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Defective protein identified as cause of serious disorder of the immune response

Researchers at the CeMM have discovered the molecular cause of a rare, previously unknown, inherited immune disorder.

(Vienna, 17 June 2015) Together with international partners, researchers in Kaan Boztug’s group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna have discovered the molecular cause of a rare, previously unknown, inherited immune disorder. According to this study, a lack of immunity to viruses and bacteria in the patients investigated is due to a genetic mutation, which modifies the DOCK2 protein. The results of the study, which also involved similarly qualified scientists from Boston Children Hospital, and Rockefeller University, New York, have now been published in the renowned "New England Journal of Medicine".

Rare diseases are one of the main interests of Kaan Boztug, who also heads up the Center for Rare and Undiagnosed Diseases (CeRUD) in Vienna. The CeRUD was set up as a joint initiative by the Department of Paediatrics and Adolescent Medicine and the Department of Dermatology of MedUni Vienna and the CeMM on the Medical University Campus, Vienna General Hospital in order to be able to offer affected patients better diagnosis and treatment options and to advance research in this area. Over the last few years, Boztug has successfully decoded several inherited immunological disorders. This makes him one of the world's leading scientists in this field.
According to the definition used throughout the EU, a disease is regarded as rare if it occurs in fewer than five people per 10,000 of population. Often the number of people suffering from a rare disease, of which there are an estimated 8,000 different types, is even lower than this. So far, molecular causes have only been identified for a proportion of rare diseases and inherited immune disorders. The study of rare immune disorders not only provides for more accurate diagnosis and forms a basis for developing targeted therapies, it is also of key important in terms of our understanding of the immune system and its components and their interaction in the molecular network.
In the present study, co-lead author Cecilia Domínguez Conde, a PhD student belonging to Kaan Boztug's group at the CeMM, together with several international research groups and under joint leadership with colleagues in Harvard and New York, has successfully discovered the molecular cause of a previously unknown immune system disorder. Using genome sequencing (Next Generation Sequencing), the researchers were able to identify the same genetic defect in patients from many different countries of origin. This genetic defect was characterized by frequent, life-threatening viral and bacterial infections.
The cause of the disordered immune response is the malformation of the DOCK2 protein, which plays an important role in cell migration and is responsible for the chemical attraction of immune cells in the blood, amongst other things. One of the surprising facts that the scientists discovered was that DOCK2 also controls non-haematopoietic immune cells for viral defence, which might explain why sufferers are so prone to viral infections. Now, for patients with comparable symptoms, it will be possible to diagnose the DOCK2 defect in a laboratory anywhere in the world. Because of the seriousness of the disease, the authors recommend early allogeneic haematopoietic stem cell transplantation to facilitate long-term restoration of the immune system.


Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. Kerry Dobbs, B.S., Cecilia Domínguez Conde, M.Sc., Shen-Ying Zhang, M.D., Ph.D., Silvia Parolini, Ph.D., Magali Audry, Ph.D., Janet Chou, M.D., Emma Haapaniemi, M.D., Sevgi Keles, M.D., Ivan Bilic, Ph.D., Satoshi Okada, M.D., Ph.D., Michel J. Massaad, Ph.D., Samuli Rounioja, M.D., Ph.D., Adel M. Alwahadneh, M.D., Nina K. Serwas, M.Sc., Kelly Capuder, B.S., Ergin Çiftçi, M.D., Kerstin Felgentreff, M.D., Toshiro K. Ohsumi, Ph.D., Vincent Pedergnana, Ph.D., Bertrand Boisson, Ph.D., Şule Haskoloğlu, M.D., Arzu Ensari, M.D., Ph.D., Michael Schuster, Ph.D., Alessandro Moretta, M.D., Yuval Itan, Ph.D., Ornella Patrizi, Ph.D., Flore Rozenberg, M.D., Pierre Lebon, M.D., Janna Saarela, M.D., Ph.D., Mikael Knip, M.D., Ph.D., Slavé Petrovski, Ph.D., David B. Goldstein, Ph.D., Roberta E. Parrott, B.S., Berna Savas, M.D., Ph.D., Axel Schambach, M.D., Ph.D., Giovanna Tabellini, Ph.D., Christoph Bock, Ph.D., Talal A. Chatila, M.D., Anne Marie Comeau, Ph.D., Raif S. Geha, M.D., Laurent Abel, M.D., Ph.D., Rebecca H. Buckley, M.D., Aydan İkincioğulları, M.D., Waleed Al-Herz, M.D., Merja Helminen, M.D., Ph.D., Figen Doğu, M.D., Jean-Laurent Casanova, M.D., Ph.D., Kaan Boztuğ, M.D., and Luigi D. Notarangelo, M.D. New England Journal of Medicine DOI: 10.1056/NEJMoa1413462 (2015).

CeMM and MedUni Vienna would like to thank the following institutions for helping to finance the study: National Institutes of Health (5R01AI100887-03, to Dr. Notarangelo), the Manton Foundation (to Dr. Notarangelo), the European Research Council (ERC starting grant 310857, to Dr. Boztuğ), the Austrian Science Fund START programme (Y595-B13, to Dr. Boztuğ), the National Center for Research Resources and the National Center for Advancing Translational Sciences (8 UL1TR000043, to Dr. Casanova), the German Research Foundation (for the Cluster of Excellence REBIRTH EXC 62/1 and CRC738, to Dr. Schambach), the New England Newborn Screening Program, University of Massachusetts Medical School (to Dr. Comeau), the Scientific and Technological Research Council of Turkey (1059B191300622, to Dr. Keles), Union Chimique Belge Celltech (to Dr. Goldstein), and Baxter Healthcare (to Dr. Buckley).


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