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

Dirks, Johannes; Haase, Gabriele; Cantaert, Tineke; Frey, Lea; Klaas, Moritz; Rickert, Christian H.; Girschick, Hermann; Meffre, Eric; Morbach, Henner

doi:10.1007/s10875-022-01233-5

Cited by 5 publications

(3 citation statements)

References 35 publications

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“…This was postulated to result from an SHM defect since it affects partial AID deficiencies with preserved AID-mediated recombination and CSR (36). However, a similar phenotype was also recently reported in a partial AID defect restricted to CSR while preserving SHM frequency, although this ended with lessened selection of those V segments with SHM appropriately focused on CDR segments (37). The impact of such partial AID defects on SHM vs CSR machinery and on B cell selection thus remains to be clarified, as well as their potential impact on the LSR process.…”

Section: Mice With Lsr Defects Show Increased Production Of Self-reac...supporting

confidence: 64%

Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

et al. 2023

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IntroductionIn mature B cells, activation-induced deaminase reshapes Ig genes through somatic hypermutation and class switch recombination of the Ig heavy chain (IgH) locus under control of its 3’ cis-regulatory region (3’RR). The 3’RR is itself transcribed and can undergo “locus suicide recombination” (LSR), then deleting the constant gene cluster and terminating IgH expression. The relative contribution of LSR to B cell negative selection remains to be determined.MethodsHere, we set up a knock-in mouse reporter model for LSR events with the aim to get clearer insights into the circumstances triggering LSR. In order to explore the consequences of LSR defects, we reciprocally explored the presence of autoantibodies in various mutant mouse lines in which LSR was perturbed by the lack of Sµ or of the 3’RR.ResultsEvaluation of LSR events in a dedicated reporter mouse model showed their occurrence in various conditions of B cell activation, notably in antigen-experienced B cells Studies of mice with LSR defects evidenced increased amounts of self-reactive antibodies.DiscussionWhile the activation pathways associated with LSR are diverse, in vivo as well as in vitro, this study suggests that LSR may contribute to the elimination of self-reactive B cells.

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Section: Mice With Lsr Defects Show Increased Production Of Self-reac...supporting

confidence: 64%

Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

et al. 2023

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“…AICDA mutations Online Mendelian Inheritance in Man (OMIM: 605257),9 usually homozygous mutations in exon 3 of chromosome 12, result in AR HIGM type 2 with deficient AID enzyme and defective CSR and SHM. Recently, an autosomal dominant variant of HIGM type 2 has been reported due to C-terminal heterozygous mutation of AICDA gene 10. While AR HIGM type 2 affects both CSR and SHM, the autosomal dominant HIGM type 2 affects only CSR.…”

Section: Discussionmentioning

confidence: 99%

Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman

et al. 2023

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We report the case of a woman in her early 20s with a history of recurrent infection, atopic dermatitis, filariasis and bilateral purulent ear discharge since childhood with tonsillar enlargement on examination. She was started on supportive care and evaluated for primary immunodeficiency disease. Blood investigations revealed increased IgM levels with reduced IgG, IgA and IgE levels. Radiological imaging of the chest revealed bilateral bronchiectasis. Otoscopic examination showed features suggestive of chronic suppurative otitis media. Next-generation sequencing identified homozygous single base pair deletion in exon 2 of the activation-induced cytidine deaminase gene. Thus, a diagnosis of hyper-IgM syndrome type 2 was confirmed. The patient was started on monthly intravenous immunoglobulin replacement therapy and is currently symptomatically better, and she remains under regular follow-up.

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“…Another puzzling feature that seems to be particularly frequent in genes associated with IEI is the observation that pathogenic variants of the same gene can follow different modes of inheritance. For example, both an autosomal recessive as well as an autosomal dominant inheritance is known to be causative in the genes such as MEFV ( 71 , 72 ), STING1 ( 73 , 74 ) and AICDA ( 75 , 76 ).…”

Section: Current Challengesmentioning

confidence: 99%

Current genetic diagnostics in inborn errors of immunity

von Hardenberg,

Klefenz,

Steinemann

et al. 2024

Front. Pediatr.

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New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.

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

Cited by 5 publications

References 35 publications

Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

Type 2 hyper-IgM syndrome with a rare variant of AICDA gene mutation in a young woman

Current genetic diagnostics in inborn errors of immunity

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