Scientists have identified genetic changes that can leave children born with little or no immune defense against infections.
In a new study of 11 affected people, researchers from the University of Newcastle, the Wellcome Sanger Institute, Great North Children’s Hospital and their collaborators were able to link mutations in the NUDCD3 gene for severe combined immunodeficiency and Omenn syndrome1 – rare and life-threatening immunodeficiency disorders. These mutations prevented the normal development of various immune cells necessary to combat different pathogens.2.
The findings, published today (May 24) in Scientific immunologyThey open opportunities for early diagnosis and intervention of this condition.
Severe combined immunodeficiency (SCID) and Omenn syndrome are rare genetic disorders that leave children without a functional immune system and at risk for life-threatening infections. Without urgent treatment, such as stem cell transplants to replace the failing immune system, many sufferers will not survive the first year.
While neonatal screening methods can detect T cell deficiency, knowledge of the specific genetic cause increases confidence in the diagnosis of SCID and informs the choice of curative therapy. Currently this remains out of reach for at least 1 in 10 affected families.
In this new study, researchers from the University of Newcastle, the Wellcome Sanger Institute and their collaborators studied 11 children from four families, two of whom had SCID while the other nine had Omenn syndrome. All had inherited mutations that altered the function of the NUDCD3 protein, which had not previously been linked to the immune system.
Using detailed studies of cells derived from patients and mouse models, the team showed that NUDCD3 The mutations disrupt a crucial genetic rearrangement process called V(D)J recombination, essential for generating the various T cell receptors and antibodies needed to recognize and combat different pathogens.
While mice designed with the same NUDCD3 Although the mutations had milder immunological problems, human patients faced serious and life-threatening consequences. However, two patients survived after receiving a stem cell transplant, reinforcing the importance of early diagnosis and intervention.
Dr Gosia Trynka, author of the study at the Wellcome Sanger Institute and scientific director of Open Targets, said: “For babies born with high-risk immunodeficiencies, early detection can mean the difference between life and death. These Diseases leave newborns essentially defenseless against pathogens that most of us can easily fend off. Identifying this new disease gene will help doctors make rapid molecular diagnosis in affected patients, meaning they will be able to receive treatments. to save their lives more quickly.
Professor Sophie Hambleton, lead author of the study at the University of Newcastle and practicing pediatric immunologist at Great North Children’s Hospital, said: “SCID and Omenn syndrome are devastating disorders that require complex and timely treatments. The more we can understand its underlying causes, the better we can care for affected babies. Our research aims to fill the gaps so families can achieve a molecular diagnosis while we continue to learn more about how the immune system works in health and disease. This study will help future generations.”
Grades
1. Children with severe combined immunodeficiency disorder completely lack the T cells needed to fight infections, while those with Omenn syndrome have abnormal T cells that not only fail to fight infections but also attack the body’s own tissues . They require urgent treatment and management of infections.
2. Specifically, the NUDCD3 mutant was unable to regulate RAG1, a key enzyme required in V(D)J recombination. This caused RAG1 to become trapped within cellular nucleoli instead of facilitating the genetic rearrangements that create immune diversity.