New research from Queen Mary University of London has identified a novel genetic defect among patients with bone marrow failure, which could reveal its underlying cause.
The study detected and identified a new disease gene (ERCC6L2). In its normal form, the gene plays a key role in protecting DNA from damaging agents, but when the gene is mutated the cell is not able to protect itself in the normal way.
The research findings suggest that the gene defect and the subsequent DNA damage was the underlying cause of bone marrow failure among the study participants.
Bone marrow failure is a term used for a group of life threatening disorders associated with an inability of the bone marrow to make an adequate number of mature blood cells.
Patients were recruited from all over the world to join an international bone marrow failure registry and researchers used new DNA sequencing technologies to study cases of bone marrow failure with similar clinical features. These included bone marrow failure associated with neurological abnormalities (learning defects and developmental delay), and patients whose parents were first cousins.
The findings mean it is now possible to carry out a reliable genetic test (including antenatal testing) in these families and get an accurate diagnosis. In the long term, with further research, the findings could lead to the development of new treatment for this specific gene defect.
Professor Inderjeet Dokal, Chair of Paediatrics and Child Health at Queen Mary University of London, comments: ‘New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure. This is a promising finding which we hope one day could lead to finding an effective treatment for this type of gene defect. Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.
‘Now we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure.’ Queen Mary University

A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates haemoglobin production.
The researchers were led by Daniel Bauer, MD, PhD, and Stuart Orkin, MD, of Dana-Farber/Boston Children’s.
Prior work by Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce foetal haemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle haemoglobin. BCL11A is thus an attractive target for treating SCD.
The disease affects roughly 90,000 to 100,000 people in the United States and millions worldwide.

However, BCL11A plays important roles in other cell types, including the immune system’s antibody-producing B cells, which raises concerns that targeting it directly in sickle cell patients could have unwanted consequences.
The discovery of this enhancer—which regulates BCL11A only in red blood cells—opens the door to targeting BCL11A in a more precise manner. Approaches that disable the enhancer would have the same end result of turning on foetal haemoglobin in red blood cells due to loss of BCL11A, but without off-target effects in other cell types.

The findings were spurred by the observation that some patients with SCD spontaneously produce higher levels of foetal haemoglobin and enjoy an improved prognosis. The researchers found that these individuals possess naturally occurring beneficial mutations that function to weaken the enhancer, turning BCL11A’s activity down and allowing red blood cells to manufacture some foetal haemoglobin.

‘This finding gives us a very specific target for sickle cell disease therapies,’ said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. ‘Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating haemoglobin production and new treatment options for haemoglobin diseases.’ Boston Children’s Hospital

Dr. Hanna Mikkola and researchers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have identified a specific type of cell and a related cell communication pathway that are key to the successful growth of a healthy placenta. The findings could greatly bolster our knowledge about the potential causes of complications during pregnancy.
Specifically, the findings could help scientists clarify the particular order in which progenitor cells grow in the placenta, which would allow researchers to track foetal development and identify complications. Progenitor cells are cells that develop into other cells and that initiate growth of the placenta.
The placenta is the organ that forms inside the uterus during pregnancy and enables oxygen and nutrients to reach the foetus, but little is understood about the biological mechanisms and cellular processes responsible for this interface. Studying mouse models, Mikkola and her colleagues tracked individual cells in the placenta to determine which cells and which cell communication routes, or signalling pathways, were responsible for the healthy development of the placenta.
The UCLA team was the first to identify the cells that form the placenta: Epcamhi labyrinth trophoblast progenitors, or LaTP cells, can become the various cells necessary to form a specific tissue, in this case the placenta.
Mikkola and her colleagues also found a signalling pathway that consists of hepatocyte growth factor and its receptor, c-Met. The researchers found that this signalling pathway was required for the placenta to keep making LaTP cells. Production of LaTP cells, in turn, continues the production of the different cells needed to maintain the growth and health of the placenta while the foetus is growing. Placental health enables healthy transmission of oxygen and nutrients through the exchange of blood between the foetus and the mother. In the mice, when c-Met signalling stopped, foetal growth slowed, the liver did not develop fully and it produced fewer blood cells, and the foetus died.
‘Identifying this novel c-Met–dependent multipotent labyrinth trophoblast progenitor is a landmark that may help us understand pregnancy complications that are caused by defective placental exchange, such as foetal growth restriction,’ Mikkola said. University of California – Los Angeles

Researchers at King’s College London have identified a genetic variant associated with an increased risk of stroke and heart attack.

Stroke and heart attack are caused when arteries, already clogged up by fatty substances (a condition known as atherosclerosis), become completely blocked by the formation of a blood clot. Risk factors for this include smoking, high blood pressure and high cholesterol.

The findings suggest a new genetic link caused by a variation in a protein known as ‘glycoprotein IIIa’. This genetic variant is found in platelets, a type of blood cell involved in the formation of blood clots.

These findings may, in future, allow clinicians to identify patients who are at particularly high risk of stroke or heart attack by looking for the genetic variant. This would represent advancement on current practice, which mainly addresses risk factors such as smoking and high blood pressure.

Previous findings surrounding this genetic variant have been inconsistent and the study at King’s represents the first large-scale meta-analysis of the literature, including over 50,000 participants from a combined total of 82 studies.

In the UK over 150,000 people have a stroke every year. Stroke is the third largest cause of death after heart disease and cancer. A stroke occurs when blood supply to part of the brain is cut off, leading to damage of brain cells. There are around 103,000 heart attacks in the UK each year, caused by blockage of a coronary artery that supplies blood to the heart and resulting in damage to heart muscles.

In the first research paper, which examined stroke patients, researchers found that carrying the PlA2 genetic variant of glycoprotein IIIa was associated with an increased risk of thrombotic stroke – that is, stroke caused by a blood clot. This equated to a higher risk of around 10-15 per cent, which was even stronger (amounting to a 70 per cent increase in risk) in people who carried two copies of this gene variant. The variant was not associated with haemorrhagic stroke, which is caused by bleeding into the brain.

The second research paper found that the same genetic variant was also associated with an increased risk of heart attack. This link was stronger in younger than in older patients, which is likely to reflect the greater influence of other cardiovascular risk factors in older patients (such as smoking and high cholesterol), according to the researchers.

Albert Ferro, Professor of Cardiovascular Clinical Pharmacology at King’s College London, said: ‘The genetic risk found in stroke and heart attack patients is likely to be caused by over-active platelets. Under normal circumstances, platelets help your body form clots to stop bleeding, but in these patients platelet activation has the undesired effect of causing their narrowed arteries to be blocked off completely. In future it may be possible to reduce the chances of this happening by examining patients for this variant on a blood test, so that if they carry the PlA2 form – and especially if they carry two copies of it – such patients could be identified for a more determined reduction of risk factors such as smoking, high blood pressure or high cholesterol.’ King’s College London