Linda Crnic Institute Holds 2nd Annual Down syndrome Symposium

December 22, 2013

Guest post By Amber Sorenson

On November 8th, the Linda Crnic Institute for Down Syndrome (LCI) held their second annual Down Syndrome Symposium. The conference was attended by researchers throughout Colorado who are interested in furthering Down syndrome research. Down syndrome (DS) is caused by an extra copy of chromosome 21, resulting in developmental defects and mental retardation.

Tom Blumenthal, the executive director of the LCI, began the day with a brief introduction to DS and the mission of the LCI. He emphasized the LCIs goal in making DS a tractable disease. The goal of the institute is not only to find ways to treat the ill effects of DS, but also to learn more about diseases that afflict patients with DS. In particular, DS individuals suffer from cognitive disabilities, including Alzheimer’s disease, and are prone to developing Leukemia. In order to accomplish these goals, the institute funded researchers in Denver and Boulder to study gene expression, autoimmune disease, leukemia, Alzheimer’s, and more in a Down syndrome context. We would get a chance to hear from some of these researchers later in the day.

The first speaker of the day was our keynote speaker, Jeanne Lawrence from the University of Massachusetts. This past year Jeanne published remarkable work in which she was able to silence the extra copy of chromosome 21 in DS with the XIST gene that is known the silence the extra X chromosome in women. Not only was Jeanne a fantastic speaker, she was also humble and sweet. She told a great story about how her interest in translational epigenetics and basic biology lead her to serendipitously address a clinical problem. Jeanne began her career interested in chromosome and nuclear structure. Her lab demonstrated that the XIST gene on the X chromosome transcribes a stable RNA that paints the inactive X chromosome. They also noticed that when the X chromosome was translocated onto an autosome, the autosome was partially silenced. This led them to ask if they could silence an autosome with XIST. However, how could they silence an autosome and maintain the cell viability? This led them to DS fiberblasts. They reprogrammed fiberblasts from DS patients to create stem cells. They then used zinc-finger editing to target XIST to chromosome 21. Chromosome 21 silencing in these cells is apparent after 5 days and fully silenced after 20 days of induction. The silencing remains stable, even after the XIST RNA expression is turned off. After silencing of the extra copy of chromosome 21 proliferation was increased in the cells to wildtype levels and the cultures were able to form neural progenitors earlier than the trisomy 21 cells. Jeanne was clear to point out that her discovery does not represent a cure of DS, but is a great research tool. And she hopes that further research may yield therapies for patients with DS.

The remainder of the day we heard from researchers who won the first round of grants from the LCI. Because this was the first year of awards from the LCI, the researchers have only had 6 months of time to get their projects off the ground. Much of the work by these researchers has been stunted by unexpected problems, such as culturing the DS iPS cells. Some of the highlights are summarized below:

• Matt Kennedy spoke about beta amyloid plaques in the brains of DS patients and the beta amyloid induced loss of dendritic spines.

• Rui Yi spoke about using quantitative miRNA-seq, mRNA seq, ribosomal profiling, and HITS-CLIP on trisomy 21, and wildtype iPS cells to better understand the mis-regulation in DS cells.

• James DeGregori hypothesized that the reduced fitness of trisomy 21 hematopoietic stem cells selects for adaptive mutations that lead to a higher risk of leukemia.

• Karl Pfenninger showed that DS neurons in culture exhibit distinct phenotypes in culture including increase in growth cone area, filopodia, axon length and adhesion. He would like to better understand brain development in DS patients, in particular the effect of increased amyloid progenitor protein (APP) on neuronal wiring.

• Rich Spitz reported that 50-80% of DS individuals have some form of auto-immune disease. His lab is profiling UBASH3A, associated with auto-immune disease, on chromosome 21 in DS individuals to determine if they have a higher rate of disease causing alleles.

For more information about the Linda Crnic Institute for Down Syndrome visit their website.


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