Down syndrome--recent progress and future prospects

Abstract

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype–phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.

Ohnologs in the human genome are dosage balanced and frequently associated with disease

“…Trisomy 21 results in DS, which is generally considered to be due to dosage imbalance caused by the extra copy of chromosome 21 and occurs at a frequency of more than 1/1,000 in human populations (36). Most trisomies are incompatible with life and are not observed in live births.…”

“…Several genes on chromosome 21 have been identified as DSrelated genes (36,37). For example, a 1.5-fold increase in dosage of DSCR1 and DYRK1A has been shown experimentally to lead to features of the DS phenotype (38).…”

Synthesis and serum protein binding of novel ring-substituted harmine derivatives

“…1,3 Several studies demonstrated that it inhibits selectively monoamine oxidases, 4 which play a key role in psychiatric and neurological disorders 5 (depression and Parkinson's diseases). Harmine was also identified as a potential inhibitor of the kinase Dyrk1A that is implicated in the pathogenesis of Down syndrome, 6 a common hereditary disorder.…”

ALK2 mutation in a patient with Down's syndrome and a congenital heart defect

“…4 Although all individuals with DS manifest these phenotypes, there is significant phenotypic variability between such individuals. 5 In conjunction with these phenotypic traits, DS individuals suffer from a higher incidence of several conditions, including CHDs. 5 The (birth) prevalence of CHDs in DS is about 40-60%, most frequently atrioventricular septal defects and ventricular septal defects.…”

“…5 In conjunction with these phenotypic traits, DS individuals suffer from a higher incidence of several conditions, including CHDs. 5 The (birth) prevalence of CHDs in DS is about 40-60%, most frequently atrioventricular septal defects and ventricular septal defects. [6][7][8] Efforts have been made to determine the critical chromosomal region for specific phenotypic features of DS by deletion mapping and characterization of patients with partial trisomy 21.…”