Researchers find new muscle repair gene



An international team of researchers from England and the Charité – Universitätsmedizin Berlin has presented new findings regarding the function of muscle stem cells, which are published in the journal Nature Genetics. The researchers investigated several families with children suffering from a progressive muscle disease. Using a genetic analysis technique known as “next generation sequencing” the scientists identified a defective gene called MEGF10 responsible for the muscle weakness.

The children suffer from severe weakness of the body musculature and of the inner organs like the diaphragm, the main breathing muscle. The consequences are that the little patients are only able to move in a wheelchair and need continuous artificial respiration. These children often have to be tube-fed as well since the musculature of the oesophagus does not work properly.

But which role plays the discovered gene here and is involved in muscle growth? In healthy humans the muscle stem cells, so called “satellite cells” stick on muscle fibres and normally remain inactive. If a muscle fibre becomes damaged or muscle growth is stimulated, as it is in muscle training, the satellite cells start to divide, fuse with the muscle fibre and so cause muscle growth.

This process is disrupted in the ill children. For them, the necessary protein which is responsible for the attachment of the satellite cells cannot be developed by the mutated MEGF10 gene. Therefore, these cells cannot stick on the muscle fibre – the muscle cannot be repaired any longer.

Prof Markus Schuelke from the NeuroCure Clinical Research Center of the Cluster of Excellence NeuroCure and the Department of Neuropediatrics of the Charité and Prof Colin A. Johnson from the Institute of Molecular Medicine of the University Leeds, who jointly directed this research project have emphasised the importance of these new methods for genome analysis and give a positive outlook for the future.

“This is good news for families with unexplained rare genetic disorders. These methods enable us to sequence hundreds or even thousands of genes at the same time and discover novel genetic defects even in single patients quickly but also cost effective,” explains Schuelke. “Many patients and their families often have been through a diagnostic Odyssey and can now hope that the cause of their disease will be found through this approach.” doi:10.1038/ng.995



Scientists find 16 new sections of genetic code associated with lung function

Scientists have discovered 16 new sections of the genetic code associated with lung function.

Published in the journal Nature Genetics, the study brought together 175 scientists across 126 research centres around the world. The discovery of these new genetic variants associated with the health of the human lung could shed more light on the molecular basis of lung diseases like Chronic Obstructive Pulmonary Disease (COPD) and in turn lead to better prevention strategies and new types of treatment.

COPD is a progressive disease that makes it hard for people to breathe and it affects around 1 in 10 adults over 40 and is the fourth most common cause of death worldwide. Although smoking is the biggest cause of COPD, not all smokers are equally likely to develop COPD and differences in susceptibility occur due to the genetic variants people carry.

One of the study authors, Professor Martin Tobin from the University of Leicester, comments on the study’s implications for COPD detection: “For the first time we understand what so many of these genetic variants are, including the underlying mechanisms that they point to. We now need to prioritise research to better understand these disease mechanisms and inform improved patient care. These discoveries could provide the key to new therapies for lung diseases such as COPD. It is too early to say whether this information would be of use as a screening test to predict the development of COPD. Stopping smoking is the best way to prevent COPD.”

The study involved an analysis of 2.5 million genetic variants in 48,201 people from around the world. The team then honed in on their work by focusing on a smaller number of the most promising genetic variants in a further 46,411 individuals. This new discovery builds on previous work published last year where the international team announced the discovery of 10 new genetic variants associated with lung function.

Another study author, Professor Ian Hall, says: “This work is important because until recently we have not understood the factors which underlie inherited variability in lung function. The very large genetic studies required to identify key genes would not have been possible without the support of many groups around the world and the input of thousands of subjects. We now need to take the knowledge gained from this study to do two things: firstly to learn more about the function of genes which contribute to the risk of developing lung diseases such as COPD, and secondly to try and develop strategies to use genetic information to improve the clinical care provided to individual patients.” doi:10.1038/ng.941



Tiny genetic variation predicts chances of survival to treatment for ovarian cancer patients

Researchers Yale Cancer Center in the US have shown that a tiny genetic variation predicts chances of survival and response to treatment for patients with ovarian cancer.

The findings, published in the journal Oncogene, provide new insights into the biology of a new class of cancer marker and suggest a genetic test may help guide the treatment of women with ovarian cancer.

“This gives us a way to identify which women are at highest risk for resistance to platinum chemotherapy, the standard treatment for ovarian cancer, and helps identify ovarian cancer patients with the worst outcomes,” said Joanne Weidhaas, associate professor of therapeutic radiology and senior author of the study. “There just aren’t many inherited gene variants than can do that.” Women who possess the biomarker identified by the Yale team – a variant of the well-known KRAS oncogene – are three times more resistant to standard platinum chemotherapy than women without the variant.

Also, post-menopausal women with the variant are significantly more likely to die from ovarian cancer.

About 12-15% of Caucasians and 6% of African-Americans are born with the variant of the gene, which helps regulate destruction of damaged cells. This variant is found in up to 25% of newly diagnosed ovarian cancer patients. Although good alternatives to chemotherapy are not yet available for women with ovarian cancer and this variant, several drugs in development which target the KRAS gene and associated pathways have shown great promise, Weidhaas said.

Weidhaas is a co-founder of a company that has licensed intellectual property from Yale that has developed a diagnostic test based on the KRAS-variant. The biomarker intrigues scientists because it is a functional variant in an area of DNA that does not code for proteins. Instead this variant disrupts how a microRNA controls gene expression.

“This is a new paradigm,” Weidhaas said. Yale researchers have also found this microRNA variant of the KRAS gene is associated with an increased risk of developing breast cancer and lung cancer. Other researchers have found associations with poor outcome in colon as well as head and neck cancers.

In laboratory tests, researchers blocked the variant and significantly reduced growth of ovarian cancer cells. This suggests targeting the variant site may someday help treat cancer in these patients.



Study finds a genetic factor that regulates how long we sleep

A collaborative European study led by LMU researchers has shown that ABCC9, a known genetic factor in heart disease and diabetes, also influences the duration of sleep in humans. This function is evolutionarily conserved as knock-out of the gene reduces the duration of nocturnal sleep in fruitflies

Legend has it that Napoleon never needed more than four hours of sleep at a stretch. Others only feel fully rested after 10 hours between the sheets. Clearly, individuals vary with respect to how much sleep they need. Indeed, sleep duration is influenced by many factors. Apart from seasonal and other variables, age and sex play a role, as does one’s sleep-wake cycle or chronotype, i.e. whether one is a lark (early to bed, early to rise) or the converse, an owl. An international team of researchers led by LMU chronobiologists Professor Till Roenneberg and Dr Karla Allebrandt has now identified the first genetic variant that has a significant effect on sleep duration and is found frequently in the general population. The variant was discovered in the course of a so-called genome-wide association study, in which the researchers scanned individual genomes for variations that were correlated with sleep patterns.

More than 4,000 people from seven European populations, from countries as diverse as Estonia and Italy, took part in the project, and filled out a questionnaire designed to assess their sleeping habits. Analysis of the genetic and behavioural data revealed that individuals who had two copies of one common variant of the gene ABCC9 generally slept for a significantly shorter period in an undisturbed environment than did persons with two copies of the other version. The gene ABCC9 codes for the protein SUR2, which forms the regulatory component of a potassium channel in the cell membrane. This ion channel acts a sensor of energy metabolism in the cell.

“It is particularly intriguing that functional studies have shown that the protein plays a role in the pathogenesis of heart disease and diabetes,” says Dr Allebrandt, first author on the new study and a chronogeneticist at LMU Munich. “So apparently the relationships of sleep duration with metabolic syndrome symptoms can be in part explained by an underlying common molecular mechanism.”

The ABCC9 gene is evolutionarily ancient, as a similar gene is present in fruitflies. Fruitflies also exhibit sleep-like behaviour. In collaboration with scientists from the Leicester University, the team blocked the function of the ABCC9 homolog in the fly nervous system, the duration of nocturnal sleep was shortened. In mammals, the gene is active in various tissues, including the heart, the skeletal muscles and the brain, as well as in parts of the pancreas.

“It is very encouraging for us that ABCC9 also affects the nocturnal sleep period in flies,” says Roenneberg. “This tells us that the genetic control of sleep duration may well be based on similar mechanisms in a wide range of highly diverse species.” doi:10.1038/mp.2011.142



Stem cells in breast milk can turn into all three embryonic germ layers

Stem cells isolated from breast milk have been shown to be able to turn in all three embryonic germ layers and may be the answer to easily obtaining pluripotent stem cells in a non-invasive manner. Peter Hartmann at the University of Western Australia in Crawley and his colleagues first announced the discovery of stem cells in breast milk in 2008. Now they have grown them in the lab and shown that they can turn into cells representative of all three embryonic germ layers.


Foteini Hassiotou, a member of Hartmann's lab team, who led the recent work, said that they can become bone cells, joint cells, fat cells, pancreatic cells that produce their own insulin, liver cells that produce albumin and also neuronal cells. Hassiotou, a PHD student at the university, won the 2011 AusBiotech-GSK Student Excellence Award for her research into breast milk stem cells. She plans to announce her findings at the 7th International Breastfeeding and Lactation Symposium in Vienna in April.

She said it is “becoming clear that breast milk can serve as an ethical, non-invasive and plentiful source for human stem cells - but a lot of questions still remain unanswered, especially about the function of these cells in the breastfed baby”.



Scientists show how telomerase controls integrity of genetic code

Researchers have revealed how a molecule called telomerase contributes to the control of the integrity of our genetic code, and when it is involved in the deregulation of the code, its important role in the development of cancer. The University of Montreal scientists involved explain how they were able to achieve their discovery by using cutting edge microscopy techniques to visualise telomerase molecules in real time in living cells in Molecular Cell on 9 December 2011.

“Each time our cells divide, they need to completely copy the genomic DNA that encodes our genes, but the genome gets shorter each time until the cell stops dividing,” said Dr Pascal Chartrand, a biochemistry professor at the University of Montreal and a senior author of the study. “However, the telomerase molecules can add bits of DNA called telomeres to the ends of our genome. Telomeres prevent the genome from deteriorating or joining up with other pieces of DNA, allowing cells to divide indefinitely and become cancerous. Normally, the telomerase gene is not active, but how it is controlled is poorly understood. One difficulty has been that we need to see exactly what individual telomerase molecules are doing on our genome and when.” Franck Gallardo, the study’s lead author, added that the team was able to apply techniques from other work that the team was doing in their lab. “We could in fact visualise what individual telomerases were doing in cells,” he said.

In collaboration with Nancy Laterreur and Dr Raymund Wellinger of the Université de Sherbrooke, Dr Gallardo was able to tag telomerase with fluorescent proteins, which allowed them to visualise telomerase in single living cells. With this technological breakthrough, they observed that, contrary to previous theories, several molecules of telomerase cluster on only a few telomeres, and elongate the telomeres at each cell cycle. Moreover, they identified regulatory factors that restrain the activity of telomerase within a narrow time window when the cell is dividing. This new technology opens up the possibility of studying the activity of a key factor in the development of cancer at the molecular level within its cellular environment. doi:10.1016/j.molcel. 2011.09.020



New reprogramming mechanism for tumour cells discovered

A study by researchers Raúl Méndez, ICREA Research Professor at the Institute for Research in Biomedicine (IRB Barcelona) and Pilar Navarro at the IMIM (Institut de Recerca Hospital del Mar, Barcelona) describes a new reprogramming mechanism for the expression of genes responsible for turning a healthy cell into a tumour cell. In the study, published in Nature Medicine, the scientists have identified the protein CPEB4 as a “cellular orchestra conductor” that “activates” hundreds of genes associated with tumour growth.

             

“The peculiarity is that it would not only be the mutation of a specific gene that promotes tumour growth but the expression of a protein in an incorrect site that “triggers” hundreds of messenger molecules (mRNAs), which transmit gene information for the synthesis of proteins, without these genes being mutated. This process leads to the expression of many “normal” genes but in unsuitable amounts and times that more greatly resemble early embryonic developmental stages rather than the stages of adult organ development”, explains Raúl Méndez, an expert in the CPEB protein family. “This would be the case of tPA (tissue plasminogen activator), a protein that is not normally found in the healthy pancreas but that shows high expression in pancreatic tumours,” clarifies Elena Ortiz-Zapater, the first author of the article, and Pilar Navarro.

One of the conclusions highlighted in the study is that in the tissues examined, pancreas and brain, CPEB4 is not detected in healthy cells but only in tumour ones. Thus inhibition of this protein would provide a highly specific anti-tumour treatment and with few adverse effects, “one of the main drawbacks of many cancer therapies”, says Pilar Navarro, a researcher specialised in pancreatic cancer.

Using experiments involving human cancer cells in mice, these researchers have demonstrated that the decrease in CPEB4 levels in cancer cells reduces the size of tumours by up to 80%. Although the study is limited to two kinds of tumour, according to the co-authors, “given the effects observed in the tumours examined and the type of genes regulated by this mechanism, it is expected to be involved in many other types of cancer”.

This study opens up avenues for new treatments for cancer, for which the researchers are designing and analysing CPEB4 inhibitors of potential therapeutic interest. “The clinical applications are very promising, although intensive research is needed to identify inhibitory molecules and to test them in various models before determining their clinical potential and, in this case, their use in patients,” warn Navarro and Méndez. doi:10.1038/nm.2540



 

                                   
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