Category Archives: Gene Medicine

The endeavor known as precision medicine, which Obama singled out in his State of the Union Address, may sound futuristic, but its been around long enough for people to have screwed it up, and badly. One of the worst medical scandals this century started with cancer researchers at Duke promising something that sounded a little too good to be true and ended with retracted papers, dashed patient hopes and lawsuits.

But precision medicine is obviously moving forward. To learn more about it, and what lessons the past has to offer, I caught up with Keith Baggerly, whose dogged investigations uncovered the problem with the Duke project. Baggerly is a professor in the Department of Bioinformatics and Computational Biology and Division of Quantitative Sciences at UT MD Anderson Cancer Center. (He is also a witness in a pending lawsuit filed by patients and their families.)

Though precision medicine has different meanings, medical researchers tend to use that term or personalized medicine to refer to the use of individual DNA differences in tailoring treatments to patients. The strategy is being driven by advances in the ability to quickly and cheaply read the sequences of code characters in DNA and by the growing use of big data to find patterns. As described in this Philadelphia Inquirer story, a number of big data cancer initiatives are gathering momentum.

The dream of precision medicine has been particularly tantalizing for cancer treatment, since cancer cells are just ordinary cells with broken DNA mutations that change the cells instructions and cause them to run amok.

And so, in 2006, cancer researchers around the word took notice when a team led by Dr. Anil Potti at Duke claimed in the prestigious journal Nature Medicine that theyd created a highly complex mathematical system that could assess a given patients tumor and determine from its genetic make-up exactly which drugs would give that patient the best odds of survival. While investigations have revealed fraud on the part of Anil Potti, many other people made mistakes in ignoring whistle blowers and allowing the technique to be used on cancer patients in a clinical trial.

While some avenues of precision medicine could lead to new, prohibitively expensive drugs used for rare subsets of patient, the Duke technique promised to chart the best course among existing treatments said Baggerly.

It would be based on the DNA in individual patients tumors. And it didnt just apply to one kind of cancer but to cancers across the board. Instead of telling a patient there was a 70% chance a drug would work to kill her tumor, he said, they could find out ahead of time if she was in the other 30% and prescribe an alternative course of treatment.

Doctors were excited and thought if the system worked, they owed it to their own patients to adopt a form of it, he said. Several groups asked Baggerly to look into it. One danger with the approach, he said, was that it was impossible to know how the technique worked. The data were so big they were measuring thousands of things per patient and there was this perception that the analysis of such data sets would be complex, he said. In most medical tests, theres some understanding of how they work. Thats true in some of the early advances in precision medicine. In some cases of melanoma, for example, theres a break in a particular gene called BRAF, and drugs that target cells with that broken gene. Theres a mechanistic understanding of how it all works.

But with the Duke project, he said, nobody has a good intuition of what 50 or 60 things are doing at once. And so there was no way for intuition to tell anyone whether it worked at all. When Baggerly started to re-analyze how the Duke researchers created the system in the first place, it didnt work. Was he using the system wrong or was there something wrong with the system?

As he investigated further, he found egregious errors that should have prevented it from working. The team had relied on cancer cell samples that had various degrees of resistance to an array of drugs. Those had been mislabeled. Some were reversed, so that the cells that were most resistant were labelled as the least.

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Bad 'Precision' Medicine -- If Nobody Knows How It Works, Sometimes It Doesn't

IMAGE:Using the zebrafish facility at Washington University School of Medicine in St. Louis, graduate student Sarah Ackerman (left) and senior author Kelly Monk, PhD, identified a gene that regulates how... view more

Credit: Robert Boston

Scientists have identified a gene that helps regulate how well nerves of the central nervous system are insulated, researchers at Washington University School of Medicine in St. Louis report.

Healthy insulation is vital for the speedy propagation of nerve cell signals. The finding, in zebrafish and mice, may have implications for human diseases like multiple sclerosis, in which this insulation is lost.

The study appears Jan. 21 in Nature Communications.

Nerve cells send electrical signals along lengthy projections called axons. These signals travel much faster when the axon is wrapped in myelin, an insulating layer of fats and proteins. In the central nervous system, the cells responsible for insulating axons are called oligodendrocytes.

The research focused on a gene called Gpr56, which manufactures a protein of the same name. Previous work indicated that this gene likely was involved in central nervous system development, but its specific roles were unclear.

In the new study, the researchers found that when the protein Gpr56 is disabled, there are too few oligodendrocytes to provide insulation for all of the axons. Still, the axons looked normal. And in the relatively few axons that were insulated, the myelin also looked normal. But the researchers observed many axons that were simply bare, not wrapped in any myelin at all.

Without Gpr56, the cells responsible for applying the insulation failed to reproduce themselves sufficiently, according to the study's senior author, Kelly R. Monk, PhD, assistant professor of developmental biology. These cells actually matured too early instead of continuing to replicate as they should have. Consequently, in adulthood, there were not enough mature cells, leaving many axons without insulation.

Monk and her team study zebrafish because they are excellent models of the vertebrate nervous system. Their embryos are transparent and mature outside the body, making them useful for observing developmental processes.

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Scientists find gene vital to central nervous system development

Researchers from Dartmouth's Norris Cotton Cancer Center, led by Casey S. Greene, PhD, reported in Pacific Symposium on Biocomputing on the use of denoising autoencoders (DAs) to effectively extract key biological principles from gene expression data and summarize them into constructed features with convenient properties.

"Cancers are very complex," explained Greene. "Our goal is to measure which genes are being expressed, and to what extent they're being expressed, and then automatically summarize what the cancer is doing and how we might control it."

Normally, it is difficult to apply computational models across different studies because the gene expression data is "noisy," meaning that there are many factors that differ in the way gene expression is measured. To begin their analysis, Greene's team added more noise to the data and then trained a computer to remove the noise. To remove the noise, the computer had to learn about key underlying features of breast cancer. "This approach of removing noise makes the models we constructed more generally applicable," Greene said.

Greene and the Dartmouth team studied DAs, which train computers directly on the data without requiring researchers to provide known biological principles to the computer, as a method to identify and extract complex patterns from genomic data. The model that the computer constructs can then be compared to previous discoveries to understand where data supports those discoveries and where the data raises new questions. The performance of DAs was evaluated by applying them to a large collection of breast cancer gene expression data. Results show that DAs were able to recognize changes in gene expression that corresponded to the cancers' molecular and clinical information.

"These techniques and findings will enable others to use the DAs to evaluate gene expression data in a variety of disease sites," reported Greene. "While noise in data is usually viewed as a problem, adding noise to data can actually be a good thing because it can help reveal the underlying signal. When we did this to analyze data from breast cancers, we found gene expression features that generalize across studies and represent important clinical factors."

Next for Greene's research team are more complex models that take multiple levels of regulation into account. Their goal is to develop methods that not only model data but that can automatically explain to researchers what the models have learned.

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Dr. Greene and his team of investigators do their research at Dartmouth's Norris Cotton Cancer Center in Hanover and Lebanon, New Hampshire. Their work is supported in part by NIH funding P20 GM103534 and the American Cancer Society Grant #IRG-82-003-27.

About Norris Cotton Cancer Center at Dartmouth-Hitchcock

Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu

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Noisy data facilitates Dartmouth investigation of breast cancer gene expression

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Newswise PHILADELPHIAA somatic mutation in the ATRX gene has recently been shown as a potential molecular marker for aggressive brain tumors, such as gliomas, neuroblastomas and pancreatic neuroendocrine tumors. Now, for the first time, researchers at at the Perelman School of Medicine at the University of Pennsylvania have found that the same mutated gene may serve as a much-needed biomarker for the pheochromocytomas and paragangliomas (PCC/PGL) that become malignant. These rare neuroendocrine tumors are typically benign, but when they go rogue, they become very aggressive.

The study was published online ahead of print today in Nature Communications.

Several inherited mutated genes, such as VHL and RET, have been found to be associated with PCC/PGL; however, little is known about the somatic genetic changes leading to tumorigenesis in these patients.

This is the first step towards a better understanding of this type of disease, and to try to identify better biomarkers of poor outcomes, said senior author Katherine Nathanson, MD, an associate professor in the division of Translational Medicine and Chief Oncogenomics Physician for the Abramson Cancer Center. The mutation could not only serve as that biomarker for metastatic disease, but also a potential therapeutic drug target in the future.

PGLs are rare tumors of nerve ganglia in the body, whereas PCCs form in the center of the adrenal gland, which is responsible for producing adrenaline. The tumor causes the glands to overproduce adrenaline, leading to elevated blood pressure, severe headaches, and heart palpitations. Both are found in about two out of every million people each year. An even smaller percentage of those tumors become malignant. For that group, the five-year survival rate is about 50 percent.

No reliable predictors of aggressive disease exist other than an inherited mutation in the SDH gene, but only half of patients who develop metastatic disease carry that mutation, meaning the other half have no known predictors.

About 60 percent of PCC/PGLs are sporadic, while the remaining 40 percent are hereditary. Most recurrent somatic mutations are observed almost exclusively in sporadic PCC/PGLs.

Researchers, including Lauren Fishbein, MD, PhD, MTR, an instructor in the division of Endocrinology, Diabetes and Metabolism at the Perelman School of Medicine, investigated the mutations using whole exome sequencing on a set of 21 tumor/matched germline DNA samples of either sporadic or inherited PCC/PGL. The idea was to compare benign tumors to clinically aggressive ones in order to spot markers of malignant potential.

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Mutated ATRX Gene Linked to Brain and Pancreatic Neuroendocrine Tumors is Potential Biomarker for Rare Adrenal Tumors ...

IMAGE:Bryan Luikart, an assistant professor of Physiology and Neurobiology in the Geisel School of Medicine at Dartmouth, leads a research team investigating the neurobiological basis of autism spectrum disorders. view more

Credit: Dartmouth College

HANOVER, N.H. - Recent research has linked autism with a lack of "pruning" in developing brain connections, but a new Dartmouth study suggests instead it is the excessive growth of new connections that causes sensory overload in people with the disorder.

The results, which have broad implications for understanding the neurobiological basis of autism spectrum disorders, appear in The Journal of Neuroscience. A PDF of the study is available on request.

"We've been working on understanding how dysfunction of the gene Pten, which is known to cause some cases of autism, effects neuronal development, and I believe our findings represent the best understanding in science today for how an autism candidate gene changes the functional characteristics of developing neurons," says senior author Bryan Luikart, an assistant professor of Physiology and Neurobiology in the Geisel School of Medicine at Dartmouth.

Mutations in the gene Pten are among the most common single-gene mutations that cause autism and a group of interrelated syndromes. People with these diseases have increased chances of having autism, intellectual disability and epilepsy. Luikart's team is investigating the neurobiological basis of the complex symptoms of autism by modeling genetic changes associated with autism in humans in neurons of mice. For their new study, the researchers generated a model in which they injected retroviruses into the brains of developing mice to both knockout the Pten gene and to label the knockout neurons with a fluorescent marker. This allowed them to study how turning off the gene alters the structural and electrical development of the neurons. They found that knocking out the Pten gene caused overt overgrowth of the neurons, which resulted in an increase in the number of excitatory synapses, or the connections that transmit signals from a nerve cell to another cell. The ultimate result of this is that the neurons become hyperactive.

Recent media coverage has surrounded the idea that autism is associated with a lack of "pruning" or refinement of excitatory synapses later in development. But the Dartmouth study argues against this, saying it is not a failure of "pruning" that results in the ultimate increase in excitatory synapses, but an increase in new production of excitatory synapses. Further, they found a tight interrelationship between the structural and functional changes produced by the Pten gene knockout.

"The broader implication for this is that mutations in the gene Pten in humans likely result in an increased developmental proliferation of excitatory synaptic connections," Luikart says. "This may result in a given sensory experience stimulating neurons or even whole brain regions that would never be excited in a normal brain. Conceptually, this could be the neurobiological basis for the inappropriate responses to sensory stimulation that is often characteristic of patients with autism."

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Assistant Professor Bryan Luikart is available to comment at Bryan.W.Luikart@dartmouth.edu

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Dartmouth study sheds light on genetic mutations in autism disorders

The research group led by Professor Magnus Andersson at University of Helsinki has discovered a new inherited disease that causes ptosis, retarded growth, intellectual disability and mortality in Ayrshire calves. The disease proved to be associated with a mutation in UBE3B gene. Of the 129 tested Ayrshire AI bulls recently used in Finland, 17% carried the mutation. Moreover, UBE3B mutation may be connected to AH1 haplotype, which is associated with reduced fertility and has a carrier frequency of 26.1% in the North American Ayrshire population. The study was published in BMC Genomics journal on 12 October 2014.

An inherited disease that causes serious developmental disorder in Ayrshire breed has been studied at the Department of Production Animal Medicine, University of Helsinki. The phenotype has been defined as PIRM syndrome according to its typical features: ptosis, intellectual disability, retarded growth and mortality. The most easily noticeable symptom of affected calves is the ptosis. The exceptionally large upper eye lid gives a characteristic sleepy appearance of the affected animals. Some affected calves also suffered from feeding problems, minor structural changes of the head and muscular hypotonia. The disease is recessively inherited i.e. affected animals have inherited the mutation from both parents

Heredity research traced the disease to a mutation in UBE3B gene, which partially prevents the normal expression of the gene. Mutation screening of the 129 Ayrshire AI bulls that are in use or have recently been used in Finland indicated a high carrier frequency of 17.1%. "The results of this study can be utilized in bovine breeding programs. With the successful prevention of PIRM syndrome the animal welfare can be increased and at the same time the financial losses for farmers and breeding companies can be reduced" says PhD student Heli Venhoranta.

In humans, mutations in UBE3B gene are associated with Kaufman oculocerebrofacial syndrome with similar pathological findings as in PIRM syndrome. Furthermore, mice engineered to lack UBE3B expression were reported having increased lethality.

The mutation in UBE3B gene might be connected to the recently discovered Ayrshire haplotype 1 (AH1). The haplotype encompasses the mutation in UBE3B gene and of those tested 129 AI bulls, 29 had a known haplotype status for AH1. AH1 haplotype is associated with reduced fertility which could imply embryonic losses that agree with the findings of UBE3B deficiency in mice. The AH1 haplotype was perfectly associated with the UBE3B mutation in this study cohort. The estimated frequency of the AH1 haplotype was 26% in the North America Ayrshire herd. "The relationship between PIRM syndrome and AH1 haplotype needs to be clarified but our study does however provide an avenue for further investigation" concludes Venhoranta.

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The above story is based on materials provided by Helsingin yliopisto (University of Helsinki). Note: Materials may be edited for content and length.

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New inherited disease identified in calves of the Ayrshire breed

Gene testing. The phrase, on its own, is chilling and foreboding on so many levels, striking a fearful chord on anybody who has to take it.

But that thought, like so many other misconceptions about gene testing, couldnt be further away from the truth.

If pseudo mathematical equations can be used to describe gene testing, the simple mathematical equation should go like this: gene + testing = good for you.

As a once-in-a-lifetime test that reads your DNA and reveals your inherited health traits, gene testing also shows you the exact levels of risk that you have for certain diseases so you can prevent it from happening even before it takes a hold of you. The concept of gene testing shouldnt be met with fear and apprehension. On the contrary, it should be welcomed with the kind of fervor and enthusiasm from anybody who wants to understand their healths predisposition.

Eschewing its relevancy is equally misplaced because at its core, gene testing allows a person to understand his or her health and carefully map out his or her health lifestyle in order to prevent health issues from arising.

Why wait for a health issue to strike when you can prevent it so you can enjoy life better?

Thats a question LifeScience is asking, and in its simplest sense, its one that highlights the tenet prevention is better than cure. Gene testing is one of the steps that one can take to become fully equipped of information about himself.

Your gene test should be able to guide you on how to live your life so those health issues that you are likely to have will not manifest and be able to pre-empt them with proper health and maintenance courtesy of specifically-tailored health-program that suits your body, said Dr. Ben Valdecanas, medical director of LifeScience Center for Wellness and Preventive Medicine. One of its most important characteristics is its capability to accurately reveal all the actual diseases that your genes carry, as well as the genetic mutations that your predecessors have passed on to you, he adds.

LifeScience has made gene testing more accessible by making it available in its center for those actively pursuing a healthy lifestyle that is backed by medical evidence. Its one thing to be diagnosed by a doctor with a certain illness when its already inside the body. Its another thing to know about what could strike even before it does. Gene testing does not only give you a glimpse of the health issues that you are most likely to catch but also how well your body will respond to medication as well as how you can modify your lifestyle that is best suited for you.

We are encouraging Filipinos to start thinking of wellness from the perspective of prevention. Our goal at LifeScience is not make you live to a hundred but to ensure that you are able to live quality life, one that you are able to enjoy even as the years are starting to add up, adds Valdecanas.

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A glimpse at the true state of your well-being

MAYWOOD, Il. - Up to 8 percent of people from India, Pakistan, Bangladesh and other South Asian countries carry a mutated gene that causes heart failure and potentially fatal heart attacks.

A new study demonstrates how this gene mutation impairs the heart's ability to pump blood. Results could point the way to eventual treatments and prevention strategies for an estimated 55 million people of South Asian descent worldwide, including 200,000 people in the United States, who carry the potentially fatal mutation.

The study, led by Sakthivel Sadayappan, PhD, MBA, of Loyola University Chicago Stritch School of Medicine, is published in the prestigious Journal of Biological Chemistry, a publication of the American Society for Biochemistry and Molecular Biology.

The mutation causes hypertrophic cardiomyopathy, the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. Previous studies by Dr. Sadayappan and other researchers have found that between 5 percent and 8 percent of South Asians carry the mutation. Carriers have about a 80 percent chance of developing heart failure after age 45. Dr. Sadayappan first reported the mutation in 2001 at the World Congress of the International Society for Heart Research, and has been studying it ever since. He said that, based on a report from one of his collaborators, the mutation likely arose in a single person roughly 33,000 to 55,000 years ago. The mutation then spread throughout South Asia.

The mutated gene encodes for a protein, called cardiac myosin binding protein-C (cMyBP-C), that controls cardiac muscle contractions and is critical for the normal functioning of the heart. In the mutated gene, 25 base pairs (DNA letters) are missing. As a result, the tail end of the protein is altered.

In his new study, Dr. Sadayappan and colleagues introduced the mutated gene into adult rat cardiomyocytes (heart muscle cells) in a petri dish. These cells were compared with cardiomyocytes that received a normal gene.

In cells with the mutant gene, the cMyBP-C protein was not incorporated into sarcomeres, the basic units of heart muscle. So rather than helping the sarcomeres contract properly, the mutant protein floated around the cell's cytoplasm, producing a toxic effect. The study showed, for the first time, that expression of the mutant protein is sufficient to cause cardiac dysfunction.

The findings point the way toward future treatments that would remove the mutant protein from cells and introduce normal cMyBP-C protein. Researchers also hope to identify lifestyle and environmental risk factors that aggravate hypertrophic cardiomyopathy in people who carry the gene mutation.

Dr. Sadayappan and colleagues concluded that determining the disease mechanism will help in developing therapies, and is the "first priority to prevent the development of heart failure in millions of carriers worldwide."

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Originally posted here:
Up to 8 percent of South Asians carry gene mutation that causes heart attacks

THURSDAY, Jan. 15, 2015 (HealthDay News) -- Medicare indicated recently that it might soon cover CT scans to check longtime smokers for early lung cancer, and these types of scans are becoming more common.

Now, an experimental test may help determine whether lung nodules detected by those scans are malignant or not, researchers say.

The test, which checks sputum (respiratory mucus) for chemical signals of lung cancer, was able to distinguish early stage lung cancer from noncancerous nodules most of the time, according to findings published Jan. 15 in the journal Clinical Cancer Research.

"We are facing a tremendous rise in the number of lung nodules identified because of the increasing implementation of the low-dose CT lung cancer screening program," Dr. Feng Jiang, associate professor, department of pathology, University of Maryland School of Medicine, explained in a journal news release.

"However, this screening approach has been shown to have a high false-positive rate," he added. "Therefore, a major challenge is the lack of noninvasive and accurate approaches for preoperative diagnosis of malignant nodules."

Testing a patient's sputum for a group of three genetic signals -- called microRNA (miRNA) biomarkers -- may help overcome this problem, Jiang said.

Jiang and his colleagues first tried the test in 122 people who were found to have a lung nodule after they underwent a chest CT scan. The sputum test was nearly 83 percent accurate in identifying lung cancer, the study found, and nearly 88 percent in correctly identifying when a lung nodule was not cancerous.

In two other groups of patients tested, the rates were about 82 percent and 88 percent, and 80 percent and 86 percent, respectively.

However, those results are still not high enough for the panel to be used for diagnosing patients, so more work must be done to boost accuracy, the researchers said.

"We are now applying new technologies to identify additional miRNA sputum biomarkers of lung cancer with the goal of expanding our biomarker panel to generate a test with high efficiency that can be practically used in clinical settings for lung cancer early detection," Jiang said.

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Gene-Based Spit Test Shows Promise in Lung Cancer Detection

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Newswise MAYWOOD, Il. Up to 8 percent of people from India, Pakistan, Bangladesh and other South Asian countries carry a mutated gene that causes heart failure and potentially fatal heart attacks.

A new study demonstrates how this gene mutation impairs the hearts ability to pump blood. Results could point the way to eventual treatments and prevention strategies for an estimated 55 million people of South Asian descent worldwide, including 200,000 people in the United States, who carry the potentially fatal mutation.

The study, led by Sakthivel Sadayappan, PhD, MBA, of Loyola University Chicago Stritch School of Medicine, is published in the prestigious Journal of Biological Chemistry, a publication of the American Society for Biochemistry and Molecular Biology.

The mutation causes hypertrophic cardiomyopathy, the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. Previous studies by Dr. Sadayappan and other researchers have found that between 5 percent and 8 percent of South Asians carry the mutation. Carriers have about a 80 percent chance of developing heart failure after age 45. Dr. Sadayappan first reported the mutation in 2001 at the World Congress of the International Society for Heart Research, and has been studying it ever since. He said that, based on a report from one of his collaborators, the mutation likely arose in a single person roughly 33,000 to 55,000 years ago. The mutation then spread throughout South Asia.

The mutated gene encodes for a protein, called cardiac myosin binding protein-C (cMyBP-C), that controls cardiac muscle contractions and is critical for the normal functioning of the heart. In the mutated gene, 25 base pairs (DNA letters) are missing. As a result, the tail end of the protein is altered.

In his new study, Dr. Sadayappan and colleagues introduced the mutated gene into adult rat cardiomyocytes (heart muscle cells) in a petri dish. These cells were compared with cardiomyocytes that received a normal gene.

In cells with the mutant gene, the cMyBP-C protein was not incorporated into sarcomeres, the basic units of heart muscle. So rather than helping the sarcomeres contract properly, the mutant protein floated around the cells cytoplasm, producing a toxic effect. The study showed, for the first time, that expression of the mutant protein is sufficient to cause cardiac dysfunction.

The findings point the way toward future treatments that would remove the mutant protein from cells and introduce normal cMyBP-C protein. Researchers also hope to identify lifestyle and environmental risk factors that aggravate hypertrophic cardiomyopathy in people who carry the gene mutation.

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Up to 8 Percent of Indians and Other South Asians Carry Gene Mutation That Causes Heart Failure