Practically everyone gets fatter as they get older, but some people can blame their genes for the extra padding. Researchers have shown that two different mutations in a gene called ankyrin-B cause cells to suck up glucose faster than normal, fattening them up and eventually triggering the type of diabetes linked to obesity.

The more severe of the two mutations, called R1788W, is carried by nearly one million Americans. The milder mutation, known as L1622I, is shared by seven percent of the African American population and is about as common as the trait for sickle cell anaemia.

The findings, which were generated in mice, could help identify at-risk individuals who might be able to tip the scales back in their favour by eating better and exercising more.

“This is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle,” said Vann Bennett, M.D., Ph.D., senior author of the study and George Barth Geller Professor of Biochemistry, Cell Biology, and Neurobiology at Duke University School of Medicine. “The obesity epidemic really took off in the 1980’s, when sugary sodas and French fries became popular. It’s not like we suddenly changed genetically in 1980, but rather we have carried susceptibility genes that were exacerbated by this new diet. We think our findings are just the beginning, and that there are going to be many genes like this.’

Bennett, who is also an investigator with the Howard Hughes Medical Institute, discovered ankyrin-B more than thirty years ago. He found that ankyrin-B acts as a kind of protein anchor, tethering important proteins to the inside of the cell’s plasma membrane. Since his initial discovery, Bennett and other researchers have implicated defects in ankyrin-B in a wide variety of human afflictions, including irregular heartbeat, autism, muscular dystrophy, aging, and, more recently, diabetes.

Diabetes is quickly becoming one of the greatest threats to public health, as waistlines expand around the world and here in the United States. If the current trends continue, one in three Americans will have diabetes by 2050. Patients with type 1 diabetes do not make enough insulin, the hormone that helps process the glucose that builds up in the bloodstream after a meal. Patients with type 2 diabetes, the form linked to obesity, make insulin but become resistant to its effects.

Several years ago, the Bennett laboratory found evidence that ankyrin-B mutations might play a role in insulin secretion and metabolism. Since then, several studies have uncovered rare ankyrin-B variants that are associated with type 2 diabetes. One mutation, called R1788W, was more common in Caucasians and Hispanics. Another, called L1622I, was found exclusively in African-Americans, a group known to be at a particularly high risk of diabetes. But it was still unclear how these changes in the genetic code could set a course for diabetes.

To get at that answer, Bennett’s MD/PhD student Jane Healy created mouse models that carried these same human genetic variants. She and her colleagues found that animals with two copies of the R1788W mutation made less insulin than normal mice. Despite this shortcoming, their blood glucose levels were normal. So the researchers performed the rodent equivalent of a glucose tolerance test –- commonly used to screen for type 2 diabetes in people — to determine how quickly glucose was cleared from the bloodstream in the mutant mice. To their surprise, the mutant mice metabolized glucose more quickly than normal mice.

“We thought that the main problem in these mice would be with the beta cells that produced and secreted insulin,’ said Healy, co-author of the study and a former trainee in Bennett’s laboratory. “Instead, our most significant finding lay with the target cells, which took up much more glucose than expected.”

Glucose doesn’t enter cells and tissues all on its own, but instead has to rely on a second molecule, called GLUT4 transporter, to gain access. Normally, GLUT4 hangs out in the cell, like a hostess waiting for party guests to arrive. When insulin is present it acts as a kind of doorbell, alerting GLUT4 to spring into action and open the door to let glucose into the cell. When insulin goes away, the GLUT4 transporters close the door, turn around, and go back into the middle of the cell.

However, postdoctoral fellow Damaris Lorenzo, Ph.D., found that wasn’t the case with the mutant mice. After conducting a number of biochemistry experiments, Lorenzo ddiscovered that the mice had lots of GLUT4 on the surface of their muscle and fat cells even when there wasn’t any insulin around. That meant that glucose could flow in without necessarily having to bother with the doorbell.

This open door policy was an advantage when they were young, because it protected the animals from low insulin levels. But when the mice got older — or switched to a particularly high-fat diet — it made the mice fatter and, eventually, led them to become insulin resistant.

The researchers believe that long ago, the R1788W mutation — and the milder L1622I mutation — may have provided an evolutionary advantage. Aging hunter-gatherer types, who weren’t as effective at chasing down their next meal, needed to gain as much fat as possible to avoid starvation. Now that high-fat, high-calorie foods are plentiful in much of the world, these variants put people at increased risk for modern afflictions like obesity and diabetes. Duke University

Despite modern chemoradiation therapy it is still very difficult to give reliable prognoses for malignant gliomas. Surgical removal of the glioma is still the preferred method of treatment. Doctors at Universitätsklinikum Erlangen’s Department of Neurosurgery have now developed a new procedure for analysing radiological imaging scans which makes it possible to predict the course of a disease relatively precisely.

The Friedlein Grading A/B (FGA/B) classification system – named after the physician Katharina Friedlein – is a quick and precise way of determining whether surgical removal is the best possible treatment method for a given tumour. Essentially, the Erlangen-based doctors classify tumours according to their position in the brain in the context of a routine magnetic resonance imaging (MRI) scan. Tumours that are not located in functional brain regions or that are located at a certain distance from such regions are classified as FGA, while tumours that are close to or inside a functional brain region are classified as FGB.

With the FGA/B method it possible to plan the consequences of tumour surgery, which is crucial for the success of the treatment, in a precise, low-risk and quantitative manner. This makes the Friedlein Grading system the first classification system which can be easily applied in clinical practice. ‘There have already been several attempts in medicine to develop such a classification system. However, most approaches were too complicated and were based on academic values only, which made it difficult to use them in clinical practice,’ says PD Dr. Nicolai Savaskan from FAU’s Chair of Neurosurgery. ‘The FGA/B method can be applied on the basis of a standard MRI scan which glioma patients have to undergo anyway and is highly reliable despite being so simple. We hope that our colleagues in neurosurgery departments in smaller hospitals will also be able to use it successfully in everyday clinical practice.’ Universitätsklinikum Erlangen

A deadly form of T cell lymphoma is caused by an unusually large number gene deletions, making it distinct among cancers, a new Yale School of Medicine study shows.

Researchers conducted a genomic analysis of normal and cancer cells from patients with cutaneous T-cell lymphoma, a cancer of T-cells of the immune system that normally reside in the skin.

Most cancers are driven by point mutations — or single DNA nucleotides that change the function of an encoded protein — rather than deletions that remove a segment of a chromosome. However, in this form of lymphoma, gene deletions that drive cancer pathogenesis outnumbered point mutations by more than 10 to 1.

“This cancer has a very distinctive biology,” said Jaehyuk Choi, assistant professor of dermatology at Yale and lead author of the paper.

Many of the deletions occurred in genes that have been known to play a role in driving the proliferation of T-cells and are potential targets for new therapies, said Choi, a researcher with the Yale Cancer Center.

It is unclear why this cancer has such a high ratio of gene deletions compared to other cancers, said Richard Lifton, Sterling Professor of Genetics, chair of the Department of Genetics, investigator for the Howard Hughes Medical Institute, and senior author of the paper. He noted, however, that during early development DNA rearrangements can produce highly diverse T cell receptors, which enables them to recognize cells bearing viruses or other abnormal proteins. These lymphomas may arise from loss of the normal regulation of these genetic rearrangements, he explained. Yale University

Researchers on Mayo Clinic’s Florida campus have identified key differences between patients with sporadic amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and those with the most common genetic form of ALS, a mutation in the C9orf72 gene.

Their findings  demonstrate that ALS patients show abnormalities in levels and processing of ribonucleic acids (RNA), biological molecules that determine what gene information is used to guide protein synthesis.

More than 30,000 Americans live with ALS, a condition that destroys motor neuron cells that control essential muscle activity, such as speaking, walking, breathing and swallowing. While increasing efforts are geared toward therapeutic development, an effective drug for ALS has yet to be identified, in large part because of our incomplete understanding of the disease.

“Our results using advanced, modern laboratory techniques called next-generation sequencing, allowed us to acquire a library of new knowledge about patients with ALS,” says the study’s senior author, Leonard Petrucelli, Ph.D., chair of the Department of Neuroscience on Mayo Clinic’s Florida campus.

Dr. Petrucelli and Hu Li, Ph.D., assistant professor of pharmacology on Mayo Clinic’s campus in Rochester, Minn., led a team of investigators who carefully analysed the RNA from human brain tissues. They found that ALS brains had numerous RNA defects, compared to non-disease brains. They also predicted molecular events that may be altered due to the changes found in RNAs involved in pathways regulating those events and that may contribute to ALS.

While the researchers observed some commonalities, they also found many distinctions between the RNAs that were altered in sporadic versus C9orf72 mutation-associated cases. This suggests there may be different factors contributing to ALS in patients. The success of future therapies may need specific tailoring to the specific root cause of a patient’s motor neuron disease. Furthermore, the large volume of data obtained from their study, which was deposited into a public genomics data repository, provides a wealth of information available to other researchers to accelerate ALS research. Mayo Clinic

Researchers at the Aortic Institute at Yale have tested the genomes of more than 100 patients with thoracic aortic aneurysms, a potentially lethal condition, and provided genetically personalized care. Their work will also lead to the development of a “dictionary” of genes specific to the disease, according to researchers.

Experts have known for more than a decade that thoracic aortic aneurysms — abnormal enlargements of the aorta in the chest area —run in families and are caused by specific genetic mutations. Until recently, comprehensive testing for these mutations has been both expensive and impractical. To streamline testing, the Aortic Institute collaborated with Dr. Allen Bale of Yale’s Department of Genetics to launch a program to test whole genomes of patients with the condition.

Over a period of three years, the researchers applied a technology known as Whole Exome Sequencing (WES) to more than 100 individuals with these aneurysms. “To our knowledge, it’s the first widespread application of this technology to this disease,” said lead author and cardiac surgeon Dr. John A. Elefteriades, director of the institute.

The researchers detected four mutations known to cause thoracic aortic aneurysms. “The key findings are that this technology can be applied to this disease and it identifies a lot of patients with genetic mutations,” said Elefteriades.

Additionally, the testing program uncovered 22 previously unknown gene variants that likely also contribute to the condition.

Using the test results, the clinicians were able to provide treatment tailored to each patient’s genetic profile. “Personalized aortic aneurysm care is now a reality,” Elefteriades noted. The personalized care ranged from more frequent imaging tests to preventive surgery for those most at risk. “Patients who have very dangerous mutations are getting immediate surgery,” he said.

Given that aneurysm disease is a highly inherited condition, affecting each generation, the researchers offered testing to family members of patients, and found mutations in relatives with no clinical signs of disease.

The researchers anticipate identifying more gene variants over time, accumulating a whole dictionary of mutations. “In a few years, we’re going to have discovered many new genes and be able to offer personalized care to an even greater percentage of aneurysm patients, ” Elefteriades said. Yale University