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HOUSTON -- (May 29, 2008) -- The deletion of all or part of a cluster of genetic material known as small nucleolar RNAs on chromosome 15 inherited from the father plays a role in the development of the genetic disorder Prader-Willi syndrome, said researchers from Baylor College of Medicine in Houston in a report in the current issue of Nature Genetics.

"Prader-Willi syndrome is the first disorder known to be associated with the loss of these small nucleolar RNAs," said Dr. Arthur Beaudet, chair of molecular and human genetics at BCM and senior author of the report. Prader-Willi syndrome is characterized by short stature, obesity as a child, developmental delay and other disorders.

The loss of these small nucleolar RNAs is associated with these symptoms, said Beaudet and his colleagues. These RNAs are a departure from the best known role of RNAs, serving as the template for making protein. Instead, they guide chemical modifications of many cellular RNAs with diverse functions, and even possibly messenger RNAs, which are the decoders of the genetic message that results in the production of proteins. Proteins are the workhorses of cells, carrying out most of their functions.

In a study involving the genome of a child with Prader-Willi syndrome, Beaudet and his colleagues found that a deletion of genetic material for a particular cluster of these small nucleolar RNAs called HBII-85 was associated with many of the symptoms attributed to Prader-Willi syndrome in this child.

Studies in mice by other investigators also suggested that the loss of these particular forms of RNA contributed to the problems associated with the disease, said Beaudet and his colleagues.

In an accompanying review of the research, Dr. Jo Peters of the Medical Research Council in Oxfordshire, United Kingdom, wrote, "Both the genetics and the phenotype (visible symptoms) of PWS (Prader-Willi syndrome) are complex, and identifying the gene(s) responsible has been a challenge, but we now have the answer."

Others who took part in this research include: Trilochan Sahoo, Daniela del Gaudio, Jennifer R German, Marwan Shinawi, Sarika U. Peters, Richard E. Person and Sau Wai Cheung, all of BCM, and Adolfo Garnica of St. Francis Hospital in Tulsa, Okla.

Funding for this research came from the National Institutes of Health, the Mental Retardation and Developmental Disabilities Research Center and the Rare Disease Clinical Research Consortia.

The article is available at http://www.nature.com/ng/journal/v40/n6/pdf/ng.158.pdf.

HOUSTON -- (May 29, 2008) -- In 1999, when Dr. Huda Zoghbi and her Baylor College of Medicine colleagues identified a mutation of the gene MeCP2 as the culprit in Rett syndrome, a neurodevelopmental disorder, the discovery was only the prelude to understanding a symphony of neurological missteps.

Unraveling the story of MeCP2 demonstrates the finicky nature of neurons that work best when the recipe for the proteins affecting them is followed exactly. Zoghbi and her collaborators describe the role MeCP2 plays in the brain in a report that appears in the current issue of the journal Science.

"Whether you lose the protein (for which the gene MeCP2 provides the genetic blueprint) or gain too much, the symptoms in the brain overlap quite a bit," said Zoghbi, who is a BCM professor of pediatrics, neurology, neuroscience, molecular and human genetics and a Howard Hughes Medical Institute investigator. "The brain is very sensitive to its physiological equilibrium."

Yet the brain or neurons in it can demonstrate a problem with only a limited range of symptoms – autism, seizures or mental retardation.

"The symptoms are those of an unhappy neuron," said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.

Zoghbi and her colleagues found that MeCP2 is a key regulator that can turn on and off genes that govern activities in the neurons of the hypothalamus. While MeCP2 can turn off a gene, it is more likely to turn it on.

As infants, girls with Rett syndrome seem normal for at least six months. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Many of their symptoms mirror those of autism. Zoghbi's laboratory was the first to identify a mutation in the MeCP2 gene that results in too little of this protein, causing girls to develop Rett. Boys who suffer from a disorder linked to an excess of MeCP2 have impaired motor function, seizures and mental retardation with autism-like behavior.

In trying to find out how the alterations in MeCP2 affect the brain, the scientists began their studies in the hypothalamus because symptoms of Rett syndrome such as anxiety, sleep disturbance and slowed growth can all be attributed to problems in that part of the brain. Previous studies of the whole brain proved inconclusive, and by targeting a very specific area of the brain, Zoghbi and her collaborators hoped to zero in on the problem.

"Loss of function of the MeCP2 gene causes Rett syndrome," said Maria Chahrour, a BCM graduate student and first author of the report. Doubling or tripling MeCP2 levels causes other neurological disorders. To better understand the protein, the scientists decided to study mice that either lacked MeCP2 or had too much of it.

They dissected the hypothalamus in both kinds of mice and looked at changes in the genes compared to the same genes in normal mice.

"There are thousands of genes changed by MeCP2," said Chahrour. In both the mice who had no MeCP2 and those who had too much of the dysfunctional gene, they found changes in expression of thousands of genes. Surprisingly, they found that in at least 85 percent of the genes, MeCP2 turned the gene on. In fact, they found that it associates with CREB1, another gene tasked with turning on genes.

Interestingly, although the two diseases share many features, having no protein versus having too much caused opposite effects on gene expression, suggesting that the symptoms indicate that the neurons are disturbed.

"Because MeCP2 regulates thousands of genes, it does not make sense to target each of them individually in designing treatments," Chahrour said. "We are going to have to find a therapeutic strategy that can bypass MeCP2 and restore the normal order in the brain," she said.

Others who took part in this work include Sung Yun Jung, Chad Shaw and Jun Qin of BCM and Xiaobo Zhou and Stephen T. C. Wong of The Methodist Hospital Research Institute and Weill Cornell College of Medicine.

Funding for this work comes from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development Mental Retardation and Developmental Disabilities Research Center, the International Rett Syndrome Foundation and the Simons Foundation.

The full article can be found at www.sciencemag.org.

HOUSTON -- (May 28, 2008) -- High throughput microscopy that uses robots and special microscopes and techniques to generate thousands of images of a cell in a short time enabled researchers at Baylor College of Medicine to describe how the genetic message of estrogen receptor-alpha is regulated, a finding that could have implications for breast cancer.

In a report in the current issue of the Public Library of Science-ONE, Dr. Michael A. Mancini and his colleagues showed that estrogen receptor-alpha's response depends on the manner of regulation.

Patient Samples

"All of this is leading to personalized medicine, said Mancini, associate professor of molecular and cellular biology at BCM and director of the Integrated Microscopy Core at the College. "We will some day be able to get functional assays of this kind on individual people. We have laid the groundwork to do patient samples."

Estrogen receptor activity is regulated in two manners. One is called ligand- or steroid-dependent in which the receptor has to bind to a small molecule to become active. The other is independent of the ligand and requires the action of another kind of molecule, such as a growth factor to become active.

Mancini and Dr. Valeria Berno, a postdoctoral associate in his lab, along with colleagues established a system that allows multiple quantitative "single-cell" analyses of how estrogen receptor regulates that transcription of genetic messages. (Transcription refers to the translation of a genetic message into the protein that carries out a function within a cell. Various factors can influence the extent to which such messages are translated within the cell).

Seeing actions

The cell line contained elements that lit up when estrogen receptor is activated. The estrogen receptor was marked with a green fluorescent protein. When it lights up, it enables researchers to "see" through a microscope the actions of a protein on the estrogen receptor.

The technique allowed them to see the receptor move in and out of the nucleus, bind to DNA and remodel the chromatin molecule that makes up the cell's chromosomes.

The system enabled them to differentiate the manner in which estrogen receptor responded to a ligand (estradiol) and to a growth factor (epidermal growth factor).

"This would never have been possible without the combination of manual and high throughput microscopy," said Mancini. The high throughput approach involves using a robot to fix slides with cells, stain them, put them under a microscope, focus and take photographs.

"You put it in the microscope, come back and all the pictures are taken," said Mancini. This particular experiment involved tens of thousands of such photographs, he said.

"You can look at DNA occupancy of receptor and coregulators, chromatin modeling and transcription (the translation of the genetic message) at the same time in the same image, this is a good example of why the approach is being called "high content analysis" he said. "What is really exciting is not only how fast we can collect the data, but the image analysis toolbox is expanding at a remarkably fast rate. This is the beginning of high throughput systems biology."

Cell Line

Maureen Mancini helped overcome a major hurdle by making the cell line that allowed the scientists to see what was happening.

"We are able to look at the receptor affected by the two different types of stimulation. They are now distinguishable because of this research," he said.

Others who took part in this research include Larbi Amazit, Cruz Hinojos, Jeannie Zhong, all of BCM and Zelton Dave Sharp of The University of Texas Health Science Center in San Antonio.

Funding for this work came from the National Institutes of Health and the U.S. Department of Defense. All imaging studies were performed with resources provided from the Center for Reproductive Biology, the Dan L. Duncan BCM Cancer Center Integrated Microscopy Shared Resource and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

The report is available at http://www.plosone.org/doi/pone.0002286.

HOUSTON -- (May 28, 2008) -- For many children, summer camp is an annual tradition. Kids with cancer – even those who are physically disabled because of their treatment or illness – don't have to be excluded from this rite of passage.

Camp is an impactful experience for children battling cancer that can instill in them the can-do attitude it takes to deal with their disease, said Dr. ZoAnn Dreyer, associate professor of pediatrics – hematology and oncology at Baylor College of Medicine in Houston.

"I always tell people that camp is the single most important thing we do next to treating the kids' cancer," said Dreyer, who serves as medical director for Camp Periwinkle, a week-long summer camp that promotes emotional healing for patients at the Texas Children's Cancer Center, a major component of the Dan L. Duncan Cancer Center at BCM.

When children don't have the right attitude, they often do not tolerate therapy well, and they may not have a good perspective on life as long-term survivors, Dreyer said.

"In that case, cancer becomes something that, instead of being a limited illness, affects them for the rest of their lives in a negative way," she said.

Camp Periwinkle is celebrating its 25th anniversary this summer. It is available to patients at the Texas Children's Cancer Center between the ages of 7 and 15 and their siblings, and it is completely free for families.

The relationships that are built at camp are very strong because they are built on the same foundation, Dreyer said.

"Each one of them has faced life-threatening illness, and they draw strength from each other and from the counselors," she said. "These children come from all sorts of different backgrounds, but at camp the playing field is equal. It doesn't matter that they have cancer and are undergoing treatment. They're just like everybody else, and there's nothing they can't do."

Often parents feel apprehension about sending their sick children off to camp, but Dreyer said they should feel secure knowing there is a full medical staff, often the same doctors who treat their children at the cancer center.

Camp Periwinkle is a program of the Periwinkle Foundation, a nonprofit organization dedicated to enriching the lives of children, young adults and families who are being treated for cancer and other life-threatening illnesses at the Texas Children's Cancer Center, a center of Baylor College of Medicine and Texas Children's Hospital.

The foundation got its name from the perennial Vinca minor, the periwinkle plant. It is the source of one of the most common chemotherapy agents used – vincristine.