Down Syndrome: From Understanding the Neurobiology to Therapy

Gardiner, Katheleen; Hérault, Yann; Lott, Ira T.; Antonarakis, Stylianos E.; Reeves, Roger H.; Dierssen, Mara

doi:10.1523/jneurosci.3728-10.2010

Cited by 129 publications

(103 citation statements)

References 25 publications

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“…Theories of the pathophysiology of DS stem from the imbalance of gene expression in critical developmental pathways caused by the presence of an extra HSA21 (17)(18)(19)(20). We analyzed global gene expression of DS1 and DS4 Ts21 iPSCs compared with isogenic euploid DS2U to determine if there were gene expression changes that might foreshadow later defects in differentiated tissues.…”

Section: Resultsmentioning

confidence: 99%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

178

214

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Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.cerebral cortex | developmental disorders D own syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID) (1). DS is caused by trisomy of chromosome 21 (Ts21) (2), resulting in the triplication of over 400 genes (3-5), which makes elucidation of the precise mechanisms underlying ID in DS a significant challenge. Confounding this difficulty is the relative inaccessibility of human tissue and incomplete human Ts21 in the context of mouse models. Despite these shortcomings, studies using mouse models containing trisomy of parts of syntenic chromosome 21 (HSA21) have put forth several critical hypotheses on the cellular and molecular mechanisms underlying DS features. It is essential, however, to test these hypotheses in human cells with full triplication of HSA21 in a context that allows for normal gene regulation. Here, we used Ts21-induced pluripotent stem cells (iPSCs) to test hypotheses of the underlying causes of ID in DS, with specific regard to neuropathophysiology. ResultsIsogenic Human Ts21 iPSCs. Fibroblasts from two individuals diagnosed with DS were reprogrammed to iPSCs. FISH for HSA21 in one fibroblast line showed mosaicism, where ∼90% of cells carried Ts21, whereas ∼10% were euploid (Fig. 1A). Reprogramming of the mosaic fibroblasts by retrovirus (6) resulted in three viable iPSC clones, two clones that carried Ts21 and one euploid (Fig. 1B). Mosaicism in DS individuals is rare, occurring in ∼1-3% of DS cases (7), but it can also emerge in vitro (8), potentially because of nondisjunction events during cell division.

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Section: Resultsmentioning

confidence: 99%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

178

214

View full text Add to dashboard Cite

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“…Correspondently, the levels of HMGN1 protein are up-regulated both in Down syndrome patients and mice models for this syndrome (15). Down syndrome is characterized by a wide range of symptoms including abnormalities in the nervous system and cognitive deficits (20). It is well established that Down syndrome is caused by the presence of an extra copy of chromosome 21 or segments of it (21); however, the specific role for a triplicate gene or a combination of genes in the etiology of Down syndrome are poorly understood.…”

Section: Hmgn1mentioning

confidence: 99%

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

Abuhatzira

Shamir

Schones

et al. 2011

Journal of Biological Chemistry

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Background: HMGN1 is a chromatin-binding protein that modulates the cellular transcription profile. Results: Mice that either overexpress or lack HMGN1 have altered behavioral phenotypes. HMGN1 is a negative regulator of MeCP2, a protein involved in neurodevelopmental disorders. Conclusion: Misregulation of HMGN1 protein levels lead to behavioral changes in mice. Significance: HMGN1 is an epigenetic factor that contributes to the development of neurodevelopmental disorders.

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“…This group was used as a proxy for children diagnosed with intellectual disability. Individuals with DS are known to have a general cognitive delay and to be intellectually disabled to some degree [30]. The identification of ASD in children with DS is complicated since the pattern of test scores across subscales among children with DS is not fully explored [31].…”

Section: Limitationsmentioning

confidence: 99%

The Observation Scale for Autism (OSA): A New Screening Method to Detect Autism Spectrum Disorder before Age Three Years

Haglund

Dahlgren

Källén

et al. 2016

J. Intellect. Disabl. Diagn. Treat.

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Background: There is an increasing body of evidence that early interventions for children with Autism Spectrum Disorder (ASD) promote a positive development of social interaction. Thus, tools for early detection of ASD are warranted. Aim: Development of, and deciding cut-off-levels for, a new screening tool for ASD, the Observation Scale for Autism (OSA). The OSA was designed to be used at the free health check-up at 30 months, offered to all children in Sweden. Method: The OSA consists of 12 observations and takes less than 10 minutes to use. The performance of the test was investigated by assessing 37 children previously diagnosed ASD, 23 with Down Syndrome (DS) and 26 typically developing children (TD). Results: Children diagnosed with ASD showed statistically significant higher scores in all 12 items compared to TD children, and significantly higher in 10 items compared to the children with DS. Most of the observations in OSA seemed to cover specific symptoms of ASD, but two of the observations were more related to developmental level. The nine most discriminative items for ASD were identified, and among those, a cut-off limit was chosen (≥3 items). Among children with ASD, 34/37 reached the proposed cut off, compared to 0/26 and 4/23 among children in the TD and DS groups, respectively. Conclusion: The results suggest that the OSA discriminates children with ASD from TD children and children with DS. Using the suggested cut off, OSA provides high sensitivity for ASD (92%) with a very low false positive rate.

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Down Syndrome: From Understanding the Neurobiology to Therapy

Cited by 129 publications

References 25 publications

Deficits in human trisomy 21 iPSCs and neurons

Deficits in human trisomy 21 iPSCs and neurons

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

The Observation Scale for Autism (OSA): A New Screening Method to Detect Autism Spectrum Disorder before Age Three Years

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