An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex.
Bottom Line: Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity.INO80 deficiency appears to be associated with defective immunoglobulin CSR.We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis.
Affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.Show MeSH
Related in: MedlinePlus
Mentions: In both patients, the presence of mutations in genes already known to be involved in CSR was ruled out through sequence analysis (AID and UNG) or the observation of normal expression (CD40L and CD40) and CD40-mediated B cell proliferative responses. Total B cell counts were normal, but the number of IgM− IgD− CD19+ CD27+–switched memory B cells was low. T cell counts were within the normal range. Likewise, the T-cell receptor (TCR) beta chain and the BCR repertoires were within the normal range, as assessed by amplification of V-J rearrangements (data not shown). Analysis of B cell function revealed a normal frequency of somatic hypermutations in the VH3-23 region of IgM in P1. The nucleotide substitution pattern was normal, suggesting that AID activity was unaffected (data not shown). In vitro CD40L+ IL4-induced CSR to IgE was consistently found impaired in peripheral blood lymphocytes from both patients, when compared with age-matched controls (Table I). An ex vivo analysis of Sμ-Sα junctions revealed that blunt junctions were less frequent in P1 and P2 than in age-matched controls. In contrast, junctions based on 4 to 9 nt microhomologies were more frequent in the patients (Fig 1, A). In agreement with the preferential usage of microhomology, both patients displayed a significantly higher portion of Sμ-Sα junction breakpoints in the distal part of the Sμ region (which has the highest degree of homology with Sα) (Fig 1, B).
Affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.