26 June 2023

A new disease has been discovered, associated with DOCK11 deficiency, that links disruptions of blood formation, the immune system and inflammation.

This groundbreaking discovery, made while trying to find the origin of puzzling symptoms in four children, will help scientists to better understand similar diseases.

Researchers from St. Anna Children’s Cancer Research Institute (CCRI), the CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences (ÖAW) and the Medical University of Vienna, Austria, identified a defect in the DOCK11 gene, which leads to abnormalities in both white and red blood cells.

Their findings are published in the New England Journal of Medicine.

Senior author Professor Kaan Boztug, scientific director of St. Anna CCRI, said: “Such rare and previously unknown diseases provide valuable insights into the fundamental principles of blood formation and the immune system. They allow us to better understand the dysregulated processes underlying these diseases.”

The gene defect was first identified in a young patient from Spain, after the child’s doctor sent blood samples to the St. Anna CCRI because no explanation could be found for the severe inflammation affecting the kidneys, intestines, and skin.

The patient’s genome sequencing revealed a severe defect in the DOCK11 gene, which is involved in cell communication and had not previously been associated with any human disease.

Through their international collaborations, the research team found additional patients with similar DOCK11 mutations, which helped provide a clearer understanding of the disease.

One had a significantly reduced number of red blood cells and required regular blood transfusions and the cause was established using a zebrafish model. They found the DOCK11 defect resulted in impaired blood cell formation, leading to a novel mechanism for anaemia.

Previous studies into the role of DOCK11 had shown the importance of the protein for the development of B cells in mouse models, but now it is known that to a certain extent B cells also do not develop properly in humans with DOCK11 deficiency. At the same time, T lymphocytes are overactivated.

First author Jana Block, a PhD student in Professor Boztug's research group, said: “The protein appears to play a role in keeping the activation of T cells within a certain range.”

This is important because overactivation can lead to damage to surrounding tissues and organs, especially in the absence of an actual pathogen.

The researchers hypothesise that DOCK11 deficiency could be treated through gene therapy, although further studies are needed to establish this.

Source: Block J, Rashkova C, Castanon I, Zoghi S, Platon J, Ardy RC, Fujiwara M, Chaves B, Schoppmeyer R, van der Made CI, Jimenez Heredia R, Harms FL, Alavi S, Alsina L, Sanchez Moreno P, Ávila Polo R, Cabrera-Pérez R, Kostel Bal S, Pfajfer L, Ransmayr B, Mautner AK, Kondo R, Tinnacher A, Caldera M, Schuster M, Domínguez Conde C, Platzer R, Salzer E, Boyer T, Brunner HG, Nooitgedagt-Frons JE, Iglesias E, Deyà-Martinez A, Camacho-Lovillo M, Menche J, Bock C, Huppa JB, Pickl WF, Distel M, Yoder JA, Traver D, Engelhardt KR, Linden T, Kager L, Hannich JT, Hoischen A, Hambleton S, Illsinger S, Da Costa L, Kutsche K, Chavoshzadeh Z, van Buul JD, Antón J, Calzada-Hernández J, Neth O, Viaud J, Nishikimi A, Dupré L, Boztug K. (2023) “Systemic inflammation and normocytic anemia in DOCK11 deficiency.” New England Journal of Medicine, doi: 10.1056/NEJMoa2210054

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2210054

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