A European team of scientists has discovered that thrombocytopenia with absent radii (TAR), a rare inherited blood and skeletal disorder, is triggered by low levels of the protein Y14. Presented in the journal Nature Genetics, the findings could help lead to the development of a medical exam that permits prenatal diagnosis and genetic counselling in families affected by TAR. The study was funded in part by the NETSIM ('An integrated study on three novel regulatory hubs in megakaryocytes and platelets, discovered as risk genes for myocardial infarction by a genome-wide association and platelet systems biology study') project, which is backed by a Marie Curie Action 'Networks for Initial Training' grant worth EUR 2.85 million under the EU's Seventh Framework Programme (FP7).
Platelets, the second most abundant cell in the blood, are a natural source of growth factors whose primary role is to plug and repair any damaged blood cells. People can be born with a low number of platelets; it is a rare condition that researchers believe to be inherited. Led by the University of Cambridge in the United Kingdom, researchers used genetic sequencing to determine how the syndrome occurs by a unique inherited mechanism.
According to the researchers, TAR syndrome combines the features of low platelet count and prominent bleeding, as well as skeletal abnormalities that impact the body's upper limb, including an absence of the radial bone in the forearm to a total absence of upper limb. Researchers tried for to determine the genetic basis of TAR syndrome for half a century with no results. But this latest study bore fruit.
'Without the use of modern genomics technologies, the discovery of this unexpected mechanism of disease inheritance would have been much more difficult,' said lead author, 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 5 patients.'
Experts identified how many people with TAR were known to have a deletion in one copy of chromosome 1: this was thought not to be the whole story, since parents who carry the same deletion are not diagnosed with TAR. So other variants had to play a role. In this study, the researchers sequenced the genomes of people affected by the disorder who also carried the deletion and found that most of them had one of two variants of a gene called RBM8A. TAR is triggered when the genetic deletion and one of the variants are co-inherited by a child.
RBM8A controls Y14 production. The combination of the genetic deletion of one copy of the RBM8A gene and the variants on the other copy decreases the level of Y14. So low levels of Y14 impact platelet formation and lead to TAR syndrome.
'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, senior author of the study. '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.'
Said co-author and the University of Bristol's Dr Ruth Newbury-Ecob: '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.'