Defective Class Switch Recombination Research Articles

Immunoglobulin class-switch recombination: Mechanism, regulation, and related diseases.

Maturation of the secondary antibody repertoire requires class-switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high-affinity antibodies. Following immune response or infection within the body, activation of T cell-dependent and T cell-independent antigens triggers the activation of activation-induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper-IgM syndrome, Waldenström macroglobulinemia, hyper-IgD syndrome, selective IgA deficiency, hyper-IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Dual novel variants in CD40 leading to hyper IgM syndrome: a case report of a school-aged female with new-onset recurrent pneumonia

Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40 ligand (CD40L) interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than those in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in the CD40 gene. Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia. Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression. Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis, and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency. Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications. Statement of novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.

Analysis of Lymphocyte and Clinical Profile among Non-monogenic Common Variable Immunodeficiency Patients with and without Class Switch Recombination Defect.

Analysis of Lymphocyte and Clinical Profile among Non-monogenic Common Variable Immunodeficiency Patients with and without Class Switch Recombination Defect.

Optimal AID expression and efficient immunoglobulin class switch recombination are dependent on the hypoxia-inducible factor.

During immune responses, B cells engaging a cognate antigen are recruited to GCs in secondary lymphoid organs where they will diversify their BCR to generate highly specific and adapted humoral responses. They do so, by inducing the expression of activation-induced cytidine deaminase (AID), which initiates somatic hypermutation (SHM) and class switch recombination (CSR). AID deaminates cytosines in ss DNA, generating U:G mismatches that are processed to induce ds DNA break intermediates during CSR that result in the expression of a different antibody isotype. Interestingly, hypoxia regions have been reported in GCs and suggesting that hypoxia could modulate the humoral response. Furthermore, hypoxia inducible transcription factor (HIF) can bind to the AID promoter and induce AID expression in a non-B-cell setting, suggesting that it might be involved in the transcriptional induction of AID in B cells, hence, regulating SHM and CSR. We, thus, hypothesized that HIF could regulate the efficiency of CSR. Here, we show that the inactivation of both the HIF-1α and HIF-1β subunits of the HIF transcription factor in murine CH12 B cells results in defective CSR and that this is due to the suboptimal induction of AID expression.

The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages

PurposePrimary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects.MethodsPatients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry.ResultsA total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6–20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2–7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity.ConclusionOur results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity.

A single-center study points to diverse features and outcome in patients with Hyperimmunoglobulin M Syndrome and Class- Switch Recombination defects.

Isotype class-switch recombination (CSR), somatic hypermutation (SHM), B cell signalling and DNA repair mechanisms defects are responsible for high IgM. The hyperimmunoglobulin M (HIGM) phenotype and CSR-related defects are now classified under primary antibody defects, combined immunodeficiencies or syndromic immunodeficiencies groups. The aim of the study is to evaluate the diverse phenotypic/genotypic/laboratory characteristics and outcome of patients with CSR defects and HIGM-related defects. We enrolled 50 patients. The most common gene defect was Activation-induced cytidine deaminase (AID) deficiency (n=18), followed by CD40 Ligand (CD40L) (n=14) and CD40 (n=3) deficiency. Median ages at first symptom and diagnosis were significantly lower in CD40L deficiency (8.5 and 30 months, respectively) than AID deficiency (30 and 114 months, respectively) (p=.001 and p=.008, respectively). Frequent clinical symptoms were recurrent (66%) and severe (14.9%) infections, and/or autoimmune/non-infectious inflammatory features (48.4%). Eosinophilia and neutropenia were at a higher rate in CD40L deficiency patients (77.8%, p=.002 and 77.8%, p=.002, respectively) when compared to AID deficiency. Median serum IgM level was low in 28.6% of CD40L deficiency patients. It was significantly lower when compared to AID deficiency (p < 0.001). Six patients (CD40L deficiency n=4, CD40 deficiency n=2) underwent hematopoietic stem cell transplantation. Five were alive at the last visit. Four patients two patients with CD40L deficiency, one with CD40 deficiency and one with AID deficiency had novel mutations. In conclusion; patients with CSR defects and HIGM phenotype may present with a wide range of clinical manifestations and laboratory findings. Low IgM, neutropenia and eosinophilia were prominent in patients with CD40L deficiency. Characterization of genetic defect-specific clinical and laboratory features may ease the diagnosis, prevent the underdiagnoses of patients and ameliorate the outcome.

A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting

Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.

Class switch recombination defect in child with ataxia–telangiectasia with hyper IgM phenotype

Class switch recombination defect in child with ataxia–telangiectasia with hyper IgM phenotype

Clinical Manifestations of Ataxia-Telangiectasia with Class Switch Recombination Defect

Background: Elevated serum levels of IgM and recurrent infections, mainly respiratory tract infections, could be the presenting features in some ataxia-telangiectasia (AT) patients, and may initially be misdiagnosed as hyper-IgM (HIgM) syndrome. Class switch recombination (CSR), which is defective in HIgM syndrome, is an important mechanism in the maturation of B lymphocytes to produce different isotypes of antibodies in response to antigen stimulation. Methods: The clinical manifestations and laboratory findings of 16 cases with low IgA and IgG levels, and normal to elevated IgM levels with CSR defect are reported. Results: In 16 cases, the median age at onset of the diseases, and median age at the time of the diagnosis were 1 year (interquartile range [IQR] = 1.6), and 4 years (IQR = 3.1), respectively. Two of the patients (12.5 %) died due to respiratory infection. In this study, Out of the studied population, four were male (25%), and 12 were female (75%). Most of the patients had consanguineous parents (81.3 %). All of the patients had ataxia, and 15 patients had telangiectasia (93.8 %), and one of the cases had malignancy (dermatofibroma). Also, 15 patients presented infections (93.8 %). Autoimmunity was seen in three patients (18.8 %). In addition, some of the patients manifested hepatosplenomegaly (31.3 %) and thrombocytopenia (18.8 %). Neurological manifestations, such as visual impairment (12.5 %), epilepsy (6.3 %), and tremor (12.5 %), were also present. Conclusion: AT patients with HIgM phenotype and CSR defect, compared to other AT patients, may present different clinical manifestations, such as various infections. Considering their manifestations, the management and treatment of these patients are necessary.

Class switch recombination defect in child with ataxia-telangiectasia with hyper IgM phenotype

Ataxia-telangiectasia (AT) is a rare autosomal recessive disease characterized by cerebellar ataxia, ocular and/or cutaneous telangiectasia, immune deficiency, enhanced radiosensitivity, and susceptibility to malignancy. It is caused by mutations in the AT mutated ( ATM ) gene. Hyper-IgM phenotypes are characterized by a class-switch recombination defect, IgG and IgA deficiencies, immune dysregulation, and lymphoproliferative disorders. In this case report, a 6.5-year-old Egyptian A-T female had progressive hepatosplenomegaly, hypersplenism, generalized lymphadenopathy, and high levels of IgM. This patient had a class switch recombination defect (CSRD), leading to the diagnosis of HIgM-phenotype of ataxia-telangiectasia with class switch defect (HIgM AT-CSD). In reporting this case, we hope to highlight its rarity and complexity in a pediatric patient with AT, as well as the potential role of an appropriate diagnostic assessment in achieving successful clinical outcomes. The presence of hepatosplenomegaly and lymphadenopathy in AT suggests malignancy or infection, but after exclusion of these causes, pediatricians must consider HIgM AT-CSD as a possible cause of lymphoproliferation.

Regulation of humoral immune response by HIF-1α-dependent metabolic reprogramming of the germinal center reaction

Hypoxia-inducible factor-1α (HIF-1α) has been implicated in the regulation of many genes responsible for aerobic glycolysis; however, the role of HIF-1α in B-cell metabolism has not been well defined. Here, we analyzed patterns of gene expression and oxygen consumption rates in B-cell subpopulations from humans and mice and described a model of HIF-1α-mediated B-cell metabolic reprogramming during the germinal center (GC) reaction. Importantly, we found that HIF-1α was highly expressed in GC B-cells, and HIF-1α deficiency in B-cells impaired a functional GC reaction, resulting in defective class-switch recombination and generation of high-affinity plasma cells. These results identified an important role of HIF-1α in regulating humoral immunity through metabolic reprogramming during the GC response. This newly discovered metabolic character of GC B-cells will advance our understanding of GC biology and B-cell lymphomagenesis.

FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (Atm⁠ RX ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in Atm⁠ RX/RX ⁠ mice compared with Atm⁠ -/- ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

Class Switch Recombination Defects: impact on B cell maturation and antibody responses

To assess how B cell phenotype analysis correlates with antigen responses in patients with class switch recombination defects (CSRD) we quantified memory B cells by flow-cytometry and immunized CSRD patients with the neoantigen bacteriophage phiX174 (phage).CSRD patients showed uniformly absent or markedly reduced switched memory B cells (IgM−IgD−CD27+). CD40L patients had reduced CD27+ memory B cells (both non-switched and switched). In NEMO patients, results varied depending on the IKKγ gene variant. Three of four AID patients had normal percentages of CD27+ memory B cells while CD27+IgM−IgD− switched memory B cells were markedly reduced in all AID patients. Antibody response to phage was remarkably decreased with lack of memory amplification and class-switching in immunized CD40L, UNG deficient, and NEMO patients.Distinct B-cell phenotype pattern correlated with abnormal antibody responses to a T-cell dependent neoantigen, representing a powerful tool to identify CSRD patients.

A novel activation-induced cytidine deaminase mutation in an adult with hyper-immunoglobulin M syndrome

The hyper-immunoglobulin M (HIGM) syndromes are a group of immunodeficiencies that exhibit low or absent levels of immunoglobulin G (IgG), IgA, and IgE and normal to high levels of IgM.1 These syndromes are characterized by inherited defects in genes encoding for the CD40L or CD40 molecule, or defects in class-switch recombination (CSR) in B cells.2 Activation-induced cytidine deaminase (AID) is a protein that is required for CSR in B cell differentiation.3,4 A mutation in the activation-induced cytidine deaminase (AICDA) gene that encodes AID causes the autosomal recessive (AR) form of HIGM syndrome known as HIGM2.

Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia.

Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities. This study aimed to examine immunologic parameters reflecting cell development, activation, proliferation, and class switch recombination (CSR) and determine their relationship to the clinical phenotype in AT patients. In this study, 40 patients with a confirmed diagnosis of AT from the Iranian immunodeficiency registry center and 28 age-sex matched healthy controls were enrolled. We compared peripheral B and T cell subsets and T cell proliferation response to CD3/CD28 stimulation in AT patients with and without CSR defects using flow cytometry. A significant decrease in naïve, transitional, switched memory, and IgM only memory B cells, along with a sharp increase in the marginal zone-like and CD21low B cells was observed in the patients. We also found CD4+ and CD8+ naïve, central memory, and terminally differentiated effector memory CD4+ (TEMRA) T cells were decreased. CD4+ and CD8+ effector memory, CD8+ TEMRA, and CD4+ regulatory T cells were significantly elevated in our patients. CD4+ T cell proliferation was markedly impaired compared to the healthy controls. Moreover, immunological investigations of 15 AT patients with CSR defect revealed a significant reduction in the marginal zone, switched memory, and more intense defects in IgM only memory B cells, CD4+ naïve and central memory T cells. The present study revealed that patients with AT have a broad spectrum of cellular and humoral deficiencies. Therefore, a detailed evaluation of T and B cell subsets increases understanding of the disease in patients and the risk of infection.

Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

AbstractMolecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus.

The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2-/- mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2-mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2-/- primary B-cells and 53BP1- and shieldin-deficient CH12F3-2 B-cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig-negative cells is also seen in other NHEJ-deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR invivo by suppressing large deletions within the Igh locus.

Effect of Class Switch Recombination Defect on the Phenotype of Ataxia-Telangiectasia Patients

ABSTRACT Objectives: Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement caused by homozygous or compound heterozygous mutations in the ataxia telangiectasia mutated (ATM) gene which encodes a serine/threonine protein kinase. The aims of this study were to investigate class switch recombination (CSR) and to review the clinical and immunologic phenotypes of 3 groups of A-T patients, including A-T patients with CSR defects (CSR-D), A-T patients with selective immunoglobulin A deficiency (IgA-D) and A-T patients with normal Ig level. Methods: In this study, 41 patients with confirmed diagnosis of A-T (16 A-T patients with HIgM, 15 A-T patients with IgA-D, and 10 A-T patients with normal Ig levels) from Iranian immunodeficiency registry center were enrolled. B-cell proliferation, in vitro CSR toward IgE and IgA were compared between three groups as well as G2 radiosensitivity assay. Results: Earliest presentation of telangiectasia was a significant hallmark in A-T patients with CSR-D (p = .036). In this investigation, we found that the frequency of respiratory infection (p = .002), pneumonia (p = .02), otitis media (p = .008), chronic fever (p < .001), autoimmunity (p = .02) and hepatosplenomegaly (p = .03) in A-T patients with HIgM phenotype were significantly higher than the other groups. As expected IgE production stimulation and IgA CSR were perturbed in HIgM patients that were aligned with the higher readiosenstivity scores in this group. Conclusion: A-T patients with HIgM compared to other A-T patients presenting more infections and noninfectious complications, therefore, early detection and careful management of these patients is necessary.

HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells

(Molecular Cell 77, 384–394.e1–e4; January 16, 2020) The authors report two minor errors in Figure 3G of the originally published article. In this panel, there appeared a letter “E” that was not relevant to the figure and may have been confusing to readers. Also, in the same panel, the authors report having inadvertently copied an older version of the bar graph, with fewer replicates, which is different from the one provided to reviewers in the revised version of the manuscript. These errors were made during the generation of high-resolution images toward the end of the production process and have since been corrected online. The errors do not change the message of the figure, nor do they impact the overall conclusions of the article. The authors apologize for any inconvenience.Figure 3GHMCES Deficiency Leads to a Defect in CSR in the CH12 B Cell Line (original)View Large Image Figure ViewerDownload Hi-res image Download (PPT) HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B CellsShukla et al.Molecular CellDecember 2, 2019In BriefHMCES (5hmC binding, embryonic stem cell-specific protein), originally found to bind 5-hydroxymethylcytosine (5hmC), was recently reported to covalently crosslink to DNA at abasic sites. Shukla et al. show that HMCES specifically enables DNA double-strand break repair through the microhomology-mediated alternative-end-joining (Alt-EJ) pathway during class switch recombination (CSR) in B cells. Full-Text PDF Open Archive

Effects of senataxin and RNA exosome on B-cell chromosomal integrity

Loss of function of senataxin (SETX), a bona-fide RNA/DNA helicase, is associated with neuronal degeneration leading to Ataxia and Ocular Apraxia (AOA) in human patients. SETX is proposed to promote transcription termination, DNA replication, DNA repair, and to unwind deleterious RNA:DNA hybrids in the genome. In all the above-mentioned mechanisms, SETX unwinds transcription complex-associated nascent RNA which is then degraded by the RNA exosome complex. Here we have used B cells isolated from a SETX mutant mouse model and compared genomic instability and immunoglobulin heavy chain locus (IgH) class switch recombination (CSR) to evaluate aberrant and programmed genomic rearrangements, respectively. Similar to RNA exosome mutant primary B cells, SETX mutant primary B cells display genomic instability but a modest decrease in efficiency of CSR. Furthermore, knockdown of Setx mRNAs from CH12–F3 B-cell lines leads to a defect in IgA CSR and accumulation of aberrant patterns of mutations in IgH switch sequences. Given that SETX mutant mice do not recapitulate the AOA neurodegenerative phenotype, it is possible that some aspects of SETX biology are rescued by redundant helicases in mice. Overall, our study provides new insights into the role of the SETX/RNA exosome axis in suppressing genomic instability so that programmed DNA breaks are properly orchestrated.