Mutation in DOCK11 gene explains rare disorder in immune system regulation

Researchers from the Institut de Recerca Sant Joan de Déu - SJD Barcelona Children's Hospital participate in an international study, published in the prestigious scientific journal New England Journal of Medicine, which describes for the first time a new disease of the immune system caused by a mutation of the DOCK11 gene.

The basic research in the study was led by the St. Anna Children's Cancer Research Institute, the Research Centre for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna. The project involved the participation of a team of researchers from the "Study of Immune Deficiency Diseases in Paediatrics (GEMDIP) " group of the Sant Joan de Déu Research Institute (IRSJD) and researchers from the Hospital Virgen del Rocío - IBIS.

This new disease is due to the anomalies which the defect in the DOCK11 gene produces in the cytoskeleton - the internal structure of cells which gives them their shape and capacity of movement. It is clinically manifested by persistent inflammation, alteration in the formation of blood cells, and alteration in the regulation of the immune system.


The genetic sequencing of the patient was first attended in Virgen del Rocío University Hospital and lately in SJD Barcelona Children's Hospital, revealed a mutation in DOCK11, a gene not previously associated with any human disease which is involved in the regulation of various cell functions.

Earlier studies had demonstrated the importance of the protein produced by this gene for the development of B cells in mouse models. Now the researchers have shown that, up to a certain point, B cells do not develop correctly in humans with DOCK11 deficiency, while other immunological cells called T lymphocytes are over-activated, explaining the state of persistent inflammation.

"This constant inflammation may bring about an accumulation of amyloid protein in tissues, producing amyloidosis", adds Dr Laia Alsina, coordinator in Study of Immune Deficiency Diseases in Paediatrics (GEMDIP) at IRSJD.

Haematopoietic cell transplantation: a possible treatment

Although all the details of the function of DOCK11 are not yet understood, the researchers suspect that the transplantation of blood-forming or haematopoietic stem cells could be a therapeutic option. It is also conceivable that DOCK11 deficiency can be treated by gene therapy.

"Even so, these two options still need to be explored and a great deal of research remains to be done. The important thing is that the description of this new entity expands our spectrum of knowledge and may allow the diagnosis of patients with inflammatory diseases whose cause is unknown", explains Dr Jordi Antón, head of the Paediatric Rheumatology Service of SJD Barcelona Children's Hospital and coordinator in Study of Immune Deficiency Diseases in Paediatrics (GEMDIP) at IRSJD.

For his part, Dr Joan Calzada, researcher in in Study of Immune Deficiency Diseases in Paediatrics (GEMDIP), adds that, in the case of rare diseases, it is very important to be able to count on the support and help of reference centres, such as Sant Joan de Déu Barcelona Children's Hospital and Virgen del Rocío University Hospital of Seville. "When it comes to undiagnosed disorders, it is crucial for care to be provided by highly specialised professionals and this is even more essential in the context of rare diseases."

Thanks to this collaboration, it will now be possible to identify other patients with this rare disease and to improve their diagnosis and, consequently, their treatment, preventing the progression of the disease from causing very serious sequels.

Reference paper

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. Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency. N Engl J Med. 2023 Jun 21. doi: 10.1056/NEJMoa2210054. Epub ahead of print. PMID: 37342957.


Se describe una nueva enfermedad causada por la mutación del gen DOCK11. Hospital Sant Joan de Déu Barcelona.

The disease produces an alteration of cytoskeleton formation, leading to a disorder in immune system regulation expressed from a very early age as persistent inflammation and haematological disorders, among other serious manifestations.