Huntington’s disease is caused by a mutation in the Huntington’s disease gene, but it has long been a mystery why some people with the exact same mutation get the disease more severely and earlier than others. A closer look at the DNA around the Huntington’s disease (HD) gene offers researchers a new understanding of how the gene is controlled and how this affects the disease. These findings set the stage for new treatments to delay or prevent the onset of this devastating brain disease.

Huntington’s disease is a genetic disorder that gets passed down in families, but symptoms generally don’t appear until later in life. It affects the brain and gradually worsens, causing problems with coordination and movement, mental decline and psychiatric issues. While every person has two copies of each gene – one on each chromosome – a single mutation in one copy of the HD gene means the person will suffer from the disease.

The HD gene is controlled by surrounding regions of DNA that function to turn the gene on and off. Dr. Blair Leavitt, professor in UBC’s Department of Medical Genetics, and his colleagues took a closer look at this part of the genetic code. They identified critical regions where proteins, called transcription factors, can bind to the DNA and control the function of the HD gene. Changes in these DNA regions can play both good and bad roles in the disease. In some cases, the DNA changes increase the severity of the disease and speed up the onset and in other cases it protects the person by delaying the onset of the disease.

“The gene for Huntington’s was discovered over twenty years ago but there is very little known about how the expression of this important gene is controlled,” said Leavitt, who is also a scientist with the Centre for Molecular Medicine and Therapeutics. “This study helps us understand how small genetic differences in the DNA surrounding the HD gene can both delay and accelerate the disease.”

Researchers found that when the DNA change is found on a normal chromosome with no HD mutation, it turns off the expression of the good gene and allows the mutant gene on the other chromosome to predominate, speeding up the onset of the disease. If the DNA change is found on a chromosome with the HD mutation, it turns off the bad gene and offers individuals some protection from the disease.

According to Leavitt, these findings provide critical evidence to support the development of new drugs that decrease the expression of the mutant HD gene, an approach called gene silencing. Leavitt is already involved in the testing of one gene silencing treatment that shows great promise, and will begin the first human trial of this therapy for HD later this year. University of British Columbia

Thoracic aortic aneurysm and dissection (TAAD), an enlargement or tearing of the walls of the aorta in the chest, is, together with abdominal aortic aneurysms, responsible for about 2% of all deaths in Western countries. The aorta is the largest artery in the body, and carries blood from the heart. About one out of every five patients with TAAD has a family member with the same disorder, therefore indicating a genetic cause. However, the relevant genetic mutations discovered so far only explain about 30% of all cases. Through the study of a large family with TAAD features, an international team of genetic researchers have now discovered that a mutation in the TGFB3 gene is also responsible for the condition.

Elisabeth Gillis, MSc, a PhD student in the Centre for Medical Genetics at Antwerp University Hospital, Antwerp, Belgium, explains that she and colleagues from seven other countries are the first to link this particular genetic mutation to serious aortic disorders. This is important, she says, because it means that the TGFB3 gene can be included in diagnostic screening. ‘Armed with this knowledge, we can screen patients with symptoms of TAAD, and also family members without symptoms. Early identification of a risk of aortic aneurysm formation will allow us to implement preventive treatment with medication aimed at slowing down the process of aneurysm and, ultimately, replacement of the aorta before a significant risk of dissection arises’, she will say.

An aortic aneurysm occurs where there is a weakness in the walls of the aorta, creating an outward bulge. Weakness in the aorta is dangerous, because it can lead to rupture (dissection) which is life-threatening.

The researchers studied 9 patients from a large Flemish-Dutch family with the cardiovascular, skeletal and facial features typical of a form of TAAD, called Loeys-Dietz syndrome. They screened DNA from each family member without finding any genetic mutations known at that stage to be connected with TAAD. However, further investigation revealed two candidate genomic regions that appeared to be involved, one of which contained the TGBF3 gene. ‘This gene was an obvious candidate because it has previously been shown that the TGFbeta-signalling pathway has a key role in the formation of aortic aneurysm,’ says Ms Gillis.

After sequencing the gene, the researchers identified a mutation that was present in all affected family members. Finally, 470 TAAD patients were screened for TGFB3 mutations, and causal mutations were found in ten other families.

‘This is an important finding because incidence of TAADs may be much higher than currently reported,’ says Ms Gillis. ‘Acute aortic dissections may be disguised as heart attacks, and we know that the genetic component of TAAD is strong – in about 20% of patients, it is also found in family members. Therefore anything we can do to enable early identification of people at risk will help. However, aortic aneurysm formation is not yet fully understood, so reversing the risk of dissections remains a challenge, even though effective treatments are available.’ EurekAlert

The investigation of a simple protein has uncovered its uniquely complicated role in the spread of the childhood cancer, osteosarcoma. It turns out the protein, called ezrin, acts like an air traffic controller, coordinating multiple functions within a cancer cell and allowing it to endure stress conditions encountered during metastasis.

It’s been known that ezrin is a key regulator of osteosarcoma’s spread to the lungs, but its mechanism was not known. Osteosarcoma is a tumour of bone that afflicts children, adolescents and young adults. In most cases, the tumour is localized in the extremities and can be completely removed by surgery or amputation.

“The main cause of death in osteosarcoma patients is not the tumour on their limbs, but the failure of their lungs when the cancer spreads there,” explains Aykut Üren, MD, professor of oncology at Georgetown Lombardi Comprehensive Cancer Center.

Üren and his colleagues have developed molecules that block ezrin’s function and prevent osteosarcoma spread in mouse models. In an attempt to explain the molecular mechanisms underlying ezrin-mediated cancer metastasis, the researchers discovered this previously unrecognized role for ezrin.

“Conventionally ezrin was believed to be functioning only on the inner surface of cancer cells,” Üren says, “but our new discovery indicates that ezrin may operate deeper in the core of the cell and regulate expression of critical genes that are important for cancer’s spread.”

The scientists say that ezrin functions in a new capacity that is unusual for its family of proteins. They found that ezrin’s unusual interaction with another protein called DDX3 results in modulation of genes that give cancer cells an edge in surviving harsh conditions.

“Knowing exactly how ezrin works will help our team develop the ezrin-targeting small molecules as potential new drugs to prevent the spread of cancer cells to lungs in osteosarcoma patients,” Uren says.

“Implications of our findings go beyond cancer research,” says the study’s first author Haydar Çelik, PhD. “Because this work suggests a new molecular mechanism on how ezrin is involved in the regulation of mRNA translation, these observations may provide important clues for scientists investigating how viruses enter and replicate in human cells too.” Georgetown Lombardi Comprehensive Cancer Center

Separating circulating cancer cells from blood cells for diagnostic, prognostic and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, according to a team of engineers.

‘Looking for circulating tumour cells in a blood sample is like looking for a needle in a haystack,’ said Tony Jun Huang, professor of engineering science and mechanics.  ‘Typically, the CTCs are about one in every one billion blood cells in the sample.’

Existing methods of separation use tumour-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance.  Other methods rely on size, deformability or electrical properties.  Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device.

Acoustic-based separations are potentially important because they are non-invasive and do not alter or damage cells.  However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.

‘In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,’ said Ming Dao, principal research scientist, materials science and engineering, Massachusetts Institute of Technology.  ‘With an integrated experimental/modelling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.’

The researchers worked both experimentally and with models to optimize the separation of CTCs from blood.   They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation.  Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection.

Tilted-angle standing surface acoustic waves can separate cells using very small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses. Also, each cell experiences the acoustic wave for only a fraction of a second.  In addition, cells do not require labelling or surface modification.  All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.

If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push very small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.

The researchers used two types of human cancer cells to optimize the acoustic separation — HELA cells and MCF7 cells.  These cells are similar in size.  They then ran an experiment separating these cells and had a separation rate of more than 83 percent.  They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83 percent.

‘Because these devices are intended for use with human blood, they need to be disposable,’ said Huang.  ‘We are currently figuring out manufacturing and mass production possibilities.’

Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis. Penn State University

Psychiatric disorders can be difficult to diagnose because clinicians must rely upon interpreted clues, such as a patient’s behaviours and feelings. For the first time, researchers at University of California, San Diego School of Medicine report identifying a biological marker: the over-production of specific genes that could be a diagnostic indicator of mental illness in female psychiatric patients.

Researchers found that the gene XIST, which is responsible for inactivating one of the two copies of the X chromosome in cells that store genetic material, works overtime in female patients with mental illnesses, such as bipolar disorder, major depression and schizophrenia.
The study suggests that over-production of XIST and genes from the inactive X chromosome are common denominators in the development of psychiatric disorders in patients with rare chromosome disorders, such as Klinefelter syndrome and Triple X syndrome, and in the general population of female psychiatric patients.

“There has been an utmost urgency to identify biomarkers for mental illness that could significantly impact research and drug development,” said Xianjin Zhou, PhD, assistant professor in the Department of Psychiatry at UC San Diego School of Medicine and lead author.

The study was conducted on 60 lymphoblastoid cell lines from female patients, most of whom had a family history of mental illness. Approximately 50 percent of the female patients exhibited abnormally higher levels of XIST and other genes related to the X chromosome.

Zhou and his team said reversing the abnormal activity of the inactive X chromosome in patients suffering from mental illness may offer a potential new strategy for treating psychiatric disorders. UC San Diego