Silencing the extra chromosome responsible for Down syndrome

Scientists at the University of Massachusetts Medical School are the first to establish that a naturally occurring X chromosome "off switch" can be rerouted to neutralize the extra chromosome responsible for trisomy 21, also known as Down syndrome, a genetic disorder characterised by cognitive impairment.

The discovery provides the first evidence that the underlying genetic defect responsible for Down syndrome can be suppressed in cells in culture (in vitro).

This paves the way for researchers to study the cell pathologies and identify genome-wide pathways implicated in the disorder, a goal that has so far proven elusive.

Doing so will improve scientist's understanding of the basic biology underlying Down syndrome and may one day help establish potential therapeutic targets for future therapies.

Details of the study by Jiang et al. were published online in Nature.

Jeanne B. Lawrence

"The last decade has seen great advances in efforts to correct single-gene disorders, beginning with cells in vitro and in several cases advancing to in vivo and clinical trials," said lead author Jeanne B. Lawrence, PhD, professor of cell & developmental biology at the University of Massachusetts Medical School.

"By contrast, genetic correction of hundreds of genes across an entire extra chromosome has remained outside the realm of possibility.

Our hope is that for individuals living with Down syndrome, this proof-of-principal opens up multiple exciting new avenues for studying the disorder now, and brings into the realm of consideration research on the concept of "chromosome therapy' in the future."

Humans are born with 23 pairs of chromosomes, including two sex chromosomes, for a total of 46 in each cell.

People with Down syndrome are born with three (rather than two) copies of chromosome 21, and this "trisomy 21" causes cognitive disability, early-onset Alzheimer's disease; and a greater risk of childhood leukemia, heart defects and immune and endocrine system dysfunction.

Unlike genetic disorders caused by a single gene, genetic correction of a whole chromosome in trisomic cells has been beyond the realm of possibility, even in cultured cells.

Harnessing the power of the RNA gene called XIST, which is normally responsible for "turning off" one of the two X chromosomes found in female mammals, UMass Medical School scientists have shown that the extra copy of chromosomes 21 responsible for Down syndrome can be silenced in the laboratory using patient-derived stem cells.

This finding opens multiple new avenues for translational scientists to study Down syndrome in ways not previously possible.

Determining the underlying cell pathologies and gene pathways responsible for the syndrome has previously proven difficult, because of the complexity of the disorder and the normal genetic and epigenetic variation between people and cells.

For example, some prior studies suggested that cell proliferation in Down syndrome patients may be impaired, but differences between people and cell lines made it difficult to conclude this definitively.

By controlling expression of the XIST gene, Lawrence and colleagues were able to compare otherwise identical cultures of the Down syndrome cells, with and without expression of the extra chromosome.

What they showed is that the Down syndrome cells have defects in cell proliferation and in neural cell differentiation, both of which are reversed by silencing one chromosome 21 by XIST.

"This highlights the potential of this new experimental model to study a host of different questions in different human cell-types, and in Down syndrome mouse models" said Lawrence.

"We now have a powerful tool for identifying and studying the cellular pathologies and pathways impacted directly due to over-expression of chromosome 21."

"Dr. Lawrence has harnessed the power of a natural process to target abnormal gene expression in cells that have an aberrant number of chromosomes," said Anthony Carter, PhD, of the National Institutes of Health's National Institute of General Medical Sciences, which partly supported the study.

"Her work provides a new tool that could yield novel insights into how genes are silenced on a chromosomal scale, and into the pathological processes associated with chromosome disorders such as Down syndrome."

More information: DOI: 10.1038/nature12394

Down syndrome: Researchers target a particular aspect

The protrusion of a neuron without Dscam protein (green) and that of a neuron with an abnormally high level of Dscam protein (red). 

The protrusions are overlaid on the fruitfly's equivalent of the human spinal cord (blue). Credit: Xin Wang 

University of Michigan researchers have determined how a gene that is known to be defective in Down syndrome is regulated and how its dysregulation may lead to neurological defects, providing insights into potential therapeutic approaches to an aspect of the syndrome.

Normally, nerve cells called neurons undergo an intense period of extending and branching of neuronal protrusions around the time of birth.

During this period, the neurons produce the proteins of the gene called Down syndrome cell-adhesion molecule, or Dscam, at high levels.

After this phase, the growth and the levels of protein taper off. However, in the brains of patients with Down syndrome, epilepsy and several other neurological disorders, the amount of Dscam remains high.

The impact of the elevated Dscam amount on how neurons develop is unknown. Bing Ye, a faculty member at U-M's Life Sciences Institute, found that in the fruit fly Drosophila, the amount of Dscam proteins in a neuron determines the size to which a neuron extends its protrusions before it forms connections with other nerve cells.

An overproduction of Dscam proteins leads to abnormally large neuronal protrusions.

Ye also identified two molecular pathways that converge to regulate the abundance of Dscam. One, dual leucine zipper kinase (DLK), which is involved in nerve regeneration, promotes the synthesis of Dscam proteins.

Another, fragile X mental retardation protein (FMRP), which causes fragile X syndrome when defective, represses Dscam protein synthesis.

Because humans share these genes with Drosophila, the DLK-FMRP-Dscam relationship presents a possible target for therapeutic intervention, Ye said.

Many genes are involved in neurological disorders like Down syndrome, and how molecular defects cause the disease is complex.

"But because of the important roles of Dscam in the development of neurons, its related defect is very likely to be an aspect of Down syndrome and it may be an aspect of the syndrome that can be treated," said Ye, an assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.

Ye's next step is to test the effects of over-expression of Dscam in mice to see how it changes the development of the nervous system and the behavior of the animal.

Down syndrome occurs in about one in 830 newborns; an estimated 250,000 people in the U.S. have the condition, according to the National Library of Medicine's Genetics Home Reference.

Ye's study is scheduled to be published online June 5 in Neuron.

Down syndrome: Neurons grown from stem cells show signature problems - Oxidative Stress

Down syndrome, the most common genetic form of intellectual disability, results from an extra copy of one chromosome.

Although people with Down syndrome experience intellectual difficulties and other problems, scientists have had trouble identifying why that extra chromosome causes such widespread effects.

Anita Bhattacharyya

In new research published this week, Anita Bhattacharyya, a neuroscientist at the Waisman Center at the University of Wisconsin-Madison, reports on brain cells that were grown from skin cells of individuals with Down syndrome.

The research, published the week of May 27 in the Proceedings of the National Academy of Sciences (PNAS), was a basic exploration of the roots of Down syndrome.

"Even though Down syndrome is very common, it's surprising how little we know about what goes wrong in the brain," says Bhattacharyya. "These new cells provide a way to look at early brain development."

The study began when those skin cells were transformed into induced pluripotent stem cells, which can be grown into any type of specialized cell.

One significant finding was a reduction in connections among the neurons, Bhattacharyya says. "They communicate less, are quieter. This is new, but it fits with what little we know about the Down syndrome brain."

Brain cells communicate through connections called synapses, and the Down neurons had only about 60 percent of the usual number of synapses and synaptic activity.

"This is enough to make a difference," says Bhattacharyya. "Even if they recovered these synapses later on, you have missed this critical window of time during early development."

The researchers looked at genes that were affected in the Down syndrome stem cells and neurons, and found that genes on the extra chromosome were increased 150 percent, consistent with the contribution of the extra chromosome.

However, the output of about 1,500 genes elsewhere in the genome was strongly affected. "It's not surprising to see changes, but the genes that changed were surprising," says Bhattacharyya.

The predominant increase was seen in genes that respond to oxidative stress, which occurs when molecular fragments called free radicals damage a wide variety of tissues.

"We definitely found a high level of oxidative stress in the Down syndrome neurons," says Bhattacharyya.

"This has been suggested before from other studies, but we were pleased to find more evidence for that. We now have a system we can manipulate to study the effects of oxidative stress and possibly prevent them."

Down syndrome includes a range of symptoms that could result from oxidative stress, Bhattacharyya says, including accelerated aging.

"In their 40s, Down syndrome individuals age very quickly. They suddenly get gray hair; their skin wrinkles, there is rapid aging in many organs, and a quick appearance of Alzheimer's disease. Many of these processes may be due to increased oxidative stress, but it remains to be directly tested."

Oxidative stress could be especially significant, because it appears right from the start in the stem cells.

"This suggests that these cells go through their whole life with oxidative stress," Bhattacharyya adds, "and that might contribute to the death of neurons later on, or increase susceptibility to Alzheimer's."

More information: Deficits in human trisomy 21 iPSCs and neurons,www.pnas.org/cgi/d… s.1216575110

Far from the Tree: Dyslexia, Down Syndrome, Autism, Schizophrenia, disability, etc.

Far from the Tree (BBC website)

The time-worn adage says that the apple doesn't fall far from the tree, meaning that a child resembles his or her parents.

The children described in this book are apples that have fallen elsewhere - some a couple of orchards away, some on the other side of the world.

Yet myriad families learn to tolerate, accept and finally celebrate children who are not what they originally had in mind.

Andrew Solomon introduces us to families coping with deafness, Down syndrome, autism, schizophrenia, and disability - as well as families who have children who are prodigies, who are gay, or who become criminals.

Episode 1:
Growing up gay and also struggling with dyslexia led Andrew Solomon to reflect on those situations where a child arrives in a family and is immediately an 'outsider'. 'Parenthood,' he writes, 'abruptly catapults us into a permanent relationship with a stranger'.

Read by Kerry Shale
Abridged and produced by Jill Waters

Read more about the book: Far From the Tree