A coronary aneurysm is an abnormal ballooning of a portion of the coronary artery and a potential consequence of Kawasaki disease. If untreated, it may result in irreversible heart damage and death. This angiography of an 18-year-old patient reveals a massive aneurysm in the right coronary artery compared to the normal left. Image courtesy of Tomio Kobayashi, Gunma University School of Medicine, Japan.
Study Evaluates Role of Infliximab in Treating Kawasaki Disease
Antibody treatment helps children with dangerous heart disorder
Kawasaki Disease (KD) is a severe childhood disease that many parents, even some doctors, mistake for an inconsequential viral infection. If not diagnosed or treated in time, it can lead to irreversible heart damage.
Signs of KD include prolonged fever associated with rash, red eyes, mouth, lips and tongue, and swollen hands and feet with peeling skin. The disease causes damage to the coronary arteries in a quarter of untreated children and may lead to serious heart problems in early adulthood. There is no diagnostic test for Kawasaki disease, and current treatment fails to prevent coronary artery damage in at least one in 10 to 20 children and death in one in 1,000 children.
Between 10 and 20 percent of patients with KD experience fever relapse following the standard therapy with a single infusion of intravenous immunoglobulin (IVIG) and aspirin. It is known that IVIG resistance increases the risk of heart damage, most commonly a ballooning of the coronary arteries called aneurysms. These children require additional therapy to interrupt the inflammatory process that can lead to damage of the coronary arteries.
A study led by physicians at the University of California, San Diego School of Medicine and Rady Children’s Hospital-San Diego looked at intensification of initial therapy for all children with KD in order to prevent IVIG-resistance and associated coronary artery abnormalities by assessing the addition of the medication infliximab to current standard therapy. The results of their study will be published in the February 24, 2014 online issue of the medical journal Lancet.
Model organism Caenorhabditis elegans.
Global Regulator of mRNA Editing Found
Protein controls editing, expanding the information content of DNA
An international team of researchers, led by scientists from the University of California, 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 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, PhD, 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.”
“To be properly expressed, all genes must be carefully converted from DNA to messenger RNA, which can then be translated into working proteins,” said Heather Hundley, PhD, assistant professor of biochemistry and molecular biology at Indiana University and co-senior author of the study. RNA editing alters nucleotides (the building blocks of DNA and RNA) within the mRNA to allow a single gene to create multiple mRNAs that are subject to different modes of regulation. How exactly this process can be modulated, however, has never been clear.
Using the nematode Caenorhabditis elegans as their model organism and a novel computational framework, Hundley, Yeo and colleagues identified more than 400 new mRNA editing sites – the majority regulated by a single protein called ADR-1, which does not directly edit mRNA but rather regulated how editing occurred by binding to the messenger RNAs subject to editing.
“Cells process their genetic code in a way analogous to how the programming language Java compiles modern software. Both systems use an intermediate representation that is modified depending on its environment” said co-first author Boyko Kakaradov, a bioinformatics PhD student in the Yeo lab. “We’re now finding how and why the mRNA code is being changed en route to the place of execution.”
The scientists noted that a protein similar to ADR-1 is expressed by humans, and that many of the same mRNA targets exist in people too. “So it is likely that a similar mechanism exists to regulate editing in humans,” said Hundley, adding that she and colleagues will now turn to teasing out the specifics of how proteins like ADR-1 regulate editing and how they might be exploited “to modulate editing for the treatment of human diseases.”
CLL cells, Wellcome Images.
The Mouse That ROR’ed
ROR1 oncogene combines with another to accelerate, worsen blood cancer
Researchers at the University of California, San Diego School of Medicine report that an oncogene dubbed ROR1, found on chronic lymphocytic leukemia (CLL) B cells but not normal adult tissues, acts as an accelerant when combined with another oncogene, resulting in a faster-developing, more aggressive form of CLL in mice.
The findings, published in the Dec. 30, 2013 Online Early Edition of PNAS, suggest ROR1 could be an important therapeutic target for patients with CLL, the most common form of blood cancer. Prevalence of CLL in the United States is high: 1 in 20 people over the age of 40 could have apparently pre-cancerous CLL-like cells in their blood. These people may develop actual CLL at a rate of about 1 percent per year. More than 15,000 new cases of CLL are diagnosed each year in the United States. Roughly 4,400 patients with CLL die annually.
The work by principal investigator Thomas Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues continues a series of discoveries about ROR1. Previously, for example, they found an association between ROR1 and the epithelial-mesenchymal transition – the process that occurs during embryogenesis when cells migrate and then grow into new organs during early development. CLL cells exploit ROR1 to spread disease. Called metastasis, it is responsible for 90 percent of cancer-related deaths.
In the PNAS paper, Kipps and colleagues created transgenic mice that expressed human ROR1, then observed that these mice produced B cells (a kind of white blood cell) that were abnormal and resembled human CLL cells while non-transgenic littermates did not.
Next they crossed the ROR1 mice with another transgenic mouse-type that produces an oncogene called TCL1. Oncogenes are genes that can lead to cancer development if over-expressed or mutated. The progeny of these cross-bred mice possessed both oncogenes – ROR1 and TCL1 – and consequently displayed an even greater proclivity toward developing aggressive, fast-acting CLL.
When researchers treated the mice with an anti-ROR1 monoclonal antibody that reduces levels of ROR1, the CLL cells were impaired and more vulnerable to treatment and destruction. Based on these findings, Kipps said investigators at UC San Diego Moores Cancer Center are planning clinical trials in 2014 using a humanized monoclonal antibody that has the same type of activity against human leukemia or cancer cells that express ROR1.
How Cells Remodel After UV Radiation
Researchers map cell’s complex genetic interactions to fix damaged DNA
Researchers at the University of California, San Diego School of Medicine, with colleagues in The Netherlands and United Kingdom, have produced the first map detailing the network of genetic interactions underlying the cellular response to ultraviolet (UV) radiation.
The researchers say their study establishes a new method and resource for exploring in greater detail how cells are damaged by UV radiation and how they repair themselves. UV damage is one route to malignancy, especially in skin cancer, and understanding the underlying repair pathways will better help scientists to understand what goes wrong in such cancers.
The findings will be published in the December 26, 2013 issue of Cell Reports.
Principal investigator Trey Ideker, PhD, division chief of genetics in the UC San Diego School of Medicine and a professor in the UC San Diego Departments of Medicine and Bioengineering, and colleagues mapped 89 UV-induced functional interactions among 62 protein complexes. The interactions were culled from a larger measurement of more than 45,000 double mutants, the deletion of two separate genes, before and after different doses of UV radiation.
Specifically, they identified interactive links to the cell’s chromatin structure remodeling (RSC) complex, a grouping of protein subunits that remodel chromatin – the combination of DNA and proteins that make up a cell’s nucleus – during cell mitosis or division. “We show that RSC is recruited to places on genes or DNA sequences where UV damage has occurred and that it helps facilitate efficient repair by promoting nucleosome remodeling,” said Ideker.
The process of repairing DNA damage caused by UV radiation and other sources, such as chemicals and other mutagens, is both simple and complicated. DNA-distorting lesions are detected by a cellular mechanism called the nucleotide excision repair (NER) pathway. The lesion is excised; the gap filled with new genetic material copied from an intact DNA strand by special enzymes; and the remaining nick sealed by another specialized enzyme.
However, NER does not work in isolation; rather it coordinates with other biological mechanisms, including RSC.
“DNA isn’t free-floating in the cell, but is packaged into a tight structure called chromatin, which is DNA wound around proteins,” said Rohith Srivas, PhD, a former research scientist in Ideker’s lab and the study’s first author. “In order for repair factors to fix DNA damage, they need access to naked DNA. This is where chromatin remodelers come in: In theory, they can be recruited to the DNA, open it up and allow repair factors to do their job.”
Rohith said that other scientists have previously identified complexes that perform this role following UV damage. “Our results are novel because they show RSC is connected to both UV damage pathways: transcription coupled repair – which acts on parts of DNA being expressed – and global genome repair, which acts everywhere. All previous remodelers were linked only to global genome repair.”
The scientists noted that the degree of genetic rewiring correlates with the dose of UV. Reparative interactions were observed at distinct low or high doses of UV, but not both. While genetic interactions at higher doses is not surprising, the authors said, the findings suggest low-dose UV radiation prompts specific interactions as well.
Confocal image of an Alzheimer’s brain showing region of amyloid plaque. Courtesy of Wellcome Images.
Understanding a Protein’s Role in Familial Alzheimer’s Disease
Novel genomic approach reveals gene mutation isn’t simple answer
Researchers at the University of California, San Diego School of Medicine have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer’s disease (AD), discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder.
The findings, published online in the journal Cell Reports, could help elucidate the still-mysterious mechanisms of Alzheimer’s disease and better inform development of effective drugs, said principal investigator Lawrence Goldstein, PhD, professor in the Departments of Cellular and Molecular Medicine and Neurosciences and director of the UC San Diego Stem Cell Program.
“In some ways, this is a powerful technical demonstration of the promise of stem cells and genomics research in better understanding and ultimately treating AD,” said Goldstein, who is also director of the new Sanford Stem Cell Clinical Center at UC San Diego. “We were able to identify and assign precise limits on how a mutation works in familial AD. That’s an important step in advancing the science, in finding drugs and treatments that can slow, maybe reverse, the disease’s devastating effects.”
Familial AD is a subset of early-onset Alzheimer’s disease that is caused by inherited gene mutations. Most cases of Alzheimer’s disease – there are an estimated 5.2 million Americans with AD – are sporadic and do not have a precise known cause, though age is a primary risk factor.
A study led by Robert N. Weinreb, chairman and Distinguished Professor of Ophthalmology at the University of California, San Diego School of Medicine, has received a $6.4 million, 5-year grant from the National Eye Institute, part of the National Institutes of Health, to elucidate the genetics of glaucoma in persons of African descent.
Glaucoma is the leading cause of blindness in African-Americans. It is four to five times more likely to occur in persons of African descent, and up to 15 times more likely to cause meaningful visual impairment in this group compared to those of European descent.
The overall goal of the study, “ADAGES III: contribution of genotype to glaucoma phenotype in African-Americans,” is to identify glaucoma genes in this high-risk, minority population, particularly persons who have rapidly worsening vision. Weinreb has teamed with Jerry Rotter, MD, Distinguished Professor of Pediatrics, Medicine and Human Genetics at Harbor-UCLA Medical Center, a renowned genetics expert, to identify relevant genes, develop predictive models for glaucoma diagnosis and progression and discover new drug targets for therapies to reduce the visual impact of glaucoma blindness.
Glaucoma results in vision loss due to damage to the optic nerve, which is irreversible if undetected or untreated. The most common form of glaucoma is called primary open angle glaucoma (POAG). The number of persons with diagnosed POAG in the United States is expected to be more 3.3 million by 2020, with millions more undiagnosed. While glaucoma affects all races, persons of African descent are disproportionately affected.
“The lack of understanding about the cause of this disease impedes our ability to identify and treat it early in its development,” said Weinreb, who is also director of the Shiley Eye Center, part of the UC San Diego Health System. “Evidence of genetic contribution in the pathogenesis of POAG is well established. Since POAG tends to run in families, it is critical to identify the genetic basis of the disease in order to develop effective therapies for early intervention.”
“A better understanding of the relationship among the stage of disease, the rate of change, ancestry, and other important risk factors being tracked in the ongoing African Descent and Glaucoma Study (ADAGES) will allow us to evaluate the relationship between genetics, visual loss and structural damage in this high-risk group,” added Linda Zangwill, PhD, a professor of ophthalmology at UC San Diego and study co-investigator.
The study will obtain detailed phenotypes – a composite of all observed characteristics or traits of an individual – of more than 2,000 subjects, establish a repository and implement a data-coordinating center at UC San Diego, as well conduct comprehensive genetic studies.
The recruitment, enrollment and phenotyping of both established and new subjects will occur at four clinical centers: UC San Diego School of Medicine; New York Eye and Ear Infirmary; University of Alabama at Birmingham; and a private practice in the Atlanta, Ga. area.
Illustration courtesy of Bani Chaudhary, Saltman Quarterly
Many causative factors have linked to the eating disorder anorexia nervosa – culture, stress, puberty, social networks, among them – but the largest influence may be genetic.
In a new paper published in the journal Molecular Psychiatry, an international team of scientists, including researchers at The Scripps Research Institute and UC San Diego School of Medicine, report that a variant of the EPHX2 gene that codes for an enzyme involved in regulating cholesterol metabolism occurs more frequently in people with anorexia.
“When we saw that, we thought that we might be onto something, because nobody else had reported this gene as having a pronounced role in anorexia,” said principal investigator Nicholas J. Schork, PhD, a professor at TSRI and professor of psychiatry at UC San Diego.
The study was the largest effort yet to probe the genetic underpinnings of anorexia, studying the DNA sequences of more than 1,200 patients and almost 2,000 non-anorexic controls.
Cholesterol is a waxy, fat-like substance that is essential to life. It’s a critical structural component of cellular membranes and a precursor molecule necessary to many biochemical processes. The human body makes it, but also derives additional amounts from diet – excessively so when it comes to most modern, high-fat Western diets.
A number of serious health conditions and diseases are associated with abnormal or dysfunctional regulation of cholesterol, most notably heart disease and obesity. Researchers say it’s not clear yet how abnormal cholesterol metabolism caused by EPHX2 variants is linked to anorexia, but they note people with anorexia often exhibit unhealthily high blood cholesterol levels, even when severely malnourished.
Anorexia is primarily an affliction of women. The gender ratio is almost 10:1, with girls and young women particularly affected. Anorexics severely restrict eating and become emaciated, yet view themselves as fat and overweight. Study co-author Walter Kaye, MD, director of the UC San Diego Eating Disorders Center for Treatment and Research, said people with anorexia tend to be anxious, depressed and obsessive.
The consequences can be deadly. The mortality rate for anorexia is estimated to be more than 10 percent, making it perhaps the deadliest of psychiatric illnesses.
Read the full TSRI news release here.