POU2AF1, encoding the Bob1 protein, was first reported in relation to autosomal recessive agammaglobulinemia in 2021 by Kury et al (PMID: 33571536). This is the only report of a patient with a Bob1 deficiency caused by a homozygous POU2AF1 null mutation (NM_006235.3:c.233del) resulting in a severe B-cell–intrinsic defect. B-cell receptor signaling was reduced and plasmablast development and immunoglobulin secretion seemed abrogated in the patient. This gene-disease relationship is supported by experimental evidence; the highly B lymphocyte-specific pattern of POU2AF1 expression in lymphocytes, together with its selective stimulatory effect on immunoglobulin promoters strongly indicates that POU2AF1is a critical determinant of immunoglobulin transcription in lymphoid cells (PMID: 7859290), which is deficient in patient cells but can be rescued by lentiviral reconstitution (PMID: 33571536). The immunologic manifestations in the patient showed some overlap with the Bob1 knockout mice (PMIDs: 8977324, 8849727, 8849728, 35603192). Patient T cells were normal in terms of distribution and activation except for a reduction in circulating T-follicular helper (TFH) cells (PMID: 33571536). While it has been shown that POU2AF1 does not act as a transcriptional coactivator for T cells (PMID: 35285071) the observed defect in T follicular helper differentiation is likely related to its functional impact in B cells, however, in a mouse model, it was shown that POU2AF1 is expressed in activated (not naïve) T cells, and when deleted in T cells had a positive regulatory impact on autoimmune diabetes, suggesting that it has a role to play in T-cell-driven autoimmunity, and facilitates polarization of activated T helper cells to a TH17 phenotype (PMID: 33295943). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Antibody Deficiencies GCEP on 09/20/2022 (SOP Version 9).
Of note, in B cells, CD19 and POU2AF1 may also serve as diagnostic and prognostic biomarkers of chronic obstructive pulmonary disease (PMID: 35479834). Additionally, expression of POU2AF1 in non-lymphocytes, specifically in airway epithelium appears to contribute to regulation of host immunity (PMID: 26927796).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.