Category Archives: Gene Medicine

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 theJournal 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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Up to eight percent of Asians carry gene mutation that causes heart failure

Kansas City, Mo. -- January 15, 2015 -- A new study published in the American Journal of Human Genetics demonstrates the continued important contributions from the Center for Pediatric Genomic Medicine at Children's Mercy Hospital in Kansas City, Mo. The study describes a new pediatric mitochondrial syndrome and discovery of the responsible gene, called CLPB. Dr. Carol Saunders and her team partnered with collaborators in Denmark to report their collective findings based on gene mapping and exome sequencing in five children with CLPB-related disease. These patients had strikingly similar clinical findings including cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, urinary excretion of 3-methylglutaconic aciduria, and death in early childhood.

"This research once again highlights the power of genomic medicine in the diagnosis and discovery of rare pediatric conditions," said Saunders, clinical laboratory director of the Center for Pediatric Genomic Medicine "In this case, we have identified one of the many genes, CLPB, involved in mitochondrial diseases. These findings emphasize the importance of basic research into the characterization of human CPLB gene function and will pave the way for the diagnosis of other patients."

The Center for Pediatric Genomic Medicine at Children's Mercy was the first genome center in the world inside a children's hospital, and the center's STAT-Seq test for critically ill newborns was one of TIME magazine's Top 10 Medical Breakthroughs of 2012. Learn more at http://www.childrensmercy.org/genomics.

About Children's Mercy Kansas City

Children's Mercy, located in Kansas City, Mo., is one of the nation's top pediatric medical centers. The 354-bed, not-for-profit hospital provides care for children from birth through the age of 21, and has been ranked by U.S. News & World Report as one of "America's Best Children's Hospitals." For the third time in a row, Children's Mercy has achieved Magnet nursing designation, awarded to fewer than seven percent of all hospitals nationally, for excellence in quality care. Its faculty of 600 pediatricians and researchers across more than 40 subspecialties are actively involved in clinical care, pediatric research, and educating the next generation of pediatric subspecialists.

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FOR INTERVIEWS WITH DR. CAROL SAUNDERS, CONTACT JAKE JACOBSON AT JAJACOBSON@CMH.EDU

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Discovery of CLPB gene associated with a new pediatric mitochondrial syndrome

Mutations in a gene that helps repair damaged chromosome ends may make smokers -- especially female smokers -- more susceptible to emphysema, according to results of a new study led by Johns Hopkins Kimmel Cancer Center researchers.

The mutations are one of a few genetic factors directly linked to chronic obstructive pulmonary disease (COPD), including emphysema, since the 1960s, says Mary Armanios, M.D., associate professor of oncology at the Johns Hopkins University School of Medicine.

Specifically, the alteration occurs in the telomerase reverse transcriptase (TERT) gene, which helps produce an enzyme called telomerase. Telomerase maintains and repairs the "caps" that protect the ends of chromosomes from degradation during cell division. Telomeres gradually shorten with age and act as a sort of cellular clock in cells. Mutations in TERT lead to excessively shortened telomeres.

Using genetic data gathered in COPD studies funded by the National Institutes of Health, Armanios and colleagues found TERT mutations in three of 292 smokers with emphysema. The researchers then looked at a sample of 50 Johns Hopkins patients with syndromes linked to telomere shortening. Among 39 nonsmokers, there were no cases of emphysema. Among smokers, seven of 11 patients, including all six female smokers, had emphysema. Armanios says this suggests that female smokers with telomerase-related mutations may be more susceptible to emphysema.

A report on the research was published Dec. 22 in the Journal of Clinical Investigation. Lung disease is the third leading cause of death in the U.S., and the main risk factors are aging and smoking. However, only about 10 percent of smokers develop COPD, according to Armanios. "Not everyone who smokes gets emphysema, so our study is part of a bigger effort to find out why some people get it and others do not," says Armanios, who notes that other studies have shown that young women who smoke may be more susceptible to emphysema.

The researchers had some clues about telomerase genes from earlier studies, including one in which Armanios and her colleagues identified the impact of shortened telomeres in mice as a risk factor for emphysema after being exposed to cigarette smoke. The scientists previously had noted a link between telomerase mutations and a severe hereditary lung disease called idiopathic pulmonary fibrosis.

Patients with emphysema often suffer from other health problems, including osteoporosis, liver disease and cancer. These disorders are common in people with shortened telomeres as well. The new study, says Armanios, "may now give us an explanation for why people with emphysema have these systemic problems. If we know that they have a telomerase mutation, it may help us take care of them in a more sophisticated way and delay the onset of those diseases."

Armanios and colleagues published a study last year showing that telomerase mutations may lead to more complications during lung transplants for people with idiopathic pulmonary fibrosis.

In the current study, only 1 percent of the smokers with severe emphysema carried the TERT mutation, but Armanios says this is comparable to the percentage who carry another known genetic factor related to COPD -- a mutation in the alpha-1 antitrypsin gene.

The researchers only looked at mutations in two telomerase genes but will now search for mutations in other telomere-regulating genes that might also predispose people to lung disease. "There are many genes that regulate the telomere, so it's likely that more than 1 percent could be impacted by these predisposing factors," says Armanios.

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Mutations linked to repair of chromosome ends may make emphysema more likely in smokers

A new study has identified genetic mutations that cause the heart condition dilated cardiomyopathy (DCM), paving the way for more accurate diagnosis.

By sequencing the gene encoding the muscle protein titin in more than 5,000 people, scientists have worked out which variations are linked to disease, providing information that will help screen high-risk patients.

Titin gene mutations were previously associated with DCM, a leading cause of inherited heart failure, but many people have variations in the genetic code that are completely benign.

The new study, published in Science Translational Medicine, sorts the harmful from the harmless mutations, giving doctors a directory to interpret patients' DNA sequences.

The information could also help researchers develop therapies to prevent or treat heart disease caused by titin mutations.

The study was led by researchers at Imperial College London and Royal Brompton & Harefield NHS Foundation Trust.

Around one in 250 people are estimated to have DCM. It causes the heart muscle to become thin and weak, often leading to heart failure.

Mutations in the titin gene that make the protein shorter, or truncated, are the most common cause of DCM, accounting for about a quarter of cases. But truncations in the gene are common - around one in 50 people have one - and most are not harmful, making it difficult to develop a useful genetic test.

The researchers sequenced the titin gene from 5,267 people, including healthy volunteers and patients with DCM, and analysed the levels of titin in samples of heart tissue. The results showed that mutations that cause DCM occur at the far end of the gene sequence. Mutations in healthy individuals tend to occur in parts of the gene that aren't included in the final protein, allowing titin to remain functional.

Professor Stuart Cook, from the Medical Research Council (MRC) Clinical Sciences Centre at Imperial College London, who led the study, said: "These results give us a detailed understanding of the molecular basis for dilated cardiomyopathy. We can use this information to screen patients' relatives to identify those at risk of developing the disease, and help them to manage their condition early."

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'Titin' gene mutations will help identify patients at risk of heart failure

Scientists are unraveling a mystery behind a fairly common disease that leads to heart failure: Why do some people with a key mutated gene fall ill while others stay healthy?

Researchers tested more than 5,200 people to tease apart when mutations really are harmful or are just bystanders. The work could help in screening families prone to heart failure but also has broader implications as more people undergo genetic tests that can turn up unnecessarily worrying results.

Heart failure, when the heart cannot pump blood properly, is caused by a variety of conditions, including damage from heart attacks. But one trigger is dilated cardiomyopathy, a condition that makes the heart's muscle walls stretch out of shape, becoming progressively weaker. It can run in families, but often there's no obvious cause.

Titin is a protein that gives muscle tissue, including heart muscle, its elasticity. In 2012, researchers reported that gene mutations that make that protein shorter, or truncated, were a common cause of dilated cardiomyopathy, accounting for a quarter of cases. The problem: A lot of healthy people also harbor mutations in that stretchy muscle protein, yet some gene tests already look for the glitches.

So a British-led research team mapped the titin-producing gene in 5,267 people, ranging from the healthy to the seriously ill. Where the DNA glitches are located in this huge gene is key, the team reported Wednesday in the journal Science Translational Medicine.

Mutations that caused dilated cardiomyopathy are located at one end of the gene sequence, while mutations in healthy people occur in other spots apparently less important for heart muscle, they reported.

Another discovery: Titin-caused cardiomyopathy is more severe than other forms of the disease, said lead researcher Angharad Roberts of Imperial College London. Those patients are more likely to suffer life-threatening irregular heartbeats, suggesting doctors might use genetic testing to guide therapy including when to implant defibrillators.

Somehow, this truncated protein is poisoning heart muscle cells, the researchers concluded.

When cardiomyopathy runs in the family, close relatives get regular heart screening to see whether they're developing it, too. The researchers said finding which kind of mutation family members harbor could help narrow who's really at risk but it would take more in-depth genetic testing than is routine today.

"In an era where genetic testing and genome sequencing is increasingly available, more and more titin mutations will be identified, often as incidental findings," Roberts said. "Accurate interpretation of these results is vital to avoid unnecessary follow-up and anxiety."

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Scientists Tease out Genes That Signal Risk of Heart Failure

Discovery paves way for new approaches for population with highest incidence and mortality rates from this kind of cancer

Case Comprehensive Cancer Center researchers have identified new gene mutations unique to colon cancers in African Americans - the population with the highest incidence and death rates of any group for this disease.

This discovery - namely, that colorectal cancers appear different on a molecular level in African Americans - offers new hope for these patients. With this groundbreaking knowledge, scientists now will seek to develop treatments that target the distinct nature of the disease in African Americans - and, they hope, begin to reduce the devastation disproportionately wrought on this population.

The findings, published in the Jan. 12 edition of PNAS (Proceedings of the National Academy of Sciences), only became possible because of technological advances in gene sequencing and computational analysis. The study that revealed this invaluable information ultimately involved review of 1.5 billion bits of data.

"This milestone study builds on our previous genetic research on colorectal cancer," said Sanford Markowitz, MD, PhD, corresponding author on the study, and principal investigator of the $11.3 million federal gastrointestinal cancers research program (GI SPORE) that includes this project. "It illustrates the extraordinary impact that dedicated, collaborative teams can make when they combine scientific experience and ingenuity with significant investment."

Announced in 2011, this GI SPORE program is one of just five in the country. Markowitz, Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine and a medical oncologist at University Hospitals Case Medical Center, included studies of the disease's behavior in minority patients as part of his team's original grant application. The disparity between colorectal cancer rates in African Americans and other groups has long existed; the most recent federal statistics, for example, put age-adjusted incidence at 46.8 cases for every 100,000 African Americans, and 38.1 cases for every 100,000 Caucasian Americans. Yet scientists have struggled to determine what factors - biological, economic, environmental, or others - account for this disparity.

"These advancements underscore the importance of university-based research," said Congresswoman Marcia L. Fudge, former chair of the Congressional Black Caucus and representative of the 11th district, which includes Case Western Reserve and UH Case Medical Center. "I am proud that researchers from Northeast Ohio are taking meaningful steps toward identifying pathways to block a devastating disease that disproportionately affects members of the African American community."

From the very start, Markowitz and his colleagues believed the answer to this question would be found through genetic analysis.

"Identifying gene mutations has been the basis of all the new drugs that have been developed to treat cancer in the last decade," Markowitz said. "Many of the new cancer drugs on the market today were developed to target specific genes in which mutations were discovered to cause specific cancers."

One of the lead researchers on the project was senior author Joseph E. Willis, MD, associate professor of pathology, Case Western Reserve School of Medicine, director of tissue management, Case Comprehensive Cancer Center, and Vice Chair of Pathology for Clinical Affairs at UH Case Medical Center.

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Researchers identify new gene mutations linked to colorectal cancer in African-Americans

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Newswise Case Comprehensive Cancer Center researchers have identified new gene mutations unique to colon cancers in African Americans the population with the highest incidence and death rates of any group for this disease.

This discovery namely, that colorectal cancers appear different on a molecular level in African Americans offers new hope for these patients. With this groundbreaking knowledge, scientists now will seek to develop treatments that target the distinct nature of the disease in African Americans and, they hope, begin to reduce the devastation disproportionately wrought on this population.

The findings, published in the Jan. 12 edition of PNAS (Proceedings of the National Academy of Sciences), only became possible because of technological advances in gene sequencing and computational analysis. The study that revealed this invaluable information ultimately involved review of 1.5 billion bits of data.

This milestone study builds on our previous genetic research on colorectal cancer, said Sanford Markowitz, MD, PhD, corresponding author on the study, and principal investigator of the $11.3 million federal gastrointestinal cancers research program (GI SPORE) that includes this project. It illustrates the extraordinary impact that dedicated, collaborative teams can make when they combine scientific experience and ingenuity with significant investment.

Announced in 2011, this GI SPORE program is one of just five in the country. Markowitz, Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine and a medical oncologist at University Hospitals Case Medical Center, included studies of the diseases behavior in minority patients as part of his teams original grant application. The disparity between colorectal cancer rates in African Americans and other groups has long existed; the most recent federal statistics, for example, put age-adjusted incidence at 46.8 cases for every 100,000 African Americans, and 38.1 cases for every 100,000 Caucasian Americans. Yet scientists have struggled to determine what factors biological, economic, environmental, or others account for this disparity.

These advancements underscore the importance of university-based research, said Congresswoman Marcia L. Fudge, former chair of the Congressional Black Caucus and representative of the 11th district, which includes Case Western Reserve and UH Case Medical Center. I am proud that researchers from Northeast Ohio are taking meaningful steps toward identifying pathways to block a devastating disease that disproportionately affects members of the African American community.

From the very start, Markowitz and his colleagues believed the answer to this question would be found through genetic analysis.

Identifying gene mutations has been the basis of all the new drugs that have been developed to treat cancer in the last decade, Markowitz said. Many of the new cancer drugs on the market today were developed to target specific genes in which mutations were discovered to cause specific cancers.

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Researchers Identify New Gene Mutations Linked to Colorectal Cancer in African American Patients

A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression.

The research, which was done in human cells and in mice, provides new routes to explore targeted treatments for this aggressive tumour type.

There are many types of breast cancers that respond differently to treatments and have different prognoses. Approximately one in five patients is affected by triple-negative breast cancer; these cancers lack three receptor proteins that respond to hormone therapies used for other subtypes of breast cancer. In recent years it has become apparent that the majority of triple-negative tumours are of the basal-like subtype.

Although new treatments are being explored, the prognosis for triple-negative cancer is poorer than for other types. To date, only a handful of genomic aberrations in genes have been associated with the development of triple-negative breast cancer.

The team looked at breast cancers from almost 3000 patients. Their search had a particular focus: they examined changes to genes that affect the behaviour of stem cells and developing tissues, because other work they have done suggests that such genes, when mutated, can often drive cancer development. Among these was BCL11A.

"Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong," says Dr Pentao Liu, senior author on the study, from the Wellcome Trust Sanger Institute. "BCL11A activity stood out because it is so active in triple-negative cancers.

"It had all the hallmarks of a novel breast cancer gene."

Higher activity of the BCL11A gene was found in approximately eight out of ten patients with basal-like breast cancer and was associated with a more advanced grade of tumour. In cases where additional copies of the BCL11A gene were created in the cancer, the prospects for survival of the patient were diminished.

"Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers," says Dr Walid Khaled, joint first author on the study from the Wellcome Trust Sanger Institute and University of Cambridge. "We also showed that adding an active human BCL11A gene to human or mouse breast cells in the lab drove them to behave as cancer cells.

"As important, when we reduced the activity of BCL11A in three samples of human triple-negative breast cancer cells, they lost some characteristics of cancer cells and became less tumorigenic when tested in mice. So by increasing BCL11A activity we increase cancer-like behaviour; by reducing it, we reduce cancer-like behaviour."

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Novel breast cancer gene found: BCL11A is active in difficult-to-treat triple-negative breast cancer

A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression.

The research, which was done in human cells and in mice, provides new routes to explore targeted treatments for this aggressive tumour type.

There are many types of breast cancers that respond differently to treatments and have different prognoses. Approximately one in five patients is affected by triple-negative breast cancer; these cancers lack three receptor proteins that respond to hormone therapies used for other subtypes of breast cancer. In recent years it has become apparent that the majority of triple-negative tumours are of the basal-like subtype.

Although new treatments are being explored, the prognosis for triple-negative cancer is poorer than for other types. To date, only a handful of genomic aberrations in genes have been associated with the development of triple-negative breast cancer.

The team looked at breast cancers from almost 3000 patients. Their search had a particular focus: they examined changes to genes that affect the behaviour of stem cells and developing tissues, because other work they have done suggests that such genes, when mutated, can often drive cancer development. Among these was BCL11A.

"Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong," says Dr Pentao Liu, senior author on the study, from the Wellcome Trust Sanger Institute. "BCL11A activity stood out because it is so active in triple-negative cancers.

"It had all the hallmarks of a novel breast cancer gene."

Higher activity of the BCL11A gene was found in approximately eight out of ten patients with basal-like breast cancer and was associated with a more advanced grade of tumour. In cases where additional copies of the BCL11A gene were created in the cancer, the prospects for survival of the patient were diminished.

"Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers," says Dr Walid Khaled, joint first author on the study from the Wellcome Trust Sanger Institute and University of Cambridge. "We also showed that adding an active human BCL11A gene to human or mouse breast cells in the lab drove them to behave as cancer cells.

"As important, when we reduced the activity of BCL11A in three samples of human triple-negative breast cancer cells, they lost some characteristics of cancer cells and became less tumorigenic when tested in mice. So by increasing BCL11A activity we increase cancer-like behaviour; by reducing it, we reduce cancer-like behaviour."

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Novel breast cancer gene found

Story highlights Roughly two-thirds of cancers in adults can be attributed to random mutations, study says "The remaining third are due to environmental factors and inherited genes" Behaviors (e.g. smoking, excessive sun exposure) still strongly tied to some cancers

That's bad luck -- and it's the primary cause of most cancer cases, says a Johns Hopkins Medicine research study.

Roughly two-thirds of cancers in adults can be attributed to random mutations in genes capable of driving cancer growth, said two scientists who ran statistics on cancer cases.

That may sound jaw-dropping. And Johns Hopkins anticipates that the study will change the way people think about cancer risk factors.

They also believe it could lead to changes in the funding of cancer studies, with a greater focus on finding ways to detect those cancers attributed to random mutations in genes at early, curable stages.

Smoking can still kill you

But, no, that's not permission to smoke or to not use sunblock.

Some forms of cancer are exceptions, where lifestyle and environment play a big role. Lung cancer is one of them. So is skin cancer.

And, if cancer runs in your family, this unfortunately doesn't mean you're in the clear. Some cancers are more strongly influenced by genetic heritage than others.

"The remaining third (of cancer cases) are due to environmental factors and inherited genes," the Kimmel Cancer Center said in a statement on the study published Friday in the magazine Science.

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Gene mutations cause most cancers