NEMO, a non-catalytically active component of the IkappaB alpha kinase (IKK) complex, is required for IKK enzymatic activity and localization. If NEMO is defective, NF-kB transcription factor family members do not translocate to the nucleus to regulate gene transcription, and normal development of the organism, including the immune system, does not occur. In addition to these developmental defects, the immune system does not function correctly if NEMO is defective. Individuals with specific mutations which result in NEMO immunodeficiency and inflammatory disease are investigated using molecular, cellular and biochemical assays/techniques. In addition to clinical and laboratory evaluation of human patients, these studies are conducted using patient-derived induced pluripotent stem cells, and a reconstitution system utilizing NEMO-deficient Jurkat T cells. Because NEMO syndrome is associated with defects in development of ectodermal structures in addition to secondary lymphoid structures in association with certain mutations, we seek to understand the function of NEMO in both of these roles in addition to its role in hematopoietically derived cells. We have generated human iPSC to study the effects of mutation on the development and function of these various cell types. NEMO is required for IKK activation, but also thought to serve as a scaffold to other signaling proteins. Its regulation is complex: splice isoforms exist, and it is post-translationally modified by serine phosphorylation, non-degradative ubiquitination, and sumoylation. Variability of clinical disease phenotypes and immune-function lab abnormalities make management of individuals with NEMO syndrome and inflammatory disease difficult. Because of our incomplete understanding, treatment paradigms such as the use of allogeneic hematopoietic stem cell transplantation cannot at this point be standardized and often result in poor outcomes. We are establishing protocols to evaluate patients at the NIH Clinical Center to be able to comprehensively characterize the spectrum of phenotypes, and are working to develop protocols to offer advanced treatment based on our clinical and laboratory findings. In a similar fashion, we are studying individuals with NEMO-Like Syndrome who have suspected monogenic diseases which phenocopy NEMO syndrome in some aspects. We hypothesize that these individuals will have defects in signaling proteins or other regulatory proteins that interact in the NF-kB signaling pathway. Our general approach to discover the genetic defects that cause disease is to use candidate gene sequencing based on the disease and clinical laboratory phenotype, or, if necessary, exome or whole genome sequencing. Candidate genes identified are evaluated using assays that interrogate different checkpoints along the NF-kB activation pathway. Insights into the role of proteins gained from study of patients with rare diseases will be applied to evaluation of the normal immune system to understand the function of these proteins in the normal immune response and more common inflammatory diseases.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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