Researchers have identified an elusive gene responsible for Thrombocytopenia with Absent Radii (TAR), a rare inherited blood and skeletal disorder. As a result, this research is now being transformed into a medical test that allows prenatal diagnosis and genetic counselling in affected families.
The team used genetic sequencing to discover that TAR results from low levels of the protein called Y14. They found that the syndrome occurs by a unique inherited mechanism.
Platelets are the second most abundant cell in the blood. Their main task is to survey the blood vessel wall for damage and to plug and repair it where required. Some people are born with low numbers of platelets and these rare conditions are thought to be inherited. TAR syndrome combines the unique features of low platelet count and prominent bleeding, especially in infancy, and skeletal abnormalities affecting the upper limb ranging from absence of the radial bone in the forearm to virtually total absence of upper limb. The genetic basis of TAR syndrome has eluded researchers for 50 years.
"Without the use of modern genomics technologies, the discovery of this unexpected mechanism of disease inheritance would have been much more difficult", said Dr Cornelis Albers, from the Sanger Institute and the University of Cambridge. "To achieve our latest findings, we deciphered about 40 million letters of genetic code in five patients."
Many people with TAR were known to have a deletion in one copy of chromosome 1, but this was thought not to be the whole story because parents who carry the same deletion are not suffering from TAR: other variants had to be involved. The team sequenced the genomes of people affected by the disorder who also carried the deletion and discovered that the vast majority of them had one of two variants of a gene called RBM8A. They found that when the genetic deletion and one of the variants are co-inherited by a child, TAR results.
RBM8A controls the production of the protein Y14. They found that the combination of the genetic deletion of one copy of the RBM8A gene and the variants on the other copy greatly reduces the level of Y14. The team concluded that it is low levels of Y14 that affect platelet formation and cause TAR disorder.
"The lack of production of adequate amounts of the protein Y14 in TAR patients only seems to effect the formation of platelets but not of other blood cells." said Dr Cedric Ghevaert from the University of Cambridge. "We have shed some light on how some inherited disorders can present with such striking features associating seemingly unconnected characteristics such as skeletal and blood defects"
This is the first human disorder identified to be caused by a presumed defect of the Exon Junction Complex, part of the cellular machinery that contributes to producing messages that direct protein production. This study opens the path that could lead to the identification of the genetic basis of other similar inherited syndromes, which will help improvements in diagnosis, genetic counselling and patient care in the NHS and beyond.
"The discovery of the gene for TAR will make it simpler to diagnose more accurately future cases with a simple DNA test. This new test is currently being developed for the NHS as part of the international ThromboGenomics initiative led by Professor Ouwehand" commented Dr Ruth Newbury-Ecob, Honorary Reader in Medical Genetics and Consultant in Clinical Genetics at the University of Bristol Hospitals.
Notes to Editors
The findings were made following a collaborative study by the NHS Blood and Transplant platelet research team at the University of Cambridge and the Wellcome Trust Sanger Institute, which is led by Dr Cedric Ghevaert and Professor Willem Ouwehand. The Cambridge researchers joined forces with Dr Ruth Newbury-Ecob from the University of Bristol and worked together with various other European research partners from Belgium, France, Germany and the Netherlands.
Nature Genetics website, 26 February 2012
Albers et al 'Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome' DOI 10.1038/ng.1083
The platelet research team in Cambridge is supported by the British Heart Foundation, the European Commission, the National Institute for Health Research for England (NIHR), NHS Blood and Transplant and the Wellcome Trust.
Dr Cedric Ghevaert and Prof Willem Ouwehand are also consultant Haematologists for NHS Blood and Transplant (NHSBT). NHSBT collects blood and platelets from non-remunerated volunteer donors. Every day about 8,000 units of blood are needed by the NHS and 1100 platelet concentrates. For the latter about 600 donors attend a special clinic at which platelets are harvested from the blood of the donor by a process called apheresis.
The National Institute for Health Research (NIHR) http://www.
The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.