UC San Diego’s William Mobley is acknowledged by Congress, honored with prize in Paris.

William Mobley, UC San Diego

William C. Mobley, M.D., Ph.D., chair of the Department of Neurosciences at the University of California, San Diego, School of Medicine and chairman of the U.S. Scientific Advisory Committee of the Jérôme Lejeune Foundation, was recognized by U.S. Rep. Pete Sessions from the floor of the House of Representatives in December. Sessions said of Mobley — who received the International Sisley-Jérôme Lejeune Prize in a ceremony at the Museum of Medical History in Paris on Dec. 8 — “Dr. Mobley’s many contributions in the field of Down syndrome have been truly valued in the special needs community. His research to identify causes of neurodegenerative disorders has brought new optimism to those afflicted with diseases, from Alzheimer’s to Down syndrome.”

The International Sisley-Jérôme Lejeune award was given to Mobley in recognition of his ambitious and innovative research into treatments for neurological disabilities, in particular Down syndrome. In his acceptance speech, Mobley commented that “Today, we have not yet developed an effective treatment, but our work shows that it will soon be possible.”

“His commitment and expertise in this area are a guarantee of excellence for the foundation,” said Jean-Marc Guilloux, executive director of the U.S. Jérôme Lejeune Foundation. “We are honored that a researcher of Dr. Mobley’s stature has agreed to assist us at this critical stage of launching this new initiative in the United States on behalf of those with genetic intellectual disabilities.” Mobley will be joined on the U.S. Scientific Advisory Committee by Dr. Randi Hagerman, professor of the MIND Institute at the University of California, Davis, and a research specialist in Fragile X syndrome, and by David Patterson, professor at the University of Denver, a researcher in the fields of Down syndrome and autism.

The International Sisley-Jérôme Lejeune Prize carries a cash award and is made possible by a generous grant of the Sisley Foundation, Paris.

The Jérôme Lejeune Foundation (Paris/U.S.) was founded in 1996 and is the world’s largest private funder of Down syndrome research, providing some $21 million worldwide. In 2010 alone the foundation invested $4 million in research, and funded more than 60 research projects which together are breaking new ground in both the understanding and management of Down syndrome, fragile X syndrome and other intellectual disabilities of genetic origin. The foundation’s mission is based upon three closely joined pillars of activity: research, care, and advocacy, all carried out in a spirit of profound respect for the dignity of all human persons.

Two genes identified as working together to disrupt cardiac development.

A novel study involving fruit flies and mice has allowed biologists to identify two critical genes responsible for congenital heart defects in individuals with Down syndrome, a major cause of infant mortality and death in people born with this genetic disorder.

In a paper published in today’s (Nov. 3) issue of the open access journal PLoS Genetics, researchers from UC San Diego, the Sanford-Burnham Medical Research Institute in La Jolla and the University of Utah report the identification of two genes that, when produced at elevated levels, work together to disrupt cardiac development and function.

Down syndrome, the most common genetic cause of cognitive impairment, is a disorder that occurs in one in 700 births when individuals have three, instead of the usual two, copies of human chromosome 21.

“Chromosome 21 is the shortest human chromosome and intensive genetic mapping studies in people with Down syndrome have identified a small region of this chromosome that plays a critical role in causing congenital heart defects,” said Ethan Bier, a biology professor at UC San Diego and one of the principal authors of the study.  “This Down syndrome region for congenital heart disease, called the ‘DS-CHD critical region,’ contains several genes that are active in the heart which our collaborator, Julie Korenberg, had suspected of interacting with each other to disrupt cardiac development or function when present in three copies.  But exactly which of these half dozen or so genes are the culprits?”

“Identifying the genes within the DS-CHD critical region contributing to congenital heart defects is challenging to address using traditional mammalian experimental models, such as mice,” added Bier, “since the number of possible genetic combinations that would need to be generated and tested is very large.”

To simplify their search, the scientists turned to fruit flies, a simpler and rapidly reproducing biological system with many of the same genes as mice and humans. With help from collaborators Amir Gamliel, Geoff Rosenfeld and Kirk Peterson at the UC San Diego School of Medicine, Rolf Bodmer and Karen Ocorr at the Sanford-Burnham Medical Research Institute, and Julie R. Korenberg at the University of Utah, biologist Tamar Grossman in Bier’s lab devised a sequential genetic approach to untangle the problem.

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UCSF event held in honor of the late Charles Epstein, a pioneer in the study and treatment of Down syndrome.

(From left) Neil Risch, Ophir Klein, Francis Collins and Lauren Weiss

Personalized medicine and new gene discoveries in human disease were a focus of a daylong symposium hosted by the UCSF Institute for Human Genetics on the Mission Bay campus on Oct. 3.

The now-annual symposium was convened to honor the late Charles J. Epstein, M.D., a pioneer in the study and treatment of Down syndrome and other genetic diseases. Epstein’s advocacy led to the establishment of medical genetics as a field of specialized medicine. He died in February as a result of pancreatic cancer.

Epstein trained many leading geneticists, including several of the symposium speakers. Other speakers, such as Francis Collins, M.D., Ph.D., director of the National Institutes of Health (NIH), were long-time friends and associates.

Collins, this year’s Charles J. and Lois B. Epstein Visiting Professor, gave a talk titled “Achieving Charlie’s Vision: The Science is Finally Catching Up with the Clinic.” Collins, who headed the Human Genome Project from 1993 to 2008, said that Epstein in his Down syndrome research pioneered the discovery of genetic and biochemical abnormalities that cause disease symptoms four decades ago, “when there were very few genes mapped to any chromosome.”

“Over the course of 40 years he brought together the clinical aspects of genetics and the research aspects in a way that has profoundly changed our understanding for all time and brought us into an era when clinical genetics, I think, has a remarkable future,” Collins said.

Through the Human Genome Project, researchers completely spelled out the DNA sequence of an entire human genome for the first time. That milestone, achieved in 2003, required more than a decade and nearly $3 billion.

With ever-improving technology and analytic tools, the cost of reading out an individual’s genome has continued to plummet while sequencing has sped up enormously. Today, Collins said, “We are on a trajectory toward the $1,000 genome.”  In the not-so-distant future the cost of obtaining an entire read-out of an individual’s DNA for use in personalizing medical care might no longer be prohibitively expensive.

Within a year the NIH will make available for research purposes a database containing all the protein-encoding genes for 75,000 individuals, including complete genomic DNA sequences for many of them, Collins said. Making this data available to researchers should greatly aid efforts to identify genetic causes of disease.

Collins described newer NIH grant competitions that put young scientists, including geneticists, on the fast track so that they can quickly begin directing more creative research in their own laboratories. Two symposium speakers, Ophir Klein, MD, PhD, and Lauren Weiss, PhD, are each recipients of one of these grants, called the NIH Director’s New Innovator Award.

Klein discussed his research on stem cells in teeth and the intestinal tract. His work is leading to basic discoveries about how stem cell populations guide the fate of cells and tissues during development. Weiss described populations studies aimed at identifying genetic mutations that may be responsible for many cases of autism.

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The finding may offer an additional clinicl tool to help diagnose dementia in adults with Down syndrome.

Gary Small, UCLA

In one of the first studies of its kind, UCLA researchers used a unique brain scan to assess the levels of amyloid plaques and neurofibrillary tangles — the hallmarks of Alzheimer’s disease — in adults with Down syndrome.

Published in the June edition of the Archives of Neurology, the finding may offer an additional clinical tool to help diagnose dementia in adults with Down syndrome, a genetic disorder caused by the presence of a complete or partial extra copy of chromosome 21.

Adults with this disorder develop Alzheimer’s-like plaque and tangle deposits early, often before the age of 40. Previously, the only way to physically detect these abnormal proteins in this population was through an autopsy.

Over the last decade, methods for identifying and imaging the neuropathology of Alzheimer’s disease in living patients have been developed. UCLA researchers have created a chemical marker called FDDNP that binds to both plaque and tangle deposits, which can then be viewed through a positron emission tomography (PET) brain scan, providing a “window into the brain.” Using this method, researchers are able to pinpoint where in the brain these abnormal protein deposits are accumulating.

Due to individual variability and difficulty in obtaining baseline levels of cognitive function in adults with Down syndrome, such imaging may be useful in helping to diagnose dementia, say researchers.

“Neuroimaging may be a helpful tool in assessing and tracking plaque and tangle development over time in this population,” said the study’s senior author, Dr. Gary Small, a professor at the Semel Institute for Neuroscience and Human Behavior at UCLA who holds UCLA’s Parlow-Solomon Chair on Aging. ”Early detection can also lead to earlier interventions and treatments, often before symptoms begin.”

For this study, researchers administered the FDDNP chemical marker intravenously and then performed PET brain scans on 19 non-demented adults with Down syndrome (average age 37), 10 healthy controls (average age 43) and 10 patients with Alzheimer’s disease (average age 66).

Analysis found significantly higher binding levels of the chemical marker in participants with Down syndrome in all brain regions, when compared with healthy controls. Compared with Alzheimer’s disease patients, subjects with Down syndrome showed significantly higher binding levels in the parietal and frontal regions — areas involved in memory, behavior and reasoning.

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The center will study and treat the condition in adults.

Michael Rafii, UC San Diego

Doctors and scientists at the UC San Diego School of Medicine will soon open one of the first programs in the United States to combine academic research with the treatment of adults with Down syndrome.

The Down Syndrome Center for Research and Treatment (DSCRT) officially launches Sunday, March 13, with a reception hosted by the Down Syndrome Association of San Diego. The event will be held from 2 to 4:30 p.m. at the Center for Neural Circuits and Behavior building on the School of Medicine campus in La Jolla.

Down syndrome is caused by a chromosomal abnormality that results in distinct physical and neurological symptoms. Patients with Down syndrome are also at greater risk of developing Alzheimer’s disease. According to the National Down Syndrome Society, approximately 400,000 people in the United States currently have Down syndrome; one in every 733 American babies is born with the condition.

The DSCRT encompasses several research labs located at the UCSD School of Medicine, plus an adult treatment center at the Perlman Medical Offices, adjacent to the UC San Diego Thornton Hospital in La Jolla. A Down Syndrome Center for pediatric treatment, sponsored by DS Action, a San Diego advocacy group, is based at Rady Children’s Hospital.

“We welcome this opportunity to deliver comprehensive care and translate the latest research discoveries to the clinical realm,” said Michael Rafii, M.D., Ph.D., assistant professor of neurosciences who treats adult Down syndrome patients and serves as DSCRT’s clinical director.

DSCRT scientists and doctors will collaborate with the Down Syndrome Consortium, a new group of leaders from local research, medical and advocacy communities who will assess needs and develop a model for expanding treatment options, said William Mobley, M.D., Ph.D., chair of the UCSD Department of Neurosciences and DSCRT executive director.

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In a study of egg cells using time-lapse microscopy, researchers at the UC San Diego School of Medicine and the Ludwig Institute for Cancer Research have discovered an unusual property of meiosis – cell division that produces reproductive cells in sexually reproducing organisms.  The discovery of an “inside out” mechanism by which egg cell chromosomes separate from each other may shed light on mistakes made in chromosome distribution that can lead to Down syndrome, high miscarriage rates in humans and the age-related decrease in fertility in human females.  Their findings are reported in the September issue of Nature Cell Biology.

Sexual reproduction relies on the merger of chromosomes present in the sperm and egg at fertilization.  Formation of sperm and egg cells requires the process of meiosis, which halves the chromosome number of each parent, so that the sperm-egg merger regenerates a cell with two copies of each chromosome.  The reduction of chromosome number in meiosis is accomplished through two divisions without an intervening duplication of the genome.

Both meiotic and mitotic divisions require specialized protein polymers called microtubules.  These polymers are organized into a football-shaped spindle with the polymer ends embedded in a special organelle – called the centrosome – at each end of the football.  Egg cells, however, are unusual in that they lack centrosomes, and instead use a spindle that is self-organized from microtubules.  Egg cells, especially in humans, are prone to mistakes in dividing the chromosomes during meiosis; mistakes which result in reproductive problems in humans such as Down syndrome, infertility and miscarriages.

Researchers led by Arshad Desai, PhD, professor of cellular and molecular medicine and investigator with the Ludwig Institute at UC San Diego, used the roundworm C. elegans, as a model to study egg cell division.  Julien Dumont, a postdoctoral fellow in the Desai lab, developed time lapse microscopy methods to observe egg cell meiosis with high precision.

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For Dr. Ira T. Lott, Alzheimer’s disease in people with Down syndrome represents a compelling detective story, the ending of which has yet to be written.

As they age, individuals born with this genetic disorder accumulate brain plaque proteins called beta-amyloids, which are hallmarks of Alzheimer’s. Generally, by the time they’re 40, the disease has taken hold.

“But what’s unknown is why some people with Down syndrome show the behavioral symptoms of Alzheimer’s — cognitive decline and dementia — and others don’t, even though they all have the pathology of the disease,” says Lott, UC Irvine pediatrics and neurology professor.

One of only two researchers in the U.S. to receive the latest round of federal support to investigate this mystery, he’s trying to determine why — and when — cognitive impairment begins.

“Down syndrome provides an important model for Alzheimer’s disease,” he says.

Lott and his colleagues in a UCI project are enrolling 60 individuals with Down syndrome over the age of 40 who exhibit no signs of mental decline. They’ll be screened for dementia, undergo PET scans and EEG exams, and supply blood and tissue samples.

Participants will then be psychologically tested at regular intervals. In those showing deterioration of cognitive abilities, researchers will look for biomarkers that reflect these neurological changes. The idea is to establish a predictive blueprint for mental decline independent of behavioral symptoms.

“Early identification is key for intervention,” says Lott, who sees pediatric patients at UCI and CHOC Children’s hospital in Orange. “Since amyloid deposition is a lifelong process in Down syndrome, what we learn here may ultimately lead to treatments for children to lessen the cognitive deterioration as they age.”

In addition, these biomarkers could facilitate early diagnosis of age-related Alzheimer’s in all people, allowing for therapies to delay the disease’s onset.

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A study by neuroscientist William C. Mobley, MD, PhD, chair of the Department of Neurosciences at the University of California, San Diego School of Medicine, and colleagues at Stanford University Medical School has demonstrated a possible new approach to slowing the inevitable progression of cognitive decline found in Down syndrome.

The study, published in Science Translational Medicine on November 18, revealed two important new findings about Down syndrome in a mouse model:  1) there is evidence that synaptic terminals involved in neurotransmission are damaged long before the cells show degeneration; and 2) while cell signaling is damaged, the receptors are not, but are functioning and still trying to find signals.

“If we focus only on damage to cell bodies, we underestimate the importance of timing and the potential window for treatment of Down syndrome,” said Mobley, one of the nation’s leading experts in the disorder.  He added that this study in mice shows some of the early changes to neurons, which are “really quite dramatic,” and may point the way to novel ways to treat Down syndrome in adult patients.

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