Researchers Report on Recurrent Mutations in Down Syndrome-related Myeloid Condition, Blood Cancer

by GenomeWeb Daily News:
A single gene appears to be the main culprit in a myeloid proliferation complication called transient abnormal myelopoiesis, or TAM, that's sometimes seen in individuals with Down syndrome, according to a study online yesterday in Nature Genetics, which usedsequencing to characterize the alterations associated with TAM and a related blood cancer.

A team led by investigators at the University of Tokyo, Kyoto University, and Hirosaki University used genome sequencing, exome sequencing, and targeted genomic assessments to tally up genetic changes involved in the often-temporary myeloid condition most akin to acute megakaryoblastic leukemia.

Gene Tied to Down Syndrome May Suggest Way to New Therapy

by Nicole Ostrow from Bloomberg:
Scientists have identified a gene on the extra chromosome causing Down syndrome that may be responsible for the early aging and cognitive defects in people with the condition, a finding that could lead to new treatments.
The gene, called Usp16, may hinder the body’s ability to make stem cells needed to maintain tissues and organs, according to research published today in the journal Nature. That includes development of organs such as the brain while in the uterus, said Michael Clarke, a senior study author.
The findings in mice and human cells are the first to help explain why people with Down syndrome show signs of early Alzheimer’s disease and age faster, the authors said. Further investigation may test whether the gene might slow down these aging effects or fight against other diseases like Alzheimer’s and cancer, Clarke said.
“Like most regulators and stem cell functions, understanding how those things work has potential implications in a wide range of diseases,” Clarke, a professor of medicine at Stanford University near Palo Alto, California, said in a telephone interview. “Now that we have a pathway, there might be drugs that could be used to improve some of the problems.”

In a laboratory dish, researchers shut down extra chromosome that causes Down syndrome

by Carolyn Y. Johnson from The Boston Globe:

Researchers at the University of Massachusetts Medical School have shown that it is possible to do what had once seemed unthinkable—shut down the extra chromosome that causes the developmental problems and intellectual disabilities in people with Down syndrome.

The surprising result—so far accomplished only with human cells grown in laboratory dishes—is the fruit of a daring, out-of-the-box approach by a scientist whose work has been shaped by her early experience counseling families of children with disabilities.

“It really is revolutionary, in terms of causing us all to rethink the one impossible thought—can you make, functionally, that extra chromosome disappear,” said Dr. Brian Skotko, co-director of the Down Syndrome Program at Massachusetts General Hospital, who was not involved in the new study. “I don’t think any of us thought it was possible or even within the current realm of scientific dreaming that we might one day be able to do it.”

New genetic cause for learning disability in Down syndrome identitfied

Neurons from a normal mouse (left) are longer and fuller than neurons from a mouse lacking SNX27 (right).

By Dr. Leila Luheshi from PHG Foundation:

Researchers have reported a novel molecular mechanism through which triplication of chromosome 21 could cause deficits in learning and memory in patients with Down syndrome.
Down syndrome is caused by the abnormal inheritance of three (rather than the usual two) copies of chromosome 21.  At a genetic level this leads to higher than normal levels of expression of the many genes and non-coding RNAs that are encoded on this chromosome.  Clinically this results in a complex constellation of symptoms of which the most prominent is a varying degree of learning disability.  Learning disability in Down syndrome is associated with reductions in the number and activity of the synapses (connections) made between neurons in the brain, and so understanding the mechanisms underlying these neurodevelopmental abnormalities may provide the key to ameliorating the effects of this disorder.

A new study in Nature Medicine reports that the protein encoded by the sorting nexin 27 (SNX27) gene, which is present at abnormally low levels in the brain of patients with Down syndrome, may underlie the presence of learning disabilities in this condition. 

The researchers showed, by knocking out the Snx27 gene in mice, that its expression is vital for brain development.  In particular they discovered that Snx27 is vital for the maintenance of synaptic activity and consequently for learning and memory, deficits in which underlie learning disability in patients with Down syndrome.  In a key experiment that linked these observations in mice more directly with the symptoms of Down syndrome in humans, the team were able to demonstrate that increasing Snx27 levels in a mouse model of Down syndrome could reverse the learning and memory deficits from which it is suffers.  

Fragile X, Down Syndrome Involve Similar Pathways

from PscyhCentral by Traci Pedersen:
Mental disabilities stemming from Fragile X and Down syndrome involve similar molecular pathways, according to a new study published in The EMBO Journal.
Both disorders are characterized by problems with the processes that regulate the way nerve cells develop dendritic spines—the small protrusions on the surface of nerve cells that are vital for communication in the brain.
“We have shown for the first time that some of the proteins altered in Fragile X and Down syndromes are common molecular triggers of intellectual disability in both disorders,” said Kyung-Tai Min, a professor at Indiana University and the Ulsan National Institute of Science and Technology in Korea.
“Specifically, two proteins interact with each other in a way that limits the formation of spines or protrusions on the surface of dendrites.”
“These outgrowths of the cell are essential for the formation of new contacts with other nerve cells and for the successful transmission of nerve signals. When the spines are impaired, information transfer is impeded and mental retardation takes hold,” he said.
Two of the most common genetic causes of intellectual disability are Fragile X and Down syndromes.
Fragile X syndrome is triggered by a single gene mutation that prevents the production of a protein needed for proper neural development (Fragile X mental retardation protein). For Down syndrome to occur, all or a part of a third copy of chromosome 21 must be present.
Although each syndrome is due to a separate genetic difference, the researchers identified a shared molecular pathway in mice that triggers intellectual disability in both disorders.
Down syndrome mice models have difficulties with memory and brain function, and the development of the heart is often compromised, symptoms that are also observed in humans with Down syndrome.
“We believe these experiments provide an important step forward in understanding the multiple roles of DSCR1 in neurons and in identifying a molecular interaction that is closely linked to intellectual disability for both syndromes,” said Min.

more from Science Daily:
http://www.sciencedaily.com/releases/2012/08/120803121010.htm