Researchers have identified an elusive gene responsible for Grey Platelet Syndrome, an extremely rare blood disorder in which only about 50 known cases have been reported. As a result, it is hoped that future cases will be easier to diagnose with a DNA test.
The findings were made following a collaborative study by Professor Willem Ouwehand and Dr Cornelis Albers, who are both based at the Wellcome Trust Sanger Institute and the University of Cambridge, and Dr Paquita Nurden, from the Rare Platelet Disorders laboratory, based in Bordeaux, who have described their study.
Platelets are the second most abundant cell in the blood. Their main task is to survey the blood vessel wall for damage and to orchestrate its repair where required. On the flip side, platelets also play a "darker" role after vessel wall damage and cause blood clots that may lead to heart attacks or stroke.
Some people are born with platelets that do not function well and these rare conditions are thought to be inherited. Grey Platelet Syndrome poses a risk of bleeds, some of which can be severe and life threatening, e.g. if they occur in the brain. Grey Platelet Syndrome was first identified in the 1970s and is named for the greyish appearance of these platelets when viewed with a microscope.
Identifying the cause of increased bleeding in young patients has been a painstaking process. An important step in translating research findings in human genetics in improvements of patient care has focused around the need to develop simpler and rapid DNA-based diagnostic test. To achieve this, researchers needed to discover the gene responsible for the rare platelet bleeding disorders.
In the past it was a major challenge to discover which genes caused rare disorders because DNA samples from numerous large families affected by the same disorder had to be identified and genetically analysed to pinpoint the region harbouring the causative gene.
To achieve their latest findings, researchers used a simpler approach and deciphered about 40 million letters of genetic code covering the entire coding fraction of the genome of four non-related French patients.
They identified the gene NBEAL2 as not functioning well in Grey Platelet Syndrome, a member of a family of genes that all contain a unique domain, called the BEACH domain. The team showed that protein encoded by this gene is altered at a different position in the four non-related cases and the patients affected by the disorder have inherited two non-functioning copies of the gene, one from father and mother each.
"It is really great to see how the use of modern genomics technologies is going to be of direct benefit for patient care. It is exciting that we have shown that the genetic basis of a rare bleeding disorder can be discovered with relative ease", said Professor Willem Ouwehand, who heads a NHS Blood and Transplant research team on platelet biology at both the Wellcome Trust Sanger Institute and the University of Cambridge. "This study is one such example and it gives us confidence to achieve the same for a large number of other rare inherited platelet bleeding disorders. It is now important that we use this discovery to improve patient care in the NHS and beyond."
The team's identification of the NBEAL2 gene was confirmed by functional studies in zebrafish. Fish also have platelets named thrombocytes, and switching off the NBEAL2 gene in fish caused a complete absence of these cells which resulted in nearly half of the fish suffering spontaneous bleeds similar to patients with the disorder.
It is hoped that this gene identification will make it simpler to diagnose future cases of Grey Platelet Syndrome with a simple DNA test. This new test is now being developed with researchers at the NHS Blood and Transplant Centre at the Addenbrooke's Biomedical campus in Cambridge as part of the international ThromboGenomics initiative.
The scientists also observed that other members from the same family of BEACH proteins are implicated in other rare inherited disorders. Their findings showed that LYST protein did not function well in Chediak-Higashi syndrome, another rare but severe disorder paralysing the immune system but also causing a mild platelet bleeding disorder. As a result, a picture is emerging that BEACH proteins are essential in the way granules in blood cells and brain cells are formed or retained showing that in platelets the BEACH proteins are essential for both alpha and dense granules.
"Our discovery that another member of the family of BEACH proteins is underlying a rare but severe granule disorder in platelets firmly nails down the important role of this class of proteins in granule biology," said Cornelis Albers, a British Heart Foundation research fellow at the Sanger Institute and the University of Cambridge. "The reasons why the platelets of patients with Grey Platelet Syndrome are grey is because they lack alpha granules. The alpha granules carry the cargo of proteins that induce vessel wall repair and also form the platelet plug.
"A better understanding of how these granules are formed and how their timely release by the platelet is coordinated at the molecular level may one day underpin the development of a new class of safer anti-platelet drugs for use in patients with heart attacks and stroke. It has been a fascinating journey to identify a new and important pathway by combining the rapid advances in sequencing technology with computational analysis."
The French collaboration leader, Dr Paquita Nurden, set up the Network for Rare Platelet Disorders at the Laboratoire d'Hématologie, Hopital Xavier Arnozan close to Bordeaux. Their team made the Heruclian effort to find the French families affected by this rare disorder.
"We have worked for years to identify the families across France that suffer from rare platelet disorders and my group of scientists have used powerful microscopes to determine what was wrong with the platelets from patients with Grey Platelet Syndrome. Researchers across the world discovered in the 1980s that something was wrong with the alpha granules because they were lacking in most of the cases," said Dr Nurden, an international expert in platelet biology. "The gene, however, remained elusive for another 30 years, and it is great how our joint working has discovered the causative gene very quickly."Notes to Editors
Albers CA, Cvejic A, Favier R, Bouwmans EE, Alessi MC, Bertone P, Jordan G, Kettleborough RN, Kiddle G, Kostadima M, Read RJ, Sipos B, Sivapalaratnam S, Smethurst PA, Stephens J, Voss K, Nurden A, Rendon A, Nurden P and Ouwehand WH
Nature genetics 2011
PUBMED: 21765411; DOI: 10.1038/ng.885Funding
Don Powell | EurekAlert!
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology