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Nature Immunology study by LBI-RUD researchers on novel rare immunodeficiency

A hitherto unknown gene mutation revealed the role of a key molecule for immune cell development. The international team led by LBI-RUD director Kaan Boztug gained fundamentally new insights into the human immune system by studying this newly discovered mutation. Moreover, their research revealed a potential personalized therapy for this rare disease. The study, published in Nature Immunology, clearly highlights the importance and opportunities of research in the field of rare diseases.

A fifteen-year old patient was the starting point of the study: Since his birth, the boy had suffered from severe, life-threatening infections. Immunological analyses revealed a disturbed ratio of white blood cells, so-called lymphocytes, hampering his immune system to fight efficiently against invading pathogens. Three of his six siblings had died within the first two years of life due to similar complications. 

“Our analyses of the patient’s and his parents’ genomes indeed confirmed that the boy’s disorder had a genetic cause”, Elisabeth Salzer, postdoctoral fellow at LBI-RUD is the first author of the study. Using next generation sequencing – a modern and highly efficient genetic method to detect disease-causing mutations – the researchers found an error in the gene encoding RASPGR1. The healthy parents, as well as the three healthy siblings, only had one copy of the mutation in their genome, while the diseased boy had inherited both faulty copies from his parents.

Until this time, the function of RASGPR1 in the immune system had only partially been studied in rodent models. Its role in humans was unknown, and a mutation that rendered the protein  unfunctional had never been reported. The case of the 15-year old patient not only showed that the lack of RASGPR1 impairs T lymphocytes, but also that the protein plays a so far unknown role for maintaining the cellular scaffold (cytoskeleton) in natural killer cells. Through a series of further experiments, the researchers were able to analyze the faulty molecular circuits in greater detail.

Eventually, the team even found an approved drug, that has the potential to reverse some effects of the newly discovered RASGRP1 deficiency, and will be studied in more detail in a follow-up project. Therefore, this study is a prime example for the importance and opportunities of rare diseases research as performed at LBI-RUD: “The whole process from discovery of a gene defect as cause for a rare disease to the exploration of the disease-causing mechanism to the development of a personalized therapy bears a great potential beyond the individual disease”, explains Kaan Boztug, “Virtually every case – such as the immunodeficiency of this young patient – provides profound new insights into the human organism and paves the way towards a future precision medicine.”

Read full press release here: Nature Immunology study October 2016



Salzer E, Cagdas D*, Hons M*, Mace EM*, Garncarz W, Petronczki ÖY, Platzer R, Pfajfer L, Bilic I, Ban SA, Willmann KL, Mukherjee M, Supper V, Hsu HT, Banerjee PP, Sinha P, McClanahan F, Zlabinger GJ, Pickl WF, Gribben JG, Stockinger H, Bennett KL, Huppa JB, Dupré L, Sanal Ö, Jäger U, Sixt M*, Tezcan I*, Orange JS*, Boztug K. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamicsNat Immunol. 2016 Dec;17(12):1352-1360. 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.


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