17:
35:. It is estimated that chromosome 21 contains 200 to 250 genes. Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome, located proximal to 21q22.3. The search for major genes involved in Down syndrome characteristics is normally in the region 21q21–21q22.3.
230:. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome." ETS2-Transgenic mice were also shown to "develop neurocranial, viscerocranial and cervical skeletal abnormalities", similar skeletal abnormalities to those seen in Down syndrome.
324:
duplicated to approximate a human chromosome-21 triplication, they only showed slight craniofacial abnormalities (688–90). 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
349:
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
414:
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.
556:
Trisomy 21 entails an increased risk of many chronic diseases that are typically associated with older age such as an increased risk of
Alzheimer's disease. The clinical manifestations of accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for
323:
The genes that may be responsible for the phenotypes associated may be located proximal to 21q22.3. Testing by Olson and others 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
335:, using 250 clones of chromosome-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 (311–13).
1040:
Pallardó FV, Degan P, d'Ischia M, Kelly FJ, Zatterale A, Calzone R, Castello G, Fernandez-Delgado R, Dunster C, Lloret A, Manini P, Pisanti MA, Vuttariello E, Pagano G (August 2006). "Multiple evidence for an early age pro-oxidant state in Down
Syndrome patients".
364:
is an
Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties. Another gene, ETS2, is Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that over-expression of ETS2 results in
523:
and adult DS fibroblasts are defective in the removal of 8-OHdG as compared with age-matched cells from control healthy donors These findings suggest that oxidative DNA damage may underlie some of the clinical and premature aging features of DS.
315:
596). Down syndrome is also characterized by increased socialization. When modified and unmodified mice were observed for social interaction, the modified mice showed as much as 25% more interactions as compared to the unmodified mice (Arron
279:. NFAT is controlled in part 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
753:
Song WJ, Sternberg LR, Kasten-Sportès C, et al. (December 1996). "Isolation of human and murine homologues of the
Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region"".
1087:
Necchi D, Pinto A, Tillhon M, Dutto I, Serafini MM, Lanni C, Govoni S, Racchi M, Prosperi E (October 2015). "Defective DNA repair and increased chromatin binding of DNA repair factors in Down syndrome fibroblasts".
789:
Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (October 1995). "A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart".
302:
597). A test involving grip strength showed that the genetically modified mice had a significantly weaker grip, much like the characteristically poor muscle tone of an individual with Down syndrome (Arron
342:
show that 41% of the genes on chromosome-21 have no functional purpose, and only 54% of functional genes have a known protein sequence. Functionality of genes was determined by a computer using
447:. 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
970:
Komatsu T, Duckyoung Y, Ito A, Kurosawa K, Maehata Y, Kubodera T, Ikeda M, Lee MC (September 2013). "Increased oxidative stress biomarkers in the saliva of Down syndrome patients".
31:
located on chromosome 21. In general, this leads to an overexpression of the genes. Understanding the genes involved may help to target medical treatment to individuals with
298:
This disregulation was discovered by testing in transgenic mice that had segments of their chromosomes duplicated to simulate a human chromosome-21 trisomy (Arron
390:
One chromosome 21 gene that might predispose Down syndrome individuals to develop
Alzheimer's pathology is the gene that encodes the precursor of the
328:
687). The exact characteristics of Down syndrome were not observed, so more genes involved for Down syndrome phenotypes have to be located elsewhere.
578:
Mao R, Zielke CL, Zielke HR, Pevsner J (May 2003). "Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain".
369:. Transgenic mice over-expressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."
1123:
Horvath S, Garagnani P, Bacalini MG, Pirazzini C, Salvioli S, Gentilini D, Di Blasio AM, Giuliani C, Tung S, Vinters HV, Franceschi C (2015).
350:
of genes that have no known purpose. Much more research would be needed to produce any appropriate or ethically acceptable treatment options.
338:
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
946:
890:
824:
394:. Neurofibrillary tangles and amyloid plaques are commonly found in both Down syndrome and Alzheimer's individuals. Layer II of the
1005:
Jovanovic SV, Clements D, MacLeod K (December 1998). "Biomarkers of oxidative stress are significantly elevated in Down syndrome".
537:
488:
424:
383:
689:
Rahmani Z, Blouin JL, Créau-Goldberg N, et al. (1990). "Down syndrome critical region around D21S55 on proximal 21q22.3".
919:
840:
Sumarsono SH, Wilson TJ, Tymms MJ, et al. (1996). "Down's
Syndrome-like skeletal abnormalities in Ets2 transgenic mice".
728:
226:
Avian
Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that overexpression of ETS2 results in
354:
88:
87:
A4 precursor protein. Suspected to have a major role in cognitive difficulties. One of the first genes studied with
484:
84:
541:
407:
292:
507:
were found to be significantly higher than in control groups. 8-OHdG levels were also found to be higher in
455:), the cells will suffer from a peroxide damage. Some scientists believe that the treatment of Down syndrome
402:, are among the first affected by the damage. A gradual decrease in the number of nerve cells throughout the
496:
346:
prediction analysis (312). Exon sequence was obtained by the same procedures of the chromosome-21 mapping.
1180:
468:
452:
118:
463:
scavengers can substantially prevent neuronal degeneration. Oxidative damage to neurons results in rapid
954:
902:
403:
272:
849:
615:"Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart"
432:
399:
114:
99:
184:
16:
561:, trisomy 21 significantly increases the age of blood and brain tissue (on average by 6.6 years).
1066:
873:
1156:
1105:
1058:
1022:
987:
865:
807:
771:
706:
646:
595:
440:
395:
1146:
1138:
1097:
1050:
1014:
979:
898:
857:
799:
763:
698:
636:
626:
587:
558:
545:
512:
492:
436:
391:
140:
853:
1151:
1124:
957:
905:
641:
614:
360:
to study specific genes in the Down syndrome critical region has yielded some results.
288:
243:
221:
200:
178:
156:
134:
109:
79:
1018:
983:
591:
1174:
480:
308:
43:
Some suspected genes involved in features of Down syndrome are given in the Table 1:
32:
1070:
923:
877:
732:
460:
411:
361:
69:
1101:
557:
this hypothesis has been sparse. According to a biomarker of tissue age known as
283:
597). The elevated levels of DSCR1 and DYRK1A keep NFAT primarily located in the
161:
Interferon, Alpha, Beta, and Omega, Receptor. Responsible for the expression of
464:
1129:
1054:
631:
516:
268:
249:
162:
803:
702:
366:
284:
227:
1160:
1109:
1062:
991:
767:
650:
599:
423:
295:
of target genes and thus the production of certain proteins (Epstein 583).
143:. May have an effect on mental development through abnormal neurogenesis.
1026:
869:
811:
775:
710:
382:
533:
205:
951:
V-ETS AVIAN ERYTHROBLASTOSIS VIRUS E26 ONCOGENE HOMOLOG 2; ETS2 - 164740
1142:
669:
861:
504:
456:
448:
271:
associated with Down syndrome can be related to the disregulation of
252:, a major component of the lens in eyes. May be cause of cataracts.
829:
520:
508:
444:
422:
381:
357:
121:. Anti-oxidant as well as possible effects on the immuno-system.
91:
15:
950:
894:
828:
343:
276:
238:
216:
195:
173:
151:
129:
104:
74:
55:
28:
431:
Some (but not all) studies have shown that the activity of the
307:
596). The mice squeezed a probe with a paw and displayed a 0.2
500:
208:, type I, alpha 1 gene. May have an effect on heart disease.
47:
Table 1: Some genes located on the long arm of chromosome 21
183:
Down
Syndrome Critical Region Gene 1. Possibly part of a
451:
responsible for removal of hydrogen peroxide (e.g.,
427:
Location of the SOD1 gene on chromosome 21 in humans
386:
Location of the APP gene on chromosome 21 in humans
248:Crystallin, Alpha-A. Involved in the synthesis of
613:Mao R, Wang X, Spitznagel EL, et al. (2005).
1125:"Accelerated epigenetic aging in Down syndrome"
1082:
1080:
895:AMYLOID BETA A4 PRECURSOR PROTEIN; APP - 104760
552:Epigenetic studies of accelerated aging effects
519:of persons with DS compared to controls. Both
722:
720:
8:
942:
940:
410:scientists created a genetically engineered
141:Tyrosine Phosphorylation-Regulated Kinase 1A
435:is elevated in Down syndrome. SOD converts
487:is a well-established marker of oxidative
1150:
640:
630:
670:"Trisomy 21: The Story of Down Syndrome"
662:
660:
187:pathway involving both heart and brain.
45:
570:
291:, preventing NFATc from activating the
25:Research of Down syndrome–related genes
20:Chromosome 21 from Human Genome Program
398:and the subiculum, both critical for
7:
691:American Journal of Medical Genetics
947:Online Mendelian Inheritance in Man
891:Online Mendelian Inheritance in Man
825:Online Mendelian Inheritance in Man
165:, which affects the immuno-system.
920:"Down syndrome traced to one gene"
729:"Down syndrome traced to one gene"
532:Human chromosome 21 contains five
14:
984:10.1016/j.archoralbio.2013.03.017
495:and the excessive production of
922:. The Scientist. Archived from
918:Shekhar, Chandra (2006-07-06).
731:. The Scientist. Archived from
727:Chandra Shekhar (6 July 2006).
503:of persons with DS measured in
499:. The levels of 8-OHdG in the
1:
1019:10.1016/S0891-5849(98)00137-3
592:10.1016/S0888-7543(03)00035-1
1102:10.1016/j.mrfmmm.2015.07.009
242:
237:
220:
215:
199:
194:
177:
172:
155:
150:
133:
128:
108:
103:
78:
73:
433:superoxide dismutase enzyme
419:Superoxide dismutase (SOD1)
1197:
960:. Retrieved on 2006-12-05.
908:. Retrieved on 2006-12-05.
406:follows. A few years ago,
275:(596), and in particular,
1055:10.1007/s10522-006-9002-5
632:10.1186/gb-2005-6-13-r107
467:aging similar to that of
85:Amyloid precursor protein
27:is based on studying the
703:10.1002/ajmg.1320370720
497:reactive oxygen species
267:shows that some of the
768:10.1006/geno.1996.0636
453:glutathione peroxidase
428:
387:
21:
1007:Free Radic. Biol. Med
804:10.1093/hmg/4.10.1935
426:
385:
273:transcription factors
19:
400:memory consolidation
117:. Possible role in
115:Superoxide dismutase
94:with Down syndrome.
854:1996Natur.379..534H
668:Leshin, L. (2003).
469:Alzheimer's disease
311:weaker grip (Arron
287:rather than in the
185:signal transduction
119:Alzheimer's disease
64:Purported Function
48:
1143:10.1111/acel.12325
429:
388:
378:Amyloid beta (APP)
263:Research by Arron
46:
22:
848:(6565): 534–537.
441:hydrogen peroxide
396:entorhinal cortex
256:
255:
139:Dual-specificity
1188:
1165:
1164:
1154:
1120:
1114:
1113:
1084:
1075:
1074:
1037:
1031:
1030:
1002:
996:
995:
967:
961:
944:
935:
934:
932:
931:
915:
909:
888:
882:
881:
862:10.1038/379534a0
837:
831:
822:
816:
815:
786:
780:
779:
750:
744:
743:
741:
740:
724:
715:
714:
686:
680:
679:
677:
676:
664:
655:
654:
644:
634:
610:
604:
603:
575:
559:epigenetic clock
493:oxidative stress
475:Oxidative stress
259:General research
49:
1196:
1195:
1191:
1190:
1189:
1187:
1186:
1185:
1171:
1170:
1169:
1168:
1122:
1121:
1117:
1086:
1085:
1078:
1039:
1038:
1034:
1004:
1003:
999:
972:Arch. Oral Biol
969:
968:
964:
945:
938:
929:
927:
917:
916:
912:
889:
885:
839:
838:
834:
823:
819:
798:(10): 1935–44.
792:Hum. Mol. Genet
788:
787:
783:
752:
751:
747:
738:
736:
726:
725:
718:
688:
687:
683:
674:
672:
667:
665:
658:
612:
611:
607:
577:
576:
572:
567:
554:
548:, and miR-802.
530:
477:
437:oxygen radicals
421:
392:amyloid protein
380:
375:
261:
179:21q22.1–21q22.2
41:
12:
11:
5:
1194:
1192:
1184:
1183:
1173:
1172:
1167:
1166:
1115:
1076:
1043:Biogerontology
1032:
997:
978:(9): 1246–50.
962:
936:
910:
883:
832:
817:
781:
745:
716:
693:. Supplement.
681:
656:
605:
569:
568:
566:
563:
553:
550:
544:, miR-125b-2,
529:
528:MicroRNA genes
526:
476:
473:
420:
417:
379:
376:
374:
373:Specific genes
371:
353:Recent use of
260:
257:
254:
253:
246:
241:
236:
232:
231:
224:
219:
214:
210:
209:
203:
198:
193:
189:
188:
181:
176:
171:
167:
166:
159:
154:
149:
145:
144:
137:
132:
127:
123:
122:
112:
107:
102:
96:
95:
82:
77:
72:
66:
65:
62:
59:
53:
40:
37:
13:
10:
9:
6:
4:
3:
2:
1193:
1182:
1181:Down syndrome
1179:
1178:
1176:
1162:
1158:
1153:
1148:
1144:
1140:
1136:
1132:
1131:
1126:
1119:
1116:
1111:
1107:
1103:
1099:
1095:
1091:
1083:
1081:
1077:
1072:
1068:
1064:
1060:
1056:
1052:
1049:(4): 211–20.
1048:
1044:
1036:
1033:
1028:
1024:
1020:
1016:
1013:(9): 1044–8.
1012:
1008:
1001:
998:
993:
989:
985:
981:
977:
973:
966:
963:
959:
956:
953:, located at
952:
948:
943:
941:
937:
926:on 2022-12-26
925:
921:
914:
911:
907:
904:
900:
896:
892:
887:
884:
879:
875:
871:
867:
863:
859:
855:
851:
847:
843:
836:
833:
830:
826:
821:
818:
813:
809:
805:
801:
797:
793:
785:
782:
777:
773:
769:
765:
761:
757:
749:
746:
735:on 2022-12-26
734:
730:
723:
721:
717:
712:
708:
704:
700:
696:
692:
685:
682:
671:
663:
661:
657:
652:
648:
643:
638:
633:
628:
624:
620:
616:
609:
606:
601:
597:
593:
589:
586:(5): 457–67.
585:
581:
574:
571:
564:
562:
560:
551:
549:
547:
543:
539:
535:
527:
525:
522:
518:
514:
510:
506:
502:
498:
494:
491:arising from
490:
486:
482:
481:DNA oxidation
474:
472:
470:
466:
462:
458:
454:
450:
446:
442:
438:
434:
425:
418:
416:
413:
409:
408:Johns Hopkins
405:
401:
397:
393:
384:
377:
372:
370:
368:
363:
359:
356:
351:
347:
345:
341:
336:
334:
329:
327:
321:
319:
314:
310:
306:
301:
296:
294:
293:transcription
290:
286:
282:
278:
274:
270:
266:
258:
251:
247:
245:
240:
234:
233:
229:
225:
223:
218:
212:
211:
207:
204:
202:
197:
191:
190:
186:
182:
180:
175:
169:
168:
164:
160:
158:
153:
147:
146:
142:
138:
136:
131:
125:
124:
120:
116:
113:
111:
106:
101:
98:
97:
93:
90:
86:
83:
81:
76:
71:
68:
67:
63:
60:
57:
54:
51:
50:
44:
38:
36:
34:
33:Down syndrome
30:
26:
18:
1137:(3): 491–5.
1134:
1128:
1118:
1093:
1089:
1046:
1042:
1035:
1010:
1006:
1000:
975:
971:
965:
928:. Retrieved
924:the original
913:
886:
845:
841:
835:
820:
795:
791:
784:
762:(3): 331–9.
759:
755:
748:
737:. Retrieved
733:the original
694:
690:
684:
673:. Retrieved
625:(13): R107.
622:
618:
608:
583:
579:
573:
555:
531:
478:
461:free radical
430:
389:
352:
348:
339:
337:
332:
330:
325:
322:
317:
312:
304:
299:
297:
280:
264:
262:
42:
24:
23:
619:Genome Biol
517:fibroblasts
1130:Aging Cell
1090:Mutat. Res
930:2006-07-11
739:2006-07-11
697:: 98–103.
675:2006-05-21
513:leukocytes
489:DNA damage
355:transgenic
269:phenotypes
250:crystallin
163:interferon
89:transgenic
58:Reference
1096:: 15–23.
367:apoptosis
285:cytoplasm
228:apoptosis
61:Location
1175:Category
1161:25678027
1110:26258283
1071:13657691
1063:16612664
992:23714170
949:(OMIM):
893:(OMIM):
827:(OMIM):
756:Genomics
651:16420667
600:12706104
580:Genomics
534:microRNA
483:product
206:Collagen
1152:4406678
1027:9870557
899:located
897:, gene
878:4365956
870:8596630
850:Bibcode
812:8595418
776:8975710
711:2149984
642:1414106
546:miR-155
538:miR-99a
536:genes:
457:neurons
449:enzymes
331:Reeves
289:nucleus
244:21q22.3
222:21q22.3
201:21q22.3
192:COL6A1
157:21q22.1
135:21q22.1
110:21q22.1
1159:
1149:
1108:
1069:
1061:
1025:
990:
876:
868:
842:Nature
810:
774:
709:
649:
639:
598:
542:let-7c
505:saliva
485:8-OHdG
404:cortex
340:et al.
333:et al.
326:et al.
320:596).
318:et al.
313:et al.
309:newton
305:et al.
300:et al.
281:et al.
265:et al.
239:123580
235:CRYA1
217:164740
196:120220
174:602917
170:DSCR1
152:107450
148:IFNAR
130:600855
105:147450
75:104760
1067:S2CID
958:q22.3
874:S2CID
565:Notes
521:fetal
509:urine
465:brain
459:with
445:water
412:mouse
213:ETS2
126:DYRK
80:21q21
52:Gene
39:Genes
29:genes
1157:PMID
1106:PMID
1059:PMID
1023:PMID
988:PMID
866:PMID
808:PMID
772:PMID
707:PMID
666:See
647:PMID
596:PMID
515:and
479:The
443:and
358:mice
344:exon
277:NFAT
100:SOD1
92:mice
56:OMIM
1147:PMC
1139:doi
1098:doi
1094:780
1051:doi
1015:doi
980:doi
906:q21
901:at
858:doi
846:379
800:doi
764:doi
699:doi
637:PMC
627:doi
588:doi
501:DNA
439:to
362:APP
70:APP
1177::
1155:.
1145:.
1135:14
1133:.
1127:.
1104:.
1092:.
1079:^
1065:.
1057:.
1045:.
1021:.
1011:25
1009:.
986:.
976:58
974:.
955:21
939:^
903:21
872:.
864:.
856:.
844:.
806:.
794:.
770:.
760:38
758:.
719:^
705:.
659:^
645:.
635:.
621:.
617:.
594:.
584:81
582:.
540:,
511:,
471:.
1163:.
1141::
1112:.
1100::
1073:.
1053::
1047:7
1029:.
1017::
994:.
982::
933:.
880:.
860::
852::
814:.
802::
796:4
778:.
766::
742:.
713:.
701::
695:7
678:.
653:.
629::
623:6
602:.
590::
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
