REL was first reported in relation to immunodeficiency 92 in a single patient in 2019 (Beaussant-Cohen S, et al., 2019, PMID: 31103457). A second patient was reported in Lévy R, et al., 2021 (PMID: 34623332) and both patients were homozygous for splice variants with a proposed loss of function mechanism. Experimentally, this gene-disease relationship is supported by its expression pattern and biochemical function. c-Rel, the protein product of REL, is strongly expressed by control EBV-B cells and was detected in all leukocyte subsets from healthy donors, the highest levels being recorded for γδ T cells, naive CD19+ B cells, CD16+ monocytes, and CD141+ conventional DCs (PMID: 34623332). c-Rel is a transcription factor in the NF-κB family, critical for T and B cell function, it binds to the promoters of genes that encode cytokines important for immunity against infectious pathogens, including IL-2, IFN-γ, IL-12, IL-21, and IL-23 (PMID: 22207895) with significant functional alteration observed in patients (PMID: 34623332). Furthermore, Rel-deficient mice have impaired T and B cell proliferation, hypogammaglobulinemia, and impaired cytokine production (PMID: 7649478, 10221648). The patient’s combined immunodeficiency mirrors the defects in T cell activation, B cell proliferation, innate immunity and humoral immunity seen in c-Rel-deficient mice. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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