A twelve-year old patient was the starting point of the study: Since his birth, the child suffered from severe, life-threatening infections. Three of his six siblings died within the first two years of life, presumably due to similar complications. Although the origin of their condition was unknown, the researchers assumed a genetic trait in four severely diseased children of the same family.
To investigate rare patients like these, the new Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) was founded in Vienna. In collaboration with CeMM, the Medical University Vienna and the St. Anna Children's Cancer Research Institute, LBI-RUD was established by the Ludwig Boltzmann Gesellschaft in April 2016. “The accumulated expertise of our institute is unique” states Kaan Boztug, Director of the LBI-RUD and head of the study. “We are the ideal place to find the molecular cause of rare – and most often genetic – diseases, and to develop this knowledge into targeted therapies”.
“Our analyses of the patient’s and his parents’ genomes indeed confirmed that the boy’s disorder had a genetic cause”, explains Elisabeth Salzer, postdoctoral fellow at CeMM and first author of the study. Using next generation sequencing, the researchers found an error in the gene encoding RASGRP1, a key protein for the development of lymphocytes. Until this time, the role of RASGRP1 in the human immune system was unknown, and a mutation that inhibited the protein had never been reported.
The case of the 12-year old patient not only showed that the lack of RASGRP1 impairs T lymphocytes, but also that the protein plays a so far unknown role for maintaining the cellular scaffold in other immune cells. Eventually, the scientist even found an approved drug, lenalidomide, that has the potential to reverse some effects of the newly discovered RASGRP1 deficiency.
Elisabeth Salzer, Deniz Cagdas*, Miroslav Hons*, Emily Margaret Mace*, Wojciech Garncarz, Özlem Yüce Petronczki, René Platzer, Laurène Pfajfer, Ivan Bilic, Sol A Ban, Katharina L. Willmann, Malini Mukherjee, Verena Supper, Hsiang Ting Hsu, Pinaki P. Banerjee, Papiya Sinha Somasundaram, Fabienne McClanahan, Gerhard J. Zlabinger, Winfried Pickl, John G. Gribben, Hannes Stockinger, Keiryn L. Bennett, Johannes B. Huppa, Loïc Dupré, Özden Sanal, Ulrich Jäger, Michael Sixt#, Ilhan Tezcan#, Jordan S. Orange# and Kaan Boztug. (* and #, contributed equally). RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics responsive to lenalidomide, Nature Immunology, 2016. DOI: 10.1038/ni.3575
This study was supported by the European Research Council (ERC), the Vienna Science and Technology Fund (WWTF), Celgene Austria, the National Institutes of Health (NIH), fellowships from the Boehringer Ingelheim Fonds and the Austrian Research Fund (FWF) Lise Meitner Programme.