An analysis of five families has revealed a previously unknown genetic immunodeficiency, says an international team led by researchers from Boston Children’s Hospital, United States.
According to the scientists benefitting in part from a European Research Council starting grant, the condition is linked to mutations in a gene called DOCK2, deactivates many features of the immune system, and leaves affected children open to a unique pattern of aggressive, potentially fatal infections early in life. DOCK2 deficiency may be detectable by newborn screening and is curable with a hematopoietic stem cell transplant (HSCT).
Speaking about the investigation, Luigi Notarangelo, of Boston Children’s Hospital’s Division of Allergy and Immunology and professor of paediatrics at Harvard Medical School, said: “Until recently, a correct diagnosis for babies born with SCID or other combined immunodeficiencies, such as DOCK2 deficiency, could be made only after these babies had developed serious infections, which could lead to death or compromise the efficacy of an HSCT.
“Newborn screening for these diseases is now available for most babies with SCID born in the USA, and this gives increased chances of definitive cure by performing the transplant while the baby is still well.”
In the study, lead investigators Notarangelo and Kerry Dobbs, as well as colleagues at the Rockefeller University and the Center for Molecular Medicine in Austria, conducted genetic, genomic, and immunological analyses on five patients from Lebanon, Finland, Turkey and Honduras/Nicaragua. In early life, the patients demonstrated symptoms indicating a severe but distinctive immunodeficiency, one that left patients susceptible to a broad range of infections but particularly vulnerable to viruses. Three out of the five patients were born of closely related parents, and three were successfully treated by HSCT.
The team discovered through whole exome sequencing that all five patients harboured mutations in DOCK2, mutations that rendered the DOCK2 protein inactive. The mutations had profound effects on multiple aspects of the patients’ immune systems, causing a profound decrease in T-cells and defects in T-, B- and natural killer cell function.
The study data show that defects in DOCK2, which helps immune cells react to external chemical signals, can have a profound effect on several aspects of immunity, including unforeseen effects on how non-immune cells (such as cells of the skin) respond to viruses.
Notarangelo added: “The knowledge gained has … allowed development of new drugs that harness the immune system to treat more common conditions, including tumours and autoimmune diseases.”
Other funders of the research include the Austrian Science Fund and the German Research Foundation. The results are published in full in the New England Journal of Medicine.