A gene essential to the production of pain-sensing neurons in humans has been identified by an international team of researchers co-led by the University of Cambridge. The discovery could have implications for the development of new methods of pain relief.

The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception.
Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals – around one in a million people in the UK – are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.

Using detailed genome mapping, two teams of researchers collaborated to analyse the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.

The team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo – they confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells (skin cells that had been reset to their ‘master state’, which enables them to develop into almost any type of cell in the body).

PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off (an effect known as epigenetics). The researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene’s function. As chromatin is particularly important during formation of particular specialised cell types such as neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.

‘The ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception,’ says Professor Geoff Woods from the Cambridge Institute for Medical Research at the University of Cambridge, who co-led the study. ‘Both are equally important to the development of new pain treatments – if we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain.’

PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials. University of Cambridge

A ‘pill on a string’ developed by researchers at the University of Cambridge could help doctors detect oesophageal cancer – cancer of the gullet – at an early stage, helping them overcome the problem of wide variation between biopsies, suggests research.

The ‘Cytosponge’ sits within a pill which, when swallowed, dissolves to reveal a sponge that scrapes off cells when withdrawn up the gullet. It allows doctors to collect cells from all along the gullet, whereas standard biopsies take individual point samples.

Oesophageal cancer is often preceded by Barrett’s oesophagus, a condition in which cells within the lining of the oesophagus begin to change shape and can grow abnormally. The cellular changes are cause by acid and bile reflux – when the stomach juices come back up the gullet. Between one and five people in every 100 with Barrett’s oesophagus go on to develop oesophageal cancer in their life-time, a form of cancer that can be difficult to treat, particularly if not caught early enough.

At present, Barrett’s oesophagus and oesophageal cancer are diagnosed using biopsies, which look for signs of dysplasia, the proliferation of abnormal cancer cells. This is a subjective process, requiring a trained scientist to identify abnormalities. Understanding how oesophageal cancer develops and the genetic mutations involved could help doctors catch the disease earlier, offering better treatment options for the patient.

An alternative way of spotting very early signs of oesophageal cancer would be to look for important genetic changes. However, researchers from the University of Cambridge have shown that variations in mutations across the oesophagus mean that standard biopsies may miss cells with important mutations. A sample was more likely to pick up key mutations if taken using the Cytosponge, developed by Professor Rebecca Fitzgerald at the Medical Research Council Cancer Unit at the University of Cambridge.

“The trouble with Barrett’s oesophagus is that it looks bland and might span over 10cm,” explains Professor Fitzgerald. “We created a map of mutations in a patient with the condition and found that within this stretch, there is a great deal of variation amongst cells. Some might carry an important mutation, but many will not. If you’re taking a biopsy, this relies on your hitting the right spot. Using the Cytosponge appears to remove some of this game of chance.” Cambridge University

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