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Down syndrome—recent progress and future prospects

By Frances K. Wiseman, Kate A. Alford, Victor L.J. Tybulewicz and Elizabeth M.C. Fisher

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

Topics: Reviews
Publisher: Oxford University Press
OAI identifier: oai:pubmedcentral.nih.gov:2657943
Provided by: PubMed Central
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    Citations

    1. 9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities.
    2. (2004). A chromosome 21 critical region does not cause specific down syndrome phenotypes.
    3. (2006). A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.
    4. (2008). A neural crest deficit in Down syndrome mice is associated with deficient mitotic response to Sonic hedgehog.
    5. (1989). A prospective study of Alzheimer disease in Down syndrome.
    6. (2008). A specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukaemia.
    7. (2005). Abnormal APP, cholinergic and cognitive function in Ts65Dn Down’s model mice.
    8. (2006). Abnormal expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex, and substantia nigra of Ts65Dn mouse: a model of Down syndrome.
    9. (2008). Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations.
    10. (2003). Acquired mutations in GATA1 in neonates with Down’s syndrome with transient myeloid disorder.
    11. (2002). Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.
    12. (2006). Activating alleles of JAK3 in acute megakaryoblastic leukemia.
    13. (2008). Activating mutations in human acute megakaryoblastic leukemia.
    14. (2008). Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test.
    15. (2007). Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain.
    16. (2005). An aneuploid mouse strain carrying human chromosome 21 with down syndrome phenotypes.
    17. (2007). Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer’s disease in adults with Down syndrome.
    18. (2008). Axonal abnormalities in cerebellar Purkinje cells of the Ts65Dn mouse.
    19. (2003). Behavioral comparison of 4 and 6 month-old Ts65Dn mice: age-related impairments in working and reference memory.
    20. (2007). Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with Down syndrome and in Ts65Dn mice.
    21. (1997). Cerebellar volume in adults with Down syndrome.
    22. (2004). Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors.
    23. (2008). Characterization of the cardiac phenotype in neonatal Ts65Dn mice.
    24. (2004). Chromosome 21 and Down syndrome: from genomics to pathophysiology.
    25. (2001). Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer’s disease.
    26. (2007). Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes.
    27. (2008). Common variants near MC4R are associated with fat mass, weight and risk of obesity.
    28. (2007). Cre/loxP-mediated chromosome engineering of the mouse genome.
    29. (2006). CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome.
    30. (2008). Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study.
    31. (2008). Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome.
    32. (2006). Defective cerebellar response to mitogenic Hedgehog signaling in Down syndrome mice.
    33. (1996). Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome.
    34. (2002). Differences in cardiovascular disease risk between nondiabetic adults with mental retardation with and without Down syndrome.
    35. (2007). Differential effects of trisomy on brain shape and volume in related aneuploid mouse models.
    36. (1991). Down syndrome: MR quantification of brain structures and comparison with normal control subjects.
    37. (2000). DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways.
    38. (2003). DSCR1(Adapt78)—a Janus gene providing stress protection but causing Alzheimer’s disease?
    39. (2008). Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease.
    40. (2007). Duplication of the entire
    41. (2007). Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome.
    42. (2006). Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation.
    43. (2008). DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
    44. (2007). DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease.
    45. (2007). Effects of aneuploidy on skull growth in a mouse model of Down syndrome.
    46. (2006). Effects of overexpression of Sim2 on spatial memory and expression of synapsin I in rat hippocampus.
    47. (2002). Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome.
    48. (2008). Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project.
    49. (2008). Excitatory– inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome.
    50. (2001). Failed retrograde transport of NGF in a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion.
    51. (1999). Fetal loss in Down syndrome pregnancies.
    52. (2006). Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome.
    53. (2008). Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome.
    54. (2007). Gene expression variation in Down’s syndrome mice allows prioritization of candidate genes.
    55. (2007). Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
    56. (2008). Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome
    57. (2008). Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome.
    58. (2006). Hippocampal hypocellularity in the Ts65Dn mouse originates early in development.
    59. (1996). Human aneuploidy: incidence, origin, and etiology.
    60. (2008). Human chromosome 21-derived miRNAs are overexpressed in Down syndrome brains and hearts.
    61. (2007). Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.
    62. (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up.
    63. (2000). Incidence and course of dementia in people with Down’s syndrome: findings from a population-based study.
    64. (2006). Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
    65. (2008). Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of Tau in Down syndrome.
    66. (2008). Inducing segmental aneuploid mosaicism in the mouse through targeted asymmetric sister chromatid event of recombination.
    67. (1999). International variation in reported livebirth prevalence rates of Down syndrome, adjusted for maternal age.
    68. (2007). JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults.
    69. (2007). Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down’s syndrome.
    70. (2008). Large recurrent microdeletions associated with schizophrenia.
    71. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.
    72. (2000). Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down’s syndrome.
    73. (1996). Low blood pressure in Down’s syndrome, a link with Alzheimer’s disease?
    74. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function.
    75. (2007). Microstructure of trabecular bone in a mouse model for Down syndrome.
    76. (2004). Minocycline prevents cholinergic loss in a mouse model of Down’s syndrome.
    77. (2006). Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome.
    78. (2004). Mnb/Dyrk1A phosphorylation regulates the interaction of dynamin 1 with SH3 domain-containing proteins.
    79. (2006). MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins.
    80. (2006). Modeling chromosomes in mouse to explore the function of genes, genomic disorders, and chromosomal organization.
    81. (2007). Modeling the monosomy for the telomeric part of human chromosome 21 reveals haploinsufficient genes modulating the inflammatory and airway responses.
    82. (2002). Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study.
    83. (2004). Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction.
    84. (1998). MRI brain changes in subjects with Down syndrome with and without dementia.
    85. (1999). MRI volumes of the hippocampus and amygdala in adults with Down’s syndrome with and without dementia.
    86. (2004). Mutagenic insertion and chromosome engineering resource (MICER).
    87. (2006). National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res. A Clin.
    88. (2007). Natural gene-expression variation in Down syndrome modulates the outcome of gene–dosage imbalance.
    89. (2001). Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome.
    90. (2008). Neurogenesis impairment and increased cell death reduce total neuron number in the hippocampal region of fetuses with Down syndrome.
    91. (2006). New techniques to understand chromosome dosage: mouse models of aneuploidy.
    92. (2006). NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.
    93. (2007). Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia.
    94. (2008). Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome.
    95. (2000). Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice.
    96. (1985). Pathological evidence for neurotransmitter deficits in Down’s syndrome of middle age.
    97. (2001). Pattern of malignant disorders in individuals with Down’s syndrome.
    98. (2007). Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome.
    99. (1998). Population-based study of the prevalence and presentation of dementia in adults with Down’s syndrome.
    100. (2006). Postnatal lethality and cardiac anomalies in the Ts65Dn Down syndrome mouse model.
    101. (2008). Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome.
    102. (2000). Prevalence of dementia and impact on intellectual disability services.
    103. (2008). Prevention of developmental delays in a Down syndrome mouse model.
    104. (2007). Prominent use of distal 5’ transcription start sites and discovery of a large number of additional exons in ENCODE regions.
    105. (2006). RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta.
    106. (2007). RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration.
    107. (2006). Review Issue 1transgenic mice show altered synaptic plasticity with learning and memory defects.
    108. (2008). Speeding of miniature excitatory post-synaptic currents in Ts65Dn cultured hippocampal neurons.
    109. (2008). Sprouty2-mediated inhibition of fibroblast growth factor signaling is modulated by the protein kinase DYRK1A.
    110. (2007). Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype–phenotype relationships.
    111. (2008). Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down’s syndrome.
    112. (2002). The changing survival profile of people with Down’s syndrome: implications for genetic counselling.
    113. (2007). The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease.
    114. (2006). The incidence patterns of Down syndrome in Qatar.
    115. (2008). The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia. Leukemia, advance online publication 2
    116. (2001). The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase.
    117. (1996). The prevalence of dementia in Down syndrome.
    118. (2007). The prevalence of Down syndrome in County Galway.
    119. (2006). The protein kinase DYRK1A phosphorylates the splicing factor SF3b1/SAP155 at Thr434, a novel in vivo phosphorylation site.
    120. (2006). The proteins of human chromosome
    121. (2008). The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome.
    122. (2008). Trisomy 21 enhances human fetal erythro-megakaryocytic development.
    123. (2007). Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice.
    124. (2007). Trisomy of chromosome 21 in leukemogenesis.
    125. (2008). Trisomy represses Apc(Min)-mediated tumours in mouse models of Down’s syndrome.
    126. (2007). Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome.
    127. (2007). Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current.
    128. (2007). What is a gene, post-ENCODE? History and updated definition.

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