Schizophrenia - Single Genetic Changes In Two Genes Raise Risk

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Main Category: Schizophrenia
Also Included In: Psychology / Psychiatry;  Genetics
Article Date: 15 Dec 2011 - 8:00 PST

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According to a study by Johns Hopkins investigators published in the Nov. 16 issue of Neuron, the risk of developing schizophrenia may be increased by carrying single DNA letter changes from two different genes.

Researchers have found identifying the causes for psychiatric diseases like autism and schizophrenia difficult as they might be activated by several small genetic alterations. Individually these small genetic alterations may be insufficient to cause any change, but in the right combination may cause psychiatric disease.

Schizophrenia, as well as other major mental disorders, is known to be caused by extreme DNA alterations in the genetic letters of the DISC1 gene. These drastic alterations are rare and do not apply to most of individuals with schizophrenia. DISC1 is considered a starting point for investigating the cause of schizophrenia. Defects in DISC1 together with defects in other genes might contribute to disease.

Guo-li Ming, M.D., Ph.D., professor of neurology and neuroscience and member of the Johns Hopkins Institute for Cell Engineering, explained:

"We studied the function of two proteins known to interact, FEZ1 and DISC1, in cells and animal models, which suggested that these proteins work together in adult brain development. When we looked at the human genetic sequences of DISC1 and FEZ1, we found that a combination of small DNA changes raises risk for schizophrenia."

The team used molecular biology methods to lower the amount of FEZ1 in the new neurons in the adult mouse hippocampus, the researchers then analyzed the cells under a microscope in order to find out if DISC1 and FEZ1 collaborate in adult brain development. The neurons with less FEZ1 were bigger and had longer feelers and looked similar to cells with less DISC1. Neurons use feelers to find and communicate with other nearby neurons. According to the investigators these proteins may be collaborating in neurons in order to control feeler length and cell size. Disruption of this process may cause psychiatric diseases.

In order to see if combinations of single-letter DNA alterations in FEZ1 and DISC1 made individuals more susceptible to schizophrenia, the researchers examined existing cases of the disease and analyzed a large patient database, the Genetic Association Information Network, produced by the National Institutes of Health to identify genome associated diseases. They used statistical methods to analyze 4 different single-letter DNA alterations in the FEZ1 sequence from 1,378 healthy individuals and 1,351 individuals with schizophrenia.

Individually, single-letter DNA alterations in FEZ1 did not contribute to the risk of developing the disease. Although, when they examined these 4 different FEZ1 DNA letter alterations together with a DISC1 single DNA letter alteration already known to slightly increase the risk of schizophrenia, they discovered that one particular FEZ1 DNA alteration combined with the DISC1 alteration dramatically increased the risk of developing the disease by two and half times.

Hongjun Song, Ph.D., professor of neurology and director of the Stem Cell Program at the Institute for Cell Engineering, explained:

"By continuing to examine interactions of key genes involved with disease in cells and correlating the results with patient databases, we can begin to unravel the genetic contributions of psychiatric disorders that previously were a mystery to us,Finding sets of proteins, like FEZ1 and DISC1, that synergistically work together to cause disease will also give us new drug targets to develop new therapies."

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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Scientists Capture Single Cancer Molecules At Work

Main Category: Cancer / Oncology
Article Date: 12 Dec 2011 - 0:00 PST

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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 visualize telomerase molecules in real time in living cells in Molecular Cell on December 9, 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 visualize 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 visualize 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.

Professor Chartrand's research is supported by Canadian Institutes of Health Research (www.cihr-irsc.gc.ca) and by the Fonds de la recherche en Santé du Québec (www.frsq.gouv.qc.ca).

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. The study, "Live cell imaging of telomerase RNA dynamics reveals cell cycle-dependent clustering of telomerase at elongating telomeres", published in Molecular Cell, was authored by Franck Gallardo, Nancy Laterreur, Emilio Cusanelli, Faissal Ouenzar, Emmanuelle Querido, Raymund J Wellinger and Pascal Chartrand.

Dr. Chartrand's research

University of Montreal

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New Columbia Engineering Technique Diagnoses Non-Periodic Arrhythmias In A Single Heartbeat

Main Category: Medical Devices / Diagnostics
Also Included In: Cardiovascular / Cardiology
Article Date: 12 Dec 2011 - 0:00 PST

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Thanks to a new study from Columbia Engineering School, doctors may now be able to diagnose in their offices non-periodic arrhythmias - noninvasively and at low cost - within a single heartbeat. Non-periodic arrhythmias include atrial and ventricular fibrillation, which are associated with severely abnormal heart rhythm that can in some cases be life-threatening. Using Electromechanical Wave Imaging (EWI), a technique recently developed at Columbia Engineering, the researchers sent unfocused ultrasound waves through the closed chest and into the heart. They were able to capture fast-frame-rate images that enabled them - for the first time - to map transient events such as the electromechanical activation that occurs over a few tens of milliseconds while also imaging the entire heart within a single beat. The Columbia Engineering study was recently published in IOPscience.

"We are very excited about extending the capabilities of our new technique," says Elisa Konofagou, an associate professor of biomedical engineering and radiology at Columbia University's Fu Foundation School of Engineering and Applied Science. "With EWI, doctors now won't have to use electrodes to detect and localize those unpredictable and potentially deadly arrhythmias and they'll be able to do this at the point of care, not only in a dedicated, interventional procedure room."

She adds that, "For the first time, EWI can be implemented without relying on multiple periodic heartbeats for the high temporal resolution imaging required. A single heartbeat, whether periodic or not, will suffice by employing tailored beamforming sequences and signal processing techniques."

Konofagou explains that the heart is essentially an electromagnetic pump that must first be electrically activated in a specific sequence to contract and relax efficiently. Abnormalities in cardiac conduction are a major cause of death and disability around the world and their prevalence is expected to rise with the aging of the population. The number of people in the U.S. with atrial fibrillation (AF), the most common arrhythmia, is expected to reach 12 million by 2050. AF causes 15 to 20 percent of strokes and costs $6.65 billion a year to treat.

EWI is a novel ultrasound-based technique that Konofagou and her team developed earlier this year to map electromechanical waves, the transient deformations occurring in immediate response to the electrical application. They were able to map these waves by reconstructing images over multiple cardiac cycles but this method did not allow them to image non-periodic arrhythmia such as fibrillation. In the new study, the researchers developed and applied new imaging sequences based on flash- and wide-beam emissions to image the entire heart at very high-frame rates (2000 fps) during free breathing in a single heartbeat.

"Potential applications of this technique include early, reliable, and electrode-free detection and diagnosis of arrhythmias and localization of arrhythmic origins to guide subsequent ablations," notes Konofagou. "For example, atrial flutter is a condition of arrhythmic activation of the atria. Physicians have to perform radio-frequency ablation to reinstate its function but often they don't know if it's the right or the left atrium. So, they start ablating the entire right atrium only to find out that the left atrium was causing the flutter, administering unnecessary treatment in the process. By pushing the current capabilities of our technology further, we can help doctors make more noninvasive diagnoses and treat the patient more efficiently."

Konofagou's study was funded by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Hemophilia B - Single Gene Therapy Treatment Offers Significant Improvement

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Academic Journal
Main Category: Blood / Hematology
Article Date: 10 Dec 2011 - 12:00 PST

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Patients with hemophilia B experienced considerable improvements and fewer injections with clotting factor to reduce bleeding after receiving just one treatment with gene therapy, researchers from St. Jude Children's Research Hospital, Memphis, USA, and University College London (UCL), England, reported in NEJM (New England Journal of Medicine).

The small Phase I study, involving just six patients, is still proof that gene therapy is a promising treatment for the disabling and potentially dangerous consequences of painful bleeding episodes experienced by patients with hemophilia B - an inherited blood disorder.

The authors say their study will be presented in San Diego, USA, on 11th December, 2011, at the 53rd annual meeting of the American Society of Hematology.

Four out of the six participants who received gene therapy no longer require further protein injections to prevent episodes of bleeding - none of those four have suffered bouts of spontaneous bleeding either. Some of them have gone on to take part in marathon running events and other activities which would have been extremely hard to do without the gene therapy.

All the patients were treated under the care of Prof. Edward Tuddenham at the Royal Free Hospital, London. Co-author Tuddenham is a pioneer in the field of blood coagulation.

First author Dr Amit Nathwani, said:

"This is a potentially life-changing treatment for patients with this disease and an important milestone for the field of gene therapy. It could have ramifications for the treatment of haemophilia A, other protein and liver disorders and chronic diseases such as cystic fibrosis."

Hemophilia B (British spelling: haemophilia B) is a blood clotting disorder, as are all types of hemophilia. In this case it is caused by a mutation in the gene that makes Factor IX, an essential protein in the blood clotting process. It is the second most common form of hemophilia, after hemophilia A.

Hemophilia B is sometimes called Christmas disease, after Sephen Christmas, the first patient to be described with the condition. The disorder was also first published in the Christmas edition of the BMJ (British Medical Journal).

Nearly all patients with hemophilia B are male, because the mutated gene is carried on the X chromosome. The authors explain that it is a relatively rare condition, affecting approximately 1 in every 30,000 people.

Previous attempts at reducing the symptoms of hemophilia B by placing a correct copy of the gene have never been successful.

Prof. Tuddenham, Dr. Nathwani and team used AAV (adeno-associated virus) 8 to deliver the correct Factor IX gene, plus other genetic material into the liver of the patient. As the rate of natural infection with AAV8 is very low, it was picked up. AAV8 is part of a virus family that targets cells in the liver without causing illness in humans; neither does the virus integrate into human DNA.

No immunosuppressant medications were administered to the participants before the gene therapy was given; an approach pioneered jointly by scientists from St. Jude and UCL.

A one-off infusion of the vector was administered into the vein in the arm of each patient. Two patients each received gradually rising doses of the vector. Afterwards, levels of Factor IX were elevated in all participants - from between 2% and 12% compared to less than 1% before the gene therapy began.

There was a correlation between dosages of the experimental vector and Factor IX levels - two volunteers, who were given the highest dosages, had the highest Factor IX levels. Their levels rose to up to 12%. The authors explained that any gain above 1% of normal levels can significantly improve patients' quality of life and reduce the number and severity of bleeding episodes.

Trial participant Sebastian Misztal (Source: UCLH/UCL NIHR Biomedical Research Centre)

Senior author, Dr Andrew Davidoff, said:

"The first patient has been followed for the longest time, and his levels have remained at 2% for more than 18 months. These results are highly encouraging and support continued research. More patients are scheduled to be enrolled in future trials scheduled to begin later this year."

The participant with the higher dosage had to undergo short-term steroid treatment, which was effective. His liver enzyme levels had risen slightly - a sign of mild liver damage - after receiving the vector infusion. His levels of Factor IX remain above what they were before gene therapy was applied, and his liver enzyme levels are back to normal. The other participant, who received the second highest dosage, also had slightly higher liver enzyme levels, but they did not rise beyond the normal range - he was also given a short course of steroids.

The authors say the rise in enzyme levels was most likely caused by an immune response. Immune responses were reported in previous gene therapy studies when a different vector was used.

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our blood / hematology section for the latest news on this subject. Article - "Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B"
Amit C. Nathwani, M.B., Ch.B., Ph.D., Edward G.D. Tuddenham, M.B., B.S., M.D., Savita Rangarajan, M.B., B.S., Cecilia Rosales, Ph.D., Jenny McIntosh, Ph.D., David C. Linch, M.B., B.Chir., Pratima Chowdary, M.B., B.S., Anne Riddell, B.Sc., Arnulfo Jaquilmac Pie, B.S.N., Chris Harrington, B.S.N., James O'Beirne, M.B., B.S., M.D., Keith Smith, M.Sc., John Pasi, M.D., Bertil Glader, M.D., Ph.D., Pradip Rustagi, M.D., Catherine Y.C. Ng, M.S., Mark A. Kay, M.D., Ph.D., Junfang Zhou, M.D., Yunyu Spence, Ph.D., Christopher L. Morton, B.S., James Allay, Ph.D., John Coleman, M.S., Susan Sleep, Ph.D., John M. Cunningham, M.D., Deokumar Srivastava, Ph.D., Etiena Basner-Tschakarjan, M.D., Federico Mingozzi, Ph.D., Katherine A. High, M.D., John T. Gray, Ph.D., Ulrike M. Reiss, M.D., Arthur W. Nienhuis, M.D., and Andrew M. Davidoff, M.D.
NEJM December 10, 2011 (10.1056/NEJMoa1108046)

Editorial - "Merry Christmas for Patients with Hemophilia B"
Katherine P. Ponder, M.D.
NEJM December 10th, 2011. DOI: 10.1056/NEJMe1111138

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