Genetics. The critical region in trisomy 21

Department of Molecular and Human Genetics and the Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Science (Impact Factor: 33.61). 11/2004; 306(5696):619-21. DOI: 10.1126/science.1105226
Source: PubMed
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    • "DS is characterized by well-defined and distinctive phenotypic features including craniofacial dysmorphism, mental retardation, almost constant muscular hypotonia, and joint laxity. Further potential abnormalities and the clinical picture include heart defects, digestive malformations , congenital cataract, short stature, sensory deficiencies, Hirschsprung's disease, West's syndrome, seizures, propensity to leukemias and other blood diseases, autoimmune and endocrine disorders, premature aging, and Alzheimer-type neuronal pathology by the third to the fourth decade of life [2] [3] [4] [5]. Although the DS phenotype has become better known in the last fifty years, the underlying pathogenic mechanisms of this complex syndrome and how the additional chromosome 21 causes this array of diseases remain to be elucidated. "
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    ABSTRACT: Down's syndrome (DS) is characterized by a complex phenotype associated with chronic oxidative stress and mitochondrial dysfunction. Overexpression of genes on chromosome-21 is thought to underlie the pathogenesis of the major phenotypic features of DS, such as premature aging. Using cultured fibroblasts with trisomy 21 (T21F), this study aimed to ascertain whether an imbalance exists in activities, mRNA, and protein expression of the antioxidant enzymes SOD1, SOD2, glutathione-peroxidase, and catalase during the cell replication process in vitro. T21F had high SOD1 expression and activity which led to an interenzymatic imbalance in the antioxidant defense system, accentuated with replicative senescence. Intracellular ROS production and oxidized protein levels were significantly higher in T21F compared with control cells; furthermore, a significant decline in intracellular ATP content was detected in T21F. Cell senescence was found to appear prematurely in DS cells as shown by SA-β-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F. These novel findings would point to a deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS.
    Oxidative Medicine and Cellular Longevity 04/2015; 2015:509241. DOI:10.1155/2015/509241 · 3.36 Impact Factor
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    • "Another challenge in using murine disease models can arise from the differences in colinearity of the human and mouse genomes and the lack of conservation of gene order. Mice engineered to be trisomic for those sections of the mouse genome that are orthologous to the human Down syndrome critical region failed to recapitulate human cranial abnormalities (Nelson and Gibbs, 2004) or neurodegeneration (Reeves et al., 1995) commonly associated with Down syndrome. Further, only a relatively small subset of ageregulated gene expression changes is conserved from mouse to man (Loerch et al., 2008). "
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    ABSTRACT: Reprogramming of human somatic cells uses readily accessible tissue, such as skin or blood, to generate embryonic-like induced pluripotent stem cells (iPSCs). This procedure has been applied to somatic cells from patients who are classified into a disease group, thus creating "disease-specific" iPSCs. Here, we examine the challenges and assumptions in creating a disease model from a single cell of the patient. Both the kinetics of disease onset and progression as well as the spatial localization of disease in the patient's body are challenges to disease modeling. New tools in genetic modification, reprogramming, biomaterials, and animal models can be used for addressing these challenges.
    Cell stem cell 12/2009; 5(6):584-95. DOI:10.1016/j.stem.2009.11.009 · 22.27 Impact Factor
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    ABSTRACT: Aneuploidies are common chromosomal defects that result in growth and developmental deficits and high levels of lethality in humans. To gain insight into the biology of aneuploidies, we manipulated mouse embryonic stem cells and generated a trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21). This "transchromosomic" mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome (DS) in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human DS. Transchromosomic mouse lines such as Tc1 may represent useful genetic tools for dissecting other human aneuploidies.
    Science 10/2005; 309(5743):2033-7. DOI:10.1126/science.1114535 · 33.61 Impact Factor
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