TAG: "Genetics"

Statins reverse learning disabilities caused by Noonan syndrome


UCLA mouse study shows drugs overcome mutation, even in adult brain.

Alcino Silva, UCLA

UCLA scientists have discovered that statins, a popular class of cholesterol drugs, reverse the learning disabilities caused by a genetic disorder called Noonan syndrome.

Their findings were published online Nov. 10 by the journal Nature Neuroscience.

The disorder, which is caused by a genetic mutation, can disrupt a child’s development in many ways. It often causes unusual facial features, short stature, heart defects and developmental delays, including learning disabilities. No treatment is currently available.

“Noonan syndrome affects 1 in 2,000 people, and up to half of these patients struggle with learning disabilities,” said Alcino Silva, the study’s principal investigator and a professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. “Our approach identified the mechanism causing the disease, as well as a treatment that reversed its effects in adult mice. We are excited about these findings because they suggest that the treatment we developed may help the millions of Noonan patients with intellectual disabilities.”

While many genes contribute to Noonan syndrome, there is one gene that causes about half of all cases. This gene encodes for a protein that regulates another protein called Ras, which controls how brain cells talk to each other, enabling learning to take place.

Working with first author Young-Seok Lee, Silva studied mice that were genetically engineered to develop Noonan syndrome. They discovered that the predominant mutation that leads to Noonan creates hyperactive Ras, which disrupts cellular conversations and undermines the learning process.

“The act of learning creates physical changes in the brain, much like grooves on a record,” said Silva, who also is a member of the UCLA Brain Research Institute and UCLA Integrative Center for Learning and Memory. “Surplus Ras tips the balance between switching signals on and off in the brain. This interrupts the delicate cell communication needed by the brain to record learned information.”

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New genetic links in autism revealed


For answers, UC San Diego researchers turn to mice, stem cells and the ‘tooth fairy.’

Alysson Muotri, UC San Diego

With the help of mouse models, induced pluripotent stem cells (iPSCs) and the “tooth fairy,” researchers at the UC San Diego School of Medicine have implicated a new gene in idiopathic or non-syndromic autism. The gene is associated with Rett syndrome, a syndromic form of autism, suggesting that different types of autism spectrum disorder (ASD) may share similar molecular pathways.

The findings are published in today’s (Nov. 11) online issue of Molecular Psychiatry.

“I see this research as an example of what can be done for cases of non-syndromic autism, which lack a definitive group of identifying symptoms or characteristics,” said principal investigator Alysson Muotri, Ph.D., associate professor in the UC San Diego departments of pediatrics and cellular and molecular medicine. “One can take advantage of genomics to map all mutant genes in the patient and then use their own iPSCs to measure the impact of these mutations in relevant cell types. Moreover, the study of brain cells derived from these iPSCs can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental/neurological disorders.”

But to effectively exploit iPSCs as a diagnostic tool, Muotri said researchers “need to compare neurons derived from hundreds or thousands of other autistic individuals.” Enter the “Tooth Fairy Project,” in which parents are encouraged to register for a “Fairy Tooth Kit,” which involves sending researchers like Muotri a discarded baby tooth from their autistic child. Scientists extract dental pulp cells from the tooth and differentiate them into iPSC-derived neurons for study.

“There is an interesting story behind every single tooth that arrives in the lab,” said Muotri.

The latest findings, in fact, are the result of Muotri’s first tooth fairy donor. He and colleagues identified a de novo or new disruption in one of the two copies of the TRPC6 gene in iPSC-derived neurons of a non-syndromic autistic child. They confirmed with mouse models that mutations in TRPC6 resulted in altered neuronal development, morphology and function. They also noted that the damaging effects of reduced TRPC6 could be rectified with a treatment of hyperforin, a TRPC6-specific agonist that acts by stimulating the functional TRPC6 in neurons, suggesting a potential drug therapy for some ASD patients.

The researchers also found that MeCP2 levels affect TRPC6 expression. Mutations in the gene MeCP2, which encodes for a protein vital to the normal function of nerve cells, cause Rett syndrome, revealing common pathways among ASD.

“Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model,” Muotri said. “This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.”

For more information on the Tooth Fairy Project, visit http://muotri.ucsd.edu.

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Genetic damage caused by asthma also shows up in circulating blood stream


Study finds disease harms more than lungs, may be more dangerous than previously thought.

Robert Schiestl, UCLA

Asthma may be more harmful than was previously thought, according to UCLA researchers who found that genetic damage is present in circulating, or peripheral, blood. Doctors previously thought that the genetic damage it caused was limited to the lungs.

In the study, researchers looked for the overexpression of a cytokine called interleukin 13 (IL-13), which is known to mediate inflammation, a critical problem for people with asthma.

The study, which was conducted in an animal model that mimicked human asthma, was the first to assess the role of IL-13 in genetic damage to cells, or genotoxicity, said its senior author, Robert Schiestl, a professor of pathology and radiation oncology at the David Geffen School of Medicine at UCLA.

“Asthma is a very widespread disease, and we show for the first time an association between asthma and genotoxicity in peripheral blood,” said Schiestl, who also is a professor of environmental health sciences at the Fielding School of Public Health at UCLA. “This is important because it shows a whole-body effect from asthma, not just damage in the lungs.”

The findings were published today in the peer-reviewed journal Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis.

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Environmental carcinogens leave genetic imprints in tumors


Chemically induced tumors bear signatures that differentiate them from genetically engineered cancers.

Genetically engineering tumors in mice, a technique that has dominated cancer research for decades, may not replicate important features of cancers caused by exposure to environmental carcinogens, according to a new study led by UC San Francisco scientists. In addition to pointing the way to better understanding of environmental causes of cancer, the findings may help explain why many patients do not benefit from, or develop resistance to, targeted drug therapies.

In the new research, reported Nov. 2 in the advance online edition of Nature, a team led by UCSF graduate student Peter M.K. Westcott found that chemically induced lung tumors in mice carry hundreds of point mutations — deleterious alterations of single “letters” in the genome — that are not present in tumors induced by genetic engineering. The researchers demonstrated that chemically induced tumors display a starkly different “mutational landscape” even when chemicals cause a tumor-initiating mutation that is identical to that created by direct genetic manipulation.

“Since the 1980s, when genetic engineering came along, the mouse model community has been working on genetically engineered cancer—you put a gene in or take a gene out, and you get a tumor,” said Allan Balmain, Ph.D., the Barbara Bass Bakar Distinguished Professor in Cancer Genetics at UCSF and senior author of the study. “But it’s only now that we’re beginning to analyze what has happened between that first engineered change and the ultimate development of an aggressive tumor.”

The new work made use of next-generation sequencing (NGS) technology, which allows researchers to analyze the genomic sequence of tumors or of normal tissue letter-by-letter. For the Nature study, the group used a form of NGS known as whole-exome sequencing, which comprehensively analyzes the portion of the genome that contains the code for producing proteins.

The findings dovetail well with those from NGS-based studies of human tumors, such as The Cancer Genome Atlas (TCGA) initiative spearheaded by the National Cancer Institute and National Human Genome Research Institute, which have revealed mutational “signatures,” some of which can be definitively tied to environmental exposures. For example, distinctive patterns of point mutations are now known to differentiate lung cancer in smokers from that affecting non-smokers.

The results are also consistent with observations that tumors arising in human organs that are most directly exposed to environmental carcinogens — the skin, gastrointestinal system and lungs — are more prone to point mutations than more “protected” organs such as the brain, breast and prostate gland.

“We humans smoke cigarettes, drink alcohol and spend too much time in the sun, all of which cause us to accumulate point mutations that are major determinants of the behavior of tumors, especially of how a tumor responds to therapy,” said Balmain, co-leader of the Cancer Genetics Program at UCSF’s Helen Diller Family Comprehensive Cancer Center. “All this heterogeneity is being missed with genetically engineered tumors, because they don’t reflect these environmental effects.”

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Nobel laureates to gather at symposium honoring Frederick Sanger


His genetics research left a legacy written in A-T-G-C.

Frederick Sanger

After a visit to UC San Diego in the early 1980s to give a lecture, the famed British biochemist Frederick Sanger was rewarded with a homemade T-shirt emblazoned with the letters DNA in sequins. It was the sort of joke only a person who studied genetics might immediately appreciate: DNA sequence, get it?

Sanger, of course, got the joke and reportedly wore the shirt often, telling friends he thoroughly enjoyed his visit to San Diego.

Alas, it was a one-time visit. Sanger never returned to UC San Diego, but his impact upon the university — indeed upon the science of genetics and its rippling, massive impact on society and life — have not been forgotten.

On Nov. 5, a daylong symposium in honor of Sanger will be held in the auditorium of the Medical Education/Telemedicine building on the School of Medicine campus. Sanger is best known for winning the Nobel Prize for chemistry twice, one of only two laureates to win in the same category. (The other was John Bardeen in physics.) He is only the fourth person to garner two Nobel Prizes (joining Bardeen, Marie Curie and Linus Pauling) and just the third to win two Prizes in the sciences (with Bardeen and Curie). [See list of UC Nobel laureates.]

The list of symposium speakers reflects Sanger’s celebrated status. Three fellow Nobel laureates – David Baltimore (1975, physiology or medicine); Hamilton Smith (1978, physiology or medicine) and Roger Kornberg (2006, chemistry) will be in attendance, along with Stanley Norman Cohen, who is credited with co-inventing DNA cloning and recombinant DNA technologies.

There will be speakers from the Swedish Royal Academy, which awards the Nobel Prize; the University of Cambridge where Sanger worked and taught; and closer to home, the Salk Institute for Biological Studies and the J. Craig Venter Institute.

The UC San Diego symposium is one of just a handful of events worldwide celebrating Sanger’s life (he died Nov. 19, 2013, at the age of 95) and his scientific legacy, which has profoundly affected UC San Diego’s rise as a leading research university in biological sciences.

“Fred did not have a close relationship with UC San Diego, but much of the scientific strength of this university and our sister institutions in La Jolla is built upon his work,” said Dr. Theodore Friedmann, a UC San Diego professor of pediatrics, a former student of Sanger’s, a pioneer himself in gene therapy and one of the symposium organizers. (It was Friedmann’s wife, Ingrid, who designed and made Sanger’s sequined DNA T-shirt.)

“We would not be where we are without Fred’s work. He has certainly been one of the principal inspirations of my own career. Our symposium pays homage not so much to any particular connection to UC San Diego, but to his service to the entire world of science.”

His first Nobel Prize, awarded in 1958, honored Sanger’s research describing the structure of proteins, in particular how amino acids linked together to form insulin.

In 1980, he shared half of the Nobel Prize for chemistry with American molecular biologist Walter Gilbert for their invention of a method to decipher the sequences of bases — adenine, thymine, guanine and cytosine, the A-T-G-C molecules essential to all life — in nucleic acids, most famously deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Paul Berg was awarded the other half for his research involving recombinant DNA.

Sanger’s twin Nobels augured the broader ramifications of his achievements.

By piecing together the chain of 51 amino acids that comprise insulin, Sanger showed scientists how to determine the sequences of other proteins.

By creating a method to read DNA simply and effectively, Sanger and colleagues made it possible to decode entire genomes. In 1977, Sanger decoded the genome of a virus – a first. Subsequent improvements and technological advances eventually made it possible for scientists in 2003 to successfully decipher the 3 billion letters that spell out the human genetic code.

“Sanger invented most of what underlies modern genetics and genomic science,” said Friedmann. “Fred was to genetics what Michelangelo and Picasso were to art, what Einstein is to physics and Darwin to evolutionary science. He was a giant among giants to whom most of us owe our careers.”

Scientific progress in biomedical research at institutions throughout the world has benefitted enormously from Fred’s revolutionary technologies, said Tony Hunter, a renowned Salk biologist who is an adjunct professor at UC San Diego and symposium co-organizer with Friedmann and Susan Taylor, professor of chemistry, biochemistry and pharmacology at UC San Diego.

“Rapid DNA sequencing is now pivotal in all areas of biology and medicine, but very few scientists who use this technology every day remember the crucial role that Fred Sanger played in making this a reality,” he said. “Perhaps it is a testament to the importance of what he did that his methods live on, but the man is largely forgotten!”

Sanger, who retired in 1983 to tend to his much-loved garden of roses and dahlias, would likely be a little dismayed by the symposium. Not the science, just the celebration. He was notably averse to publicity and never sought fame. He refused a knighthood from the Queen and, in his obituary, was quoted as describing himself as “just a chap who messed about in a lab.”

Maybe so, but his achievements are writ large in the letters of our DNA.

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Researchers seek middle-aged and older men for aging study


UC Davis study will follow groups of men with and without the fragile X premutation.

David Hessl, UC Davis

How alterations in a single gene on the X chromosome affects neurological and psychological functioning in men as they age is the subject of a new study by UC Davis MIND Institute researchers.

The gene is FMR1 (fragile X mental retardation 1), and those with an alteration in this gene, known as a “premutation,” are at risk for a range of psychological and medical conditions including decreased cognitive capacity and anxiety. In older adults with the premutation it can cause fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder that has motor symptoms that are similar to Parkinson’s disease and dementia and psychiatric symptoms that are similar to Alzheimer’s disease.

Researchers with the MIND Institute’s Fragile X Research and Treatment Center are seeking individuals the fragile X premutation who will participate in the study over five years, allowing researchers to track their brain changes, motor functioning, thinking and memory skills, as well as their emotional well‐being. They also are seeking healthy men of the same age, who will act as controls.

The study is co‐led by David Hessl, professor of psychiatry and behavioral sciences, and Susan Rivera, professor in the Department of Psychology.

“This study will follow groups of men with and without the fragile X premutation. It will examine the trajectory of change in their cognitive and emotional functioning, and the structure and function of their brains, in an effort to determine which factors are important for predicting the disease process that will occur in some of these men,” Hessl said.

Healthy male control participants must be between 40 and 75 and live in Northern California. Fragile X premutation carriers of the same age may travel to the MIND Institute from their homes anywhere in North America. Participation involves three two‐day study visits over five years. Compensation of $200, as well as travel reimbursement, will be provided for each two-day visit.

Once enrolled, individuals will receive tests to assess their ability to think and their memory skills. They will be interviewed and fill out questionnaires about their health history. They also will be asked to provide blood samples and will have brain scans taken while engaged in a variety of tasks.

For further information, please contact Jessica Famula, recruitment coordinator, (916) 703‐0470 or email jessica.famula@ucdmc.ucdavis.edu.

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Better education about prenatal testing leads to fewer tests


UCSF study shows importance of clear information on all prenatal testing options.

Miriam Kuppermann, UC San Francisco

A clinical trial led by UC San Francisco has found that when pregnant women are educated about their choices on prenatal genetic testing, the number of tests actually drops, even when the tests are offered with no out-of-pocket costs.

The findings underscore the need for clear information on all prenatal testing options and their possible outcomes, including the option of no testing, before pregnant women decide whether or not to have genetic testing, the authors said.

The study also suggests that some women may have undergone prenatal screening for Down syndrome without having full information about the implications of testing, the authors said.

The article is published in today’s (Sept. 24) issue of JAMA.

“Our findings show that prenatal testing is not appropriate for everyone, and that all women need information that is readily understood and unbiased to enable them to make informed choices reflecting their own preferences and values,” said lead author Miriam Kuppermann, Ph.D., M.P.H., professor and vice chair for clinical research at the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences.

“Decisions about prenatal testing are personal and should be reflective of the patient’s own values and preferences, not those of her health care providers,” said Kuppermann.

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How to delay the aging process by ‘remote control’


UCLA biologists ID gene that can slow the aging process.

David Walker, UCLA

UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems.

Working with fruit flies, the life scientists activated a gene called AMPK that is a key energy sensor in cells; it gets activated when cellular energy levels are low.

Increasing the amount of AMPK in fruit flies’ intestines increased their lifespans by about 30 percent — to roughly eight weeks from the typical six — and the flies stayed healthier longer as well.

The research, published Sept. 4 in the open-source journal Cell Reports, could have important implications for delaying aging and disease in humans, said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research.

“We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated,” Walker said.

Walker said that the findings are important because extending the healthy life of humans would presumably require protecting many of the body’s organ systems from the ravages of aging — but delivering anti-aging treatments to the brain or other key organs could prove technically difficult. The study suggests that activating AMPK in a more accessible organ such as the intestine, for example, could ultimately slow the aging process throughout the entire body, including the brain.

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Study IDs genetic factors involved in pediatric ulcerative colitis


Findings point to novel approaches for prevention, treatment.

Microscope images of a normal mouse colon (left) and one with colitis (right).

UCLA researchers were part of a team that has discovered the interplay of several genetic factors that may be involved in the development of early-onset ulcerative colitis, a severe type of inflammatory bowel disease.

The early research findings may offer new targets for prevention and treatment strategies to address the inflammation generated by early-onset ulcerative colitis.

The rare disease affects infants and young children and can lead to early development of colon cancer and an increased risk of liver damage.

Scientists from the David Geffen School of Medicine at UCLA and Pusan National University in South Korea also created a first-of-its-kind animal model that mimics early-onset ulcerative colitis and can be used to help test new drug candidates to treat the disease. Their findings are published in the current issue of the peer-reviewed journal Gastroenterology.

“We hope that identifying these key genetic factors and providing a unique research model will help lead to new approaches to treat early-onset ulcerative colitis, a devastating disease that currently has no cure,” said Dr. Sang Hoon Rhee, the study’s senior author and an associate adjunct professor of medicine in the Division of Digestive Diseases at the David Geffen School of Medicine at UCLA.

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Chicken gene provides insight on craniofacial birth defects


UC Davis findings significant for humans as well as poultry and livestock.

These chicks are part of UC Davis' living library of poultry and avian genetics, which includes the talpid lines examined in this study. (Photo by Mary Delany, UC Davis)

Each year, thousands of babies are born in the U.S. with craniofacial defects, from cleft lips and palates to more severe abnormalities of the face or head. Now new discoveries in chicken genetics and biology are shedding light on the basis of these abnormalities in both birds and humans.

The work, by a team including UC Davis animal science professor Mary Delany, was made possible by information from the chicken genome sequence and a stock of rare chicken lines kept at UC Davis. The findings appear in the August issue of the journal Development.

The researchers focused on a mutation of the gene named talpid2, known to be associated with a number of congenital abnormalities, including limb malformations and cleft lip or palate.

They found that talpid2 — like other limb and craniofacial mutations found in both humans and chickens — is related to the malfunction of “cilia,” tiny, hairlike structures on the surface of cells of the body.

Cilia play a vital role in passing along signals during development. When a gene mutation interferes with the normal structure and function of the cilia, it sets off a chain reaction of molecular miscues that result in physical abnormalities, in chickens or in people.

“Now that this new information is available, the talpid2 mutation can be expanded as a model for studying similar congenital abnormalities in humans including oral-facial defects, which affect many people around the world,” said Delany, who also serves as executive associate dean of the College of Agricultural and Environmental Sciences.

Delany said that the findings also are significant for production of poultry and livestock, which are likewise vulnerable to genetic mutations that cause similar physical abnormalities.

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Tackling rare diseases


UC Irvine researchers’ search for genetic clues is giving new hope to families.

“In our lab, we don’t give up,” says Virginia Kimonis, a UC Irvince specialist in rare genetic diseases. “If people are reaching out, you have to do all you can about rare diseases.” (Photo by Steve Zylius, UC Irvine)

By the time families meet with Dr. Virginia Kimonis, hope is about all they have left.

Her pediatric patients are afflicted with debilitating diseases caused by mutations in an alphabet soup of genes – VCP and NUBPL among them. Prader-Willi, Rett, Paget’s and the like are difficult to diagnose and even harder to treat. But with cutting-edge genomic sequencing and old-fashioned scientific sleuthing, physician-researchers such as Kimonis are on the vanguard of modern medicine, finding therapies where none seemed possible.

Kimonis specializes in one of the most challenging areas: rare genetic diseases. What she and others in her field are learning about disorders that impact only a few is paving the way to a greater understanding of diseases that impact millions.

“It’s wonderful to show in the lab and in the clinic that we can offer these patients some hope,” says Kimonis, a UC Irvine pediatrician and clinical geneticist.

A rare disease is defined as one diagnosed in no more than 200,000 people worldwide; 70 percent, though, affect fewer than 6,000. And of the nearly 7,000 known rare diseases, half involve children, and 80 percent are linked to genetic flaws. These are Kimonis’ focus.

According to UC Irvine’s Dr. J. Jay Gargus, an expert in genetic metabolic diseases, rare disease research can be a springboard to understanding and treating more common ailments.

“We have a special opportunity with rare genetic diseases to provide an insight into how common diseases arise,” says Gargus, who directs the campus’s Center for Autism Research & Translation. “This is an important venue for drug discovery. The National Institutes of Health and the Food & Drug Administration recognize this and have programs established for target diseases. UC Irvine has a great strength in diagnostics, and we should be very involved in this.”

Gargus himself is making a breakthrough on a rare genetic disease. He recently held the first U.S. clinical trial of a treatment for Wolman disease, a cholesterol storage disorder, at UC Irvine Medical Center – with promising results.

Kimonis is also helping the campus establish itself as a leader in the field. She manages a section of the NIH’s Rare Diseases Clinical Research Network dedicated to Prader-Willi, Rett and Angelman syndromes.

Children with Prader-Willi – which is caused by the loss of several genes on chromosome 15 – are characterized by obesity, low muscle tone and cognitive disabilities. In addition to treating Prader-Willi patients with novel approaches, Kimonis is building a national database of those with the disease and designing studies to identify promising therapies.

In one project, she plans to partner with Daniele Piomelli – UC Irvine’s Louise Turner Arnold Chair in the Neurosciences, who examines the endocannabinoid system – to see how marijuana-like chemicals called OEAs created in the body can help curb the insatiable appetites of Prader-Willi children. By creating mice models with Prader-Willi gene mutations, the two hope to learn if the hunger-curbing signal provided by OEA is missing and whether compounds that boost OEA can aid satiety.

“If successful, our experiments will achieve two important objectives,” Piomelli says. “First, they will help us understand why Prader-Willi causes hunger; second, and more importantly, they will suggest new possible therapies to reduce appetite.”

Another focus of Kimonis’ work centers on disorders triggered by mutations in the valosin-containing protein gene. VCP programs enzymes that help maintain cell health by breaking down and clearing away old and damaged proteins that are no longer necessary. Mutations in the VCP gene have been discovered in people who have a muscle-weakening disease called inclusion body myopathy, early-onset Paget’s disease of the bone or frontotemporal dementia.

Kimonis was the first scientist to map and identify mutations in the VCP gene in inclusion body myopathy, and in 2012, she developed the first genetically modified mouse model that exhibits many of the clinical features of diseases largely caused by VCP gene mutations.

“Mouse models like these are important because they let researchers study how these now-incurable, degenerative disorders progress in vivo and will provide a platform for translational studies that could lead to lifesaving treatments,” says Kimonis, who co-directs UC Irvine’s MitoMed laboratory, which offers testing for many rare diseases.

Her research breakthroughs are coinciding with greater public recognition of rare genetic diseases. The NIH has established an Office of Rare Diseases Research, and nonprofit groups such as the Orange County-based Global Genes Project are increasing awareness, advocating and soliciting philanthropic aid on behalf of this issue. (The GGP is hosting a patient advocacy summit Sept. 11 and 12 in Huntington Beach.)

Parents of children with rare genetic diseases are also speaking out. Cristy and Rick Spooner of Rancho Santa Margarita, who’ve endured a long quest to identify a disabling condition affecting two of their three daughters, have gone public with their story, hoping to raise the profile of such diseases.

After the Spooners spent years seeking help from doctors, Kimonis contacted them about a new technique, called exome sequencing, that examines the tens of thousands of genes in the human body for disease-causing mutations. Aliso Viejo-based Ambry Genetics, which partners with Kimonis’ research group, provided the sequencing services.

Test results showed that Cali and Ryann Spooner harbored mutations in the NUBPL gene. This defect prevents their mitochondria – the power generators in cells – from efficiently producing energy. Armed with this information, Kimonis developed dietary and drug treatments for the Spooner sisters.

“What’s even more satisfying about our work is that it has huge implications for other diseases,” she says.

Kimonis is seeking funding to determine whether mitochondrial defects caused by mutated NUBPL genes underlie the onset of Parkinson’s disease. She hopes to partner with UC Irvine neurologist Dr. Neal Hermanowicz, who manages the movement disorders program, to establish a clinical research network for this effort.

“In our lab, we don’t give up,” Kimonis says. “If people are reaching out, you have to do all you can about rare diseases.”

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Target ID’d for rare inherited neurological disease in men


Finding provides insight for Kennedy’s disease, other neurodegenerative diseases.

Researchers at the UC San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.

The study, published today (Aug. 10) in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy’s disease impairs the body’s ability to degrade, remove and recycle clumps of “trash” proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.

“We’ve known since the mid-1990s that Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over,” said senior author Albert La Spada, M.D., Ph.D. and professor of pediatrics, cellular and molecular medicine, and neurosciences. “The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function.”

Of the 400 to 500 men in the U.S. with Kennedy’s disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheelchair bound during later stages of the disease.

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