jerram M, Pearlson GD (April 1999). "MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia". Am J Psychiatry. 156 (4): 564–8. doi:10.1176/ajp.156.4.564. PMID 10200735.
  22. ↑ Di Filippo M, Tozzi A, Ghiglieri V, Picconi B, Costa C, Cipriani S, Tantucci M, Belcastro V, Calabresi P (April 2010). "Impaired plasticity at specific subset of striatal synapses in the Ts65Dn mouse model of Down syndrome". Biol. Psychiatry. 67 (7): 666–71. doi:10.1016/j.biopsych.2009.08.018. PMID 19818432.
  23. ↑ Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, Goo JS, Choi SY, Han JS, Ha I, Song WJ (June 2006). "DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects". Neurobiol. Dis. 22 (3): 463–72. doi:10.1016/j.nbd.2005.12.006. PMID 16455265.
  24. ↑ Yu HH, Yang JS, Wang J, Huang Y, Lee T (February 2009). "Endodomain diversity in the Drosophila Dscam and its roles in neuronal morphogenesis". J. Neurosci. 29 (6): 1904–14. doi:10.1523/JNEUROSCI.5743-08.2009. PMC 2671081. PMID 19211897.
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  26. ↑ Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, Inokuchi K, Katsuki M, Fujii-Kuriyama Y (August 1999). "Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome". Hum. Mol. Genet. 8 (8): 1409–15. PMID 10400987.
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  28. ↑ Meng X, Shi J, Peng B, Zou X, Zhang C (April 2006). "Effect of mouse Sim2 gene on the cell cycle of PC12 cells". Cell Biol. Int. 30 (4): 349–53. doi:10.1016/j.cellbi.2005.11.012. PMID 16530433.
  29. ↑ Rachidi M, Delezoide AL, Delabar JM, Lopes C (June 2009). "A quantitative assessment of gene expression (QAGE) reveals differential overexpression of DOPEY2, a candidate gene for mental retardation, in Down syndrome brain regions". Int. J. Dev. Neurosci. 27 (4): 393–8. doi:10.1016/j.ijdevneu.2009.02.001. PMID 19460634.
  30. ↑ Busciglio J, Yankner BA (1995). "Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro". Nature. 378 (6559): 776–9. doi:10.1038/378776a0. PMID 8524410.
  31. ↑ Micali N, Longobardi E, Iotti G, Ferrai C, Castagnaro L, Ricciardi M, Blasi F, Crippa MP (June 2010). "Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress". Nucleic Acids Res. 38 (11): 3595–604. doi:10.1093/nar/gkq019. PMC 2887940. PMID 20110257.
  32. ↑ Suizu F, Hiramuki Y, Okumura F, Matsuda M, Okumura AJ, Hirata N, Narita M, Kohno T, Yokota J, Bohgaki M, Obuse C, Hatakeyama S, Obata T, Noguchi M (December 2009). "The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt". Dev. Cell. 17 (6): 800–10. doi:10.1016/j.devcel.2009.09.007. PMID 20059950.
  33. ↑ Lepagnol-Bestel AM, Zvara A, Maussion G, Quignon F, Ngimbous B, Ramoz N, Imbeaud S, Loe-Mie Y, Benihoud K, Agier N, Salin PA, Cardona A, Khung-Savatovsky S, Kallunki P, Delabar JM, Puskas LG, Delacroix H, Aggerbeck L, Delezoide AL, Delattre O, Gorwood P, Moalic JM, Simonneau M (April 2009). "DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome". Hum. Mol. Genet. 18 (8): 1405–14. doi:10.1093/hmg/ddp047. PMID 19218269.
  34. ↑ Canzonetta C, Mulligan C, Deutsch S, Ruf S, O'Doherty A, Lyle R, Borel C, Lin-Marq N, Delom F, Groet J, Schnappauf F, De Vita S, Averill S, Priestley JV, Martin JE, Shipley J, Denyer G, Epstein CJ, Fillat C, Estivill X, Tybulewicz VL, Fisher EM, Antonarakis SE, Nizetic D (September 2008). "DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome". Am. J. Hum. Genet. 83 (3): 388–400. doi:10.1016/j.ajhg.2008.08.012. PMC 2556438. PMID 18771760.
  35. ↑ Kuhn DE, Nuovo GJ, Terry AV, Martin MM, Malana GE, Sansom SE, Pleister AP, Beck WD, Head E, Feldman DS, Elton TS (January 2010). "Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains". J. Biol. Chem. 285 (2): 1529–43. doi:10.1074/jbc.M109.033407. PMC 2801278. PMID 19897480.
  36. ↑ Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D (January 2006). "APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy". Nat. Genet. 38 (1): 24–6. doi:10.1038/ng1718. PMID 16369530.
  37. ↑ Cabrejo L, Guyant-Maréchal L, Laquerrière A, Vercelletto M, De la Fournière F, Thomas-Antérion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D (November 2006). "Phenotype associated with APP duplication in five families". Brain. 129 (Pt 11): 2966–76. doi:10.1093/brain/awl237. PMID 16959815.
  38. ↑ Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC (July 2006). "Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration". Neuron. 51 (1): 29–42. doi:10.1016/j.neuron.2006.05.022. PMID 16815330.
  39. ↑ Seo H, Isacson O (June 2005). "Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice". Exp. Neurol. 193 (2): 469–80. doi:10.1016/j.expneurol.2004.11.017. PMID 15869949.
  40. ↑ Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH, Ahn YS, Chung SH, Song WJ (November 2007). "DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease". J. Biol. Chem. 282 (48): 34850–7. doi:10.1074/jbc.M707358200. PMID 17906291.
  41. ↑ 41.0 41.1 Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (September 2002). "Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome". Nat. Genet. 32 (1): 148–52. doi:10.1038/ng955. PMID 12172547.
  42. ↑ Izraeli S, Rainis L, Hertzberg L, Smooha G, Birger Y (2007). "Trisomy of chromosome 21 in leukemogenesis". Blood Cells Mol. Dis. 39 (2): 156–9. doi:10.1016/j.bcmd.2007.04.004. PMID 17532652.
  43. ↑ 43.0 43.1 Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K, Macintyre EA, Villeval JL, Vainchenker W, Berger R, Bernard OA, Delabesse E, Penard-Lacronique V (March 2007). "Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia". Blood. 109 (5): 2202–4. doi:10.1182/blood-2006-09-045963. PMID 17068151.
  44. ↑ Groet J, McElwaine S, Spinelli M, Rinaldi A, Burtscher I, Mulligan C, Mensah A, Cavani S, Dagna-Bricarelli F, Basso G, Cotter FE, Nizetic D (May 2003). "Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder". Lancet. 361 (9369): 1617–20. doi:10.1016/S0140-6736(03)13266-7. PMID 12747884.
  45. ↑ Stepensky P, Brooks R, Waldman E, Revel-Vilk S, Izraeli S, Resnick I, Weintraub M (July 2010). "A rare case of GATA1 negative chemoresistant acute megakaryocytic leukemia in an 8-month-old infant with trisomy 21". Pediatr Blood Cancer. 54 (7): 1048–9. doi:10.1002/pbc.22331. PMID 20108342.
  46. ↑ Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E (May 2008). "Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome". Br. J. Haematol. 141 (5): 681–8. doi:10.1111/j.1365-2141.2008.07081.x. PMID 18397343.
  47. ↑ De Vita S, Mulligan C, McElwaine S, Dagna-Bricarelli F, Spinelli M, Basso G, Nizetic D, Groet J (May 2007). "Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome". Br. J. Haematol. 137 (4): 337–41. doi:10.1111/j.1365-2141.2007.06574.x. PMID 17456055.
  48. ↑ Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, Plon SE, Basso G, Pession A, Rabin KR (March 2009). "Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia". Br. J. Haematol. 144 (6): 930–2. doi:10.1111/j.1365-2141.2008.07552.x. PMC 2724897. PMID 19120350.
  49. ↑ Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S, Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S (February 2010). "Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group". Blood. 115 (5): 1006–17. doi:10.1182/blood-2009-08-235408. PMID 19965641.
  50. ↑ See Leshin, L. (2003). "Trisomy 21: The Story of Down Syndrome". Retrieved 2006-05-21.
  51. ↑ Chandra Shekhar (6 July 2006). "Down syndrome traced to one gene". The Scientist. Retrieved 2006-07-11. Check date values in: |date= (help)
  52. ↑ 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.
  53. ↑ 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.
  54. ↑ OMIM, NIH. "V-ETS Avian Erythroblastosis virus E26 Oncogene Homolog 2". Retrieved 2006-06-29.

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