Researchers headed by teams at Newcastle University, the Wellcome Sanger Institute, and the Great North Children’s Hospital have identified a single gene mutation common to 11 pediatric patients with either severe combined immunodeficiency (SCID) or Omenn syndrome (OS). These two closely related congenital errors in T cell development manifest early in life and leave children with little or no immune defenses against infection.

Through the newly reported study, the scientists were able to link mutations in the NUDCD3 gene to both disorders. These mutations prevented the normal development of diverse immune cells needed to combat different pathogens.

The findings, reported in Science Immunology, could point to opportunities for early diagnosis and intervention. Gosia Trynka, PhD, at the Wellcome Sanger Institute and science director at 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. The identification of this new disease gene will help clinicians to make a prompt molecular diagnosis in affected patients, meaning they can receive life-saving treatments more quickly.” Trynka is co-author of the paper, which is titled, “NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.”

SCID and OS are both rare genetic disorders that leave children without a functional immune system and at risk of life-threatening infections. Children with SCID completely lack the T cells needed to combat infections, while those with OS have abnormal T cells that not only fail to combat infections but also mount attacks on the body’s own tissues.

Without urgent treatment, such as stem cell transplants to replace the faulty immune system, many affected will not survive their first year. While newborn screening methods can flag 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.

The authors further commented: “Because these conditions are both treatable and life-threatening, many nations have recently introduced newborn screening for T cell immunodeficiency. In affected infants, a specific molecular diagnosis may guide precision medicine such as enzyme replacement, gene therapy, or hematopoietic stem cell transplantation (HSCT).”

For their newly reported study, the investigators studied 11 children across four families, two of the children had SCID, marked by a complete absence of T and B cells, while the other nine presented symptoms consistent with OS. All 11 patients had the same homozygous missense mutation in the gene NUDCD3—a protein that had not previously been linked to the immune system—which resulted in reduced expression of NUDCD3 protein. The patients all displayed defects in V(D)J recombination, which is a critical step in the early development of T and B cells because it ensures they will possess the diverse range of antigen receptors essential for a healthy adaptive immune system. “By integrative analysis of whole-exome sequencing (WES) data, we identified a single homozygous missense variant in the gene NUDCD3 (NudC domain–containing 3), which segregated with disease in all four affected kindreds,” the team stated.

V(D)J recombination is tightly controlled by a series of recombinase enzymes, including RAG1. Further analyses of the patients’ cells showed that reduced levels of NUDCD3 protein correlated with difficulties in RAG1 exiting the nucleoli. Specifically, the mutant NUDCD3 could not regulate RAG1, a key enzyme needed in V(D)J recombination. This caused RAG1 to get trapped within cell nucleoli instead of facilitating the gene rearrangements that build immune diversity. The findings suggest that NUDCD3 could serve as an essential co-chaperone, along with RAG2, in mediating RAG1 egress.

In follow-up experiments, Chen et al. generated a knock-in mouse model bearing the same mutation and found that the mice displayed similar—albeit less severe—immunological defects. Their research showed that while mice engineered with the same NUDCD3 mutations had milder immune problems, the human patients faced severe, life-threatening consequences.

The mutation, they commented, “… appears to produce an incomplete developmental block with its major impact on V(D)J recombination in both species, one that differs in severity between humans and mice and between developing B and T cells … These studies establish NUDCD3 as a disease gene for T-B- SCID and OS. Its integrity is required for efficient B and T cell development, specifically for RAG-dependent V(D)J recombination, and consequently the generation of antigen receptor diversity upon which adaptive immunity depends.”

Senior study author Sophie Hambleton, MD, PhD, at Newcastle University and a practicing pediatric immunologist at the Great North Children’s Hospital, said, “SCID and OS are devastating disorders, requiring complex and timely treatments. The more we can understand about its underlying causes, the better we can look after affected babies. Our research is aimed at filling in the gaps so that families can achieve a molecular diagnosis while we continue learning more about how the immune system works in health and disease. We are deeply grateful to the families whose invaluable participation in this study will help future generations.”

Two of the study patients did survive after receiving a stem cell transplant, whereas the remaining patients succumbed to a variety of infectious and inflammatory complications, reinforcing the importance of early diagnosis and intervention. “The generally poor outcome of this cohort highlights the life-threatening nature of SCID/OS and the importance of early diagnosis and therapy,” the researchers stated. “Infants with suspected T cell immunodeficiency, including those identified through newborn TREC screening, should be screened for pathogenic variants of the NUDCD3 gene.”

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