TAG: "Genetics"

Melanoma of the eye caused by two gene mutations


Therapeutic target identified for treatment.

Researchers at the UC San Diego School of Medicine have identified a therapeutic target for treating the most common form of eye cancer in adults. They have also, in experiments with mice, been able to slow eye tumor growth with an existing FDA-approved drug.

The findings are published online in today’s (May 29) issue of the journal Cancer Cell.

“The beauty of our study is its simplicity,” said Kun-Liang Guan, Ph.D., professor of pharmacology at UC San Diego Moores Cancer Center and co-author of the study. “The genetics of this cancer are very simple and our results have clear implications for therapeutic treatments for the disease.”

The researchers looked specifically at uveal melanoma. Uveal collectively refers to parts of the eye, notably the iris, that contain pigment cells. As with melanoma skin cancer, uveal melanoma is a malignancy of these melanin-producing cells.

Approximately 2,000 people in the United States are diagnosed with uveal melanoma each year. If the cancer is restricted to just the eye, the standard treatment is radiation and surgical removal of the eye. But uveal melanoma often spreads to the liver, and determining the metastatic status of the disease can be difficult. In cases of uveal melanoma metastasis, patients typically succumb within two to eight months after diagnosis.

Scientists have long suspected a genetic association with uveal melanoma because one of two gene mutations is present in approximately 70 percent of all tumors. Until this study, however, they had not identified a mechanism that could explain why and how these mutations actually caused tumors.

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Better cognition seen with gene variant carried by 1 in 5 people


Finding could have implications for treating age-related diseases like Alzheimer’s.

A scientific team led by the Gladstone Institutes and UC San Francisco has discovered that a common form of a gene already associated with long life also improves learning and memory, a finding that could have implications for treating age-related diseases like Alzheimer’s.

The researchers found that people who carry a single copy of the KL-VS variant of the KLOTHO gene perform better on a wide variety of cognitive tests. When the researchers modeled the effects in mice, they found it strengthened the connections between neurons that make learning possible – what is known as synaptic plasticity – by increasing the action of a cell receptor critical to forming memories.

The discovery is a major step toward understanding how genes improve cognitive ability and could open a new route to treating diseases like Alzheimer’s. Researchers have long suspected that some people may be protected from the disease because of their greater cognitive capacity, or reserve. Since elevated levels of the klotho protein appear to improve cognition throughout the lifespan, raising klotho levels could build cognitive reserve as a bulwark against the disease.

“As the world’s population ages, cognitive frailty is our biggest biomedical challenge,” said Dena Dubal, M.D., Ph.D., assistant professor of neurology, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at UCSF and lead author of the study, published today in Cell Reports. “If we can understand how to enhance brain function, it would have a huge impact on people’s lives.”

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Detecting fetal chromosomal defects without risk


Noninvasive sequencing is faster, cheaper and safer for mother and fetus, say researchers.

Human karyotype

Chromosomal abnormalities that result in birth defects and genetic disorders like Down syndrome remain a significant health burden in the United States and throughout the world, with some current prenatal screening procedures invasive and a potential risk to mother and unborn child.

In a paper published online this week in the Early Edition of PNAS, a team of scientists at the UC San Diego School of Medicine and in China describe a new benchtop semiconductor sequencing procedure and newly developed bioinformatics software tools that are fast, accurate, portable, less expensive and can be completed without harm to mother or fetus.

“We believe this approach could become the standard of care for screening of prenatal chromosomal abnormalities,” said Kang Zhang, M.D., Ph.D., professor of ophthalmology, founding director of the Institute for Genomic Medicine at UC San Diego and a staff physician at the San Diego VA Healthcare System.

The incidence of chromosomal abnormalities – in numbers or structure – is one in 160 live births in the United States, higher in other countries. In China, for example, the rate is one in 60 live births. The effects of these abnormalities, known as aneuploidies, can be severe, from developmental delays and neurological disorders to infertility and death. The incidence rate rises with maternal age, most notably after age 35.

Current diagnoses of fetal aneuploidies often rely upon invasive tests that sample amniotic fluid or placental tissues for fetal DNA that can then be analyzed using a variety of complex and expensive methods, including full karyotyping in which the entire set of chromosomes is viewed microscopically. While highly reliable, these invasive tests may cause infections in the pregnant woman and pose as much as a 1 percent risk of miscarriage and fetal loss. Results are not available for one to two weeks, extending anxiety for families waiting for information.

The new method relies upon massively parallel sequencing of cell-free fetal DNA using a benchtop semiconductor sequencing platform (SSP) called an Ion Torrent sequencer developed by Life Technologies. Cell-free fetal DNA is genetic material from the fetus that circulates naturally and freely in the mother’s bloodstream. It can be obtained through an ordinary blood draw, with SSP analysis achieved in less than four days.

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Progressive neurodegenerative disorder linked to R-loop formation


UC Davis findings suggest R-loops may be potential targets for drug development.

Paul Hagerman, UC Davis

Researchers at UC Davis have identified a new feature of the genetic mutation responsible for the progressive neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS) — the formation of “R-loops,” which they believe may be associated with the disorder’s neurological symptoms, such as tremors, lack of balance, features of Parkinsonism and cognitive decline.

The finding suggests that the R-loops may be potential targets for drug development, said Paul Hagerman, senior study author, professor in the Department of Biochemistry and Molecular Medicine and director of the UC Davis NeuroTherapeutics Research Institute. The study, “Transcription-associated R-loop Formation across the Human FMR1 CGG-repeat Region,” is published today in the online journal PLoS Genetics.

An R-loop is formed when the messenger RNA being made at the gene reinserts itself into the DNA helix, displacing one strand of DNA, which creates the “loop.” Such loops are known to be prone to damage, which can in turn lead to loss of cell function, particularly in neurons.

Hagerman and his collaborators discovered the R-loops while investigating mutations in the gene that causes FXTAS and other conditions associated with the fragile X mental retardation gene 1 (FMR1). R-loops are not unique to FXTAS and can occur in the promoter regions of many genes.

“But in FXTAS, the R-loops are more numerous and much longer than they are in FMR1 genes that are not mutated,” said Hagerman, a researcher who also is affiliated with the UC Davis MIND Institute.

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Cleft palate discovery in dogs to aid in understanding human birth defect


UC Davis study also shows that dogs have multiple genetic causes of cleft palate.

This puppy is a Nova Scotia Duck Tolling Retriever, the breed with the newly discovered genetic mutation for cleft palate.

UC Davis School of Veterinary Medicine researchers have identified the genetic mutation responsible for a form of cleft palate in the dog breed Nova Scotia Duck Tolling Retrievers.

They hope that the discovery, which provides the first dog model for the craniofacial defect, will lead to a better understanding of cleft palate in humans. Although cleft palate is one of the most common birth defects in children, affecting approximately one in 1,500 live human births in the United States, it is not completely understood.

The findings appear this week online in the journal PLOS Genetics and are available online at https://tinyurl.com/knr8wb3.

“This discovery provides novel insight into the genetic cause of a form of cleft palate through the use of a less conventional animal model,” said professor Danika Bannasch, a veterinary geneticist who led the study. “It also demonstrates that dogs have multiple genetic causes of cleft palate that we anticipate will aid in the identification of additional candidate genes relevant to human cleft palate.”

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Tweaking potassium levels in brain could be a key to fighting Huntington’s


UCLA findings could point to new drug targets for treating the devastating disease.

Astrocytes in brain tissue

By boosting the ability of a specific type of cell to absorb potassium in the brain, UCLA researchers were able to improve walking and prolong survival in a mouse model of Huntington’s disease.

Their findings, published March 30 in the online edition of the journal Nature Neuroscience, could point to new drug targets for treating the devastating disease, which strikes one in every 20,000 Americans.

Huntington’s disease is passed from parent to child through a mutation in the huntingtin gene. By killing brain cells called neurons, the disorder gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. No cure exists, and patients with aggressive cases can die in as little as 10 years.

The laboratories of Baljit Khakh, a UCLA professor of physiology and neurobiology, and Michael Sofroniew, a UCLA professor of neurobiology, teamed up at the David Geffen School of Medicine at UCLA to unravel the role that astrocytes — large, star-shaped cells found in the brain and spinal cord — play in Huntington’s.

“Astrocytes appear in the brain in equal numbers to neurons yet haven’t been closely studied,” Khakh said. “They enable neurons to signal each other by maintaining an optimal chemical environment outside the cells. We used two mouse models to explore whether astrocytes behave differently during Huntington’s disease.”

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Kaiser, UCSF add genetic, health information to NIH online database


Information is largest-ever genetic resource for researchers.

Catherine Schaefer

Researchers worldwide will now have access to genetic data linked to medical information on a diverse group of more than 78,000 people, enabling investigations into many diseases and conditions. The data have just been made available to qualified researchers through the database of Genotypes and Phenotypes (dbGaP), the online database of the National Institutes of Health (NIH). The announcement was made today (Feb. 26) at the National Advisory Council on Aging by Richard Hodes, director of the National Institute on Aging (NIA).

The data come from one of the nation’s largest and most diverse genomics projects — the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort — which was developed collaboratively by the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) and UC San Francisco. The addition of the data to dbGaP was made possible with $24.9 million in support from the NIA and the National Institute of Mental Health at NIH, as well as from the Office of the NIH Director.

“Data from this immense and ethnically diverse population will be a tremendous resource for science,” said NIH Director Francis Collins. “It offers the opportunity to identify potential genetic risks and influences on a broad range of health conditions, particularly those related to aging.”

Neil Risch

The GERA cohort is part of the RPGEH, which includes more than 430,000 adult members of the Kaiser Permanente Northern California health plan who volunteered to participate in the research program. Data on this larger cohort include electronic medical records, behavioral and demographic information from surveys, and saliva or blood samples from 200,000 participants obtained with informed consent for genomic and other analyses.

This work was made possible with the investment of an $8.6 million grant from the Robert Wood Johnson Foundation, which saw the potential to build a resource that would transform genomic research. “This massive influx of new, high quality data will help scientists discover bigger breakthroughs faster,” said Nancy Barrand, the foundation’s senior adviser for Program Development. “Researchers used to have to go through the painstaking process of collecting and studying genomic samples on their own. Now researchers worldwide can find valuable clues for improving health by studying the genetic information from a cohort of 78,000 diverse individuals in dbGaP.”

Additional support for development of the RPGEH resource was provided by the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente.

The genetic information on more than 78,000 individuals translates into over 55 billion bits of genetic data for the cohort. The researchers conducted genome-wide genotyping using the newly developed Affymetrix Axiom Gene Titan system employed in the UCSF Institute for Human Genetics Genomics Core Facility to rapidly scan selected markers of genetic variation called single nucleotide polymorphisms (SNPs) in the genomes of the people in the GERA cohort. The RPGEH then combined the genetic data with information derived from Kaiser Permanente’s comprehensive longitudinal electronic medical records, as well as extensive survey data on participants’ health habits and backgrounds, providing researchers with an unparalleled research resource. These data form the basis of genome-wide association studies (GWAS) that can look at hundreds of thousands to millions of SNPs at the same time in relation to many different health conditions.

“The transfer of this data will greatly accelerate research on genetic influences on health, disease and aging,” said Catherine Schaefer, Ph.D., executive director of the Research Program on Genes, Environment and Health and co-principal investigator for GERA. “Making these data on such a large diverse cohort broadly available will enable many more scientists to work at a much greater scale that is likely to help answer important questions concerning health.”

“It’s all about time and money,” added Neil Risch, Ph.D., director of the UCSF Institute for Human Genetics and co-principal investigator for GERA. “Collecting large amounts of health data from people — and processing it — is labor intensive and expensive. With this data set, no one has to collect clinical information, take bio samples, safeguard and store them, or conduct genome-wide genotyping of their DNA. They can simply sit at a computer, ask questions of the data, and extract information.”

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Personalized medicine a cost-effective way to tailor drug therapy after stents


Knowing patients’ genetic profiles can save money, improve outcomes.

Dhruv Kazi, UC San Francisco

Genetic testing can help doctors choose the most effective and economical drugs to prevent blood clots in the half a million patients in the U.S. who receive coronary stents each year, according to a new study led by a UC San Francisco researcher.

The work, reported in the Feb. 18 Annals of Internal Medicine, demonstrates that genetically guided personalized medicine, often perceived as pricier than traditional approaches, can both lower costs and increase the quality of health care.

“Our results counter the general perception that personalized medicine is expensive,” said Dhruv Kazi, M.D., M.Sc., M.S., assistant professor of medicine at UCSF and first author of the new study. “What we have shown is that individualizing care based on genotype may in fact be very cost-effective in some settings, because it allows us to target the use of newer, more expensive drugs to the patients who are most likely to benefit from them.”

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Genetic cue found for sudden cardiac death syndrome


UC Irvine discovery could lead to improved early detection and prevention strategies.

Geoffrey Abbott, UC Irvine

UC Irvine researchers have found a specific genetic flaw that is connected to sudden death due to heart arrhythmia – a leading cause of mortality for adults around the world.

While a number of genes have been linked with arrhythmias, UC Irvine’s Geoffrey Abbott and his colleagues discovered that the functional impairment of a gene called KCNE2 underlies a multisystem syndrome that affects both heart rhythm and blood flow and can activate chemical triggers that can cause sudden cardiac death.

“With these findings, we can now explore improved early detection and prevention strategies for people who are at higher risk of sudden cardiac death, such as those with diabetes,” said Abbott, a professor of pharmacology and physiology & biophysics in the UC Irvine School of Medicine.

Study results appear in the February issue of Circulation: Cardiovascular Genetics, a publication of the American Heart Association.

Distinct from a heart attack, in which the heart continues to beat but blood flow is blocked, sudden cardiac death occurs when the heart ceases to beat because of the uncontrolled twitching of muscle fibers in its ventricles. Without defibrillation within minutes, this type of event is fatal.

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Understanding the basic biology of bipolar disorder


Scientists from UCLA, UCSF take steps to ID genetic component to mental illness.

Brain regions

Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.

Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behavior measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioral measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.

The results are published in today’s (Feb. 12) edition of the Journal JAMA Psychiatry.

A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.

“The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder,” Bearden said. “This is an innovative approach to identifying genetically influenced brain and behavioral measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are.”

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Global regulator of mRNA editing found


Protein controls editing, expanding the information content of DNA.

Model organism Caenorhabditis elegans

An international team of researchers, led by scientists from the UC San Diego School of Medicine and Indiana University, have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad of proteins necessary for life.

The findings, published today (Feb. 6) in the journal Cell Reports, help explain how a relatively limited number of genes can provide versatile instructions for making thousands of different messenger RNAs and proteins used by cells in species ranging from sea anemones to humans. In clinical terms, the research might also help researchers parse the underlying genetic mechanisms of diverse diseases, perhaps revealing new therapeutic targets.

“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer and blood disorders,” said Gene Yeo, Ph.D., assistant professor in the Department of Cellular and Molecular Medicine at UC San Diego. “This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides a method to screen for them and opens up new ways to study human biology and disease.”

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Researchers ID more pesticides linked to Parkinson’s


They also find gene that increases risk.

Pesticides and Parkinson'sStudies have shown that certain pesticides can increase people’s risk of developing Parkinson’s disease. Now, UCLA researchers have found that the strength of that risk depends on an individual’s genetic makeup, which, in the most pesticide-exposed populations, could increase a person’s chance of developing the debilitating disease two- to six-fold.

In an earlier study, published January 2013 in Proceedings of the National Academy of Sciences, the UCLA team discovered a link between Parkinson’s and the pesticide benomyl, a fungicide that has been banned by the U.S. Environmental Protection Agency. That study found that benomyl prevents the enzyme aldehyde dehydrogenase (ALDH) from converting aldehydes — organic compounds that are highly toxic to dopamine cells in the brain — into less toxic agents, thereby contributing to the risk of Parkinson’s.

For the current study, UCLA researchers tested a number of additional pesticides and found 11 that also inhibit ALDH and increase the risk of Parkinson’s — and at levels much lower than they are currently being used, said the study’s lead author, Jeff Bronstein, a professor of neurology and director of the movement disorders program at UCLA.

Bronstein said the team also found that people with a common genetic variant of the ALDH2 gene are particularly sensitive to the effects of ALDH-inhibiting pesticides and are two to six times more likely to develop Parkinson’s when exposed to these pesticides than those without the variant.

The results of the new epidemiological study appear Feb. 5 in the online issue of Neurology, the medical journal of the American Academy of Neurology.

“We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations — concentrations that were way below what was needed for the pesticides to do their job,” Bronstein said. “These pesticides are pretty ubiquitous and can be found on our food supply. They are used in parks and golf courses and in pest control inside buildings and homes. So this significantly broadens the number of people at risk.”

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