Mental retardation in Down syndrome: From gene dosage imbalance to molecular and cellular mechanisms

Rachidi, Mohammed; Lopes, Carmela

doi:10.1016/j.neures.2007.08.007

Cited by 94 publications

(70 citation statements)

References 208 publications

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“…The "few critical genes" hypothesis predicts that a small number of triplicated genes causes the growth, developmental, and cognitive abnormalities characteristic of the condition. Indeed, previous studies mapped DS phenotypes to a genomic region known as the DS critical region (DSCR) (Rahmani et al 1990; for review, see Rachidi and Lopes 2007). DSCR1, located in this region, was shown to protect individuals with DS from developing solid tumors (Baek et al 2009).…”

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confidence: 99%

Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes

2015

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Aneuploidy—the gain or loss of one or more whole chromosome—typically has an adverse impact on organismal fitness, manifest in conditions such as Down syndrome. A central question is whether aneuploid phenotypes are the consequence of copy number changes of a few especially harmful genes that may be present on the extra chromosome or are caused by copy number alterations of many genes that confer no observable phenotype when varied individually. We used the proliferation defect exhibited by budding yeast strains carrying single additional chromosomes (disomes) to distinguish between the “few critical genes” hypothesis and the “mass action of genes” hypothesis. Our results indicate that subtle changes in gene dosage across a chromosome can have significant phenotypic consequences. We conclude that phenotypic thresholds can be crossed by mass action of copy number changes that, on their own, are benign.

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Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes

2015

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“…[8][9][10] Overall, about one in five children with DS die before the age of 5 years, and about two out of five survivors have major health problems in addition to mental retardation in early childhood. 10 Congenital heart diseases are the most frequently documented birth defects in infants with DS and approximately 46% are born with one or more heart defects that include atrioventricular canal defects, ventricular septal defects and patent ductus ateriousus.…”

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confidence: 99%

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

Fuchs

Ciani

Guidi

et al. 2012

Laboratory Investigation

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Down syndrome (DS) is a genetic pathology due to the triplication of human chromosome 21. In addition to mental retardation, individuals with DS exhibit a large range of variable traits, including co-occurring congenital malformations. It is now clear that neurogenesis impairment underlies the typically reduced brain size and, hence, mental retardation in individuals with DS. The small body size and the constellation of congenital malformations in children with DS suggest that proliferation defects may involve peripheral tissues, in addition to the brain. The goal of the current study was to establish whether a generalized impairment of cell proliferation is a key feature of the trisomic condition. We used the Ts65Dn mouse, a widely used DS model, and examined proliferation in tissues with different embryological origin by 5-bromo-2-deoxyuridine immunohistochemistry. We found that 2-day-old (P2) Ts65Dn mice had notably fewer proliferating cells in the heart and liver, and in all proliferating niches of the skin and intestine. A reduced proliferation rate was still present in the intestine at P15. In all tissues, Ts65Dn mice had a similar number of apoptotic cells as euploid mice, indicating no unbalance in cell death. In the skin, liver and intestine of trisomic mice, we found a higher expression of patched1 (Ptch1), a receptor that represses the mitogenic sonic hedgehog (Shh) pathway. This suggests that Ptch1-dependent inhibition of Shh signaling may underlie proliferation impairment in trisomic peripheral tissues. In agreement with the widespread reduction in proliferation, neonate trisomic mice had a reduced body weight and this defect was still present at 30 days of age. Our findings show that, in all examined peripheral tissues, Ts65Dn mice exhibit a notable reduction in proliferation rate, suggesting that proliferation impairment may be a generalized defect of trisomic precursor cells.

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“…Chromosome 18 has the lowest gene density among human chromosomes (6). Unlike other trisomy syndromes such as trisomy 21, knowledge about the pathology and molecular mechanisms of 18T is very limited (7,8). This may be partly due to the lack of disease-associated samples and disease models as a result of the syndrome's rareness and extremely high mortality rate (2,9).…”

Section: Introductionmentioning

confidence: 99%

Establishment of a human trisomy 18 induced pluripotent stem cell line from amniotic fluid cells

Xing

Cui

Luan

et al. 2018

IRDR

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Mental retardation in Down syndrome: From gene dosage imbalance to molecular and cellular mechanisms

Cited by 94 publications

References 208 publications

Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes

Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

Establishment of a human trisomy 18 induced pluripotent stem cell line from amniotic fluid cells

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