Biallelic <i>PAX5</i> mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Kaiser, Fabian; Gruenbacher, Sarah; Oyaga, Maria Roa; Nio, Enzo; Jaritz, Markus; Sun, Qiong; Zwaag, Wietske van der; Kreidl, Emanuel; Zopf, Lydia M.; Dalm, Virgil A. S. H.; Pel, J.J.M.; Gaiser, Carolin; Vliet, Rick van der; Wahl, Lucas; Rietman, André B.; Hill, Louisa; Leca, Ines; Laffeber, Charlie; Brooks, Alice S.; Katsikis, Peter D.; Lebbink, Joyce H.G.; Tachibana, Kikuë; Burg, Mirjam van der; Zeeuw, Chris I. De; Badura, Aleksandra; Busslinger, Meinrad

doi:10.1084/jem.20220498

Cited by 15 publications

(6 citation statements)

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“… AMutation of the Pax5‐binding sequence of PAIR4. The nucleotides of PAIR4, which match the Pax5 consensus recognition sequence (Kaiser et al , 2022), are underlined and were mutated to the nucleotides indicated in red (∆Pax5). BMutation of the CTCF‐binding sequence of PAIR4. The nucleotides of PAIR4, corresponding to the consensus CTCF‐binding motif (Hill et al , 2020), are underlined and were mutated to the nucleotides indicated in red (∆CTCF). C, DSchematic diagram of the Gfp ‐linked PAIR4‐V8.7E module with the Pax5‐ or CTCF‐binding site mutation, which was used for the generation of the Igh P4∆Pax5GV or Igh P4∆CtcfGV allele, respectively. E, GPax5 and CTCF binding to the wild‐type and mutant PAIR4 sequences.…”

Section: Resultsmentioning

confidence: 99%

Enhancers of the PAIR4 regulatory module promote distal V_H gene recombination at the Igh locus

et al. 2023

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While extended loop extrusion across the entire Igh locus controls V H -DJ H recombination, local regulatory sequences, such as the PAIR elements, may also activate V H gene recombination in pro-B-cells. Here, we show that PAIR-associated V H 8 genes contain a conserved putative regulatory element (V8E) in their downstream sequences. To investigate the function of PAIR4 and its V8.7E, we deleted 890 kb containing all 14 PAIRs in the Igh 5 0 region, which reduced distal V H gene recombination over a 100-kb distance on either side of the deletion. Reconstitution by insertion of PAIR4-V8.7E strongly activated distal V H gene recombination. PAIR4 alone resulted in lower induction of recombination, indicating that PAIR4 and V8.7E function as one regulatory unit. The pro-B-cell-specific activity of PAIR4 depends on CTCF, as mutation of its CTCF-binding site led to sustained PAIR4 activity in pre-B and immature B-cells and to PAIR4 activation in T-cells. Notably, insertion of V8.8E was sufficient to activate V H gene recombination. Hence, enhancers of the PAIR4-V8.7E module and V8.8E element activate distal V H gene recombination and thus contribute to the diversification of the BCR repertoire in the context of loop extrusion.

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Section: Resultsmentioning

confidence: 99%

Enhancers of the PAIR4 regulatory module promote distal V_H gene recombination at the Igh locus

et al. 2023

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“…PAX5. A single individual with compound heterozygous PAX5 variants had reduced levels of all serum Ig isotypes and peripheral B-lymphopenia ( Kaiser et al, 2022 ). Mice expressing patient-specific PAX5 alleles ( Pax5 R31Q/E242 * ) had an accumulation of pro-B cells and 5–10-fold fewer pre- and immature B cells in BM compared to WT mice ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Pax5 R31Q/E242 * mice also had significantly reduced peripheral B cells and levels of serum IgG (10–20-fold), IgA (∼5-fold), and IgM (2-fold). Mechanistically, Pax5 R31Q encoded a hypomorphic protein, impaired in regulating 10–20% of PAX5 target genes ( Kaiser et al, 2022 ). Thus, human PAX5 deficiency blocks B cell development resulting in B cell cytopenia, hypogammaglobulinemia, and impaired Ab responses.…”

Section: Introductionmentioning

confidence: 99%

Inborn errors of human B cell development, differentiation, and function

Tangye

Nguyen

Deenick

et al. 2023

Journal of Experimental Medicine

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B cells develop from hematopoietic stem cells in the bone marrow. Once generated, they serve multiple roles in immune regulation and host defense. However, their most important function is producing antibodies (Ab) that efficiently clear invading pathogens. This is achieved by generating memory B cells that rapidly respond to subsequent Ag exposure, and plasma cells (PCs) that continually secrete Ab. These B cell subsets maintain humoral immunity and host protection against recurrent infections for extended periods of time. Thus, the generation of antigen (Ag)-specific memory cells and PCs underlies long-lived serological immunity, contributing to the success of most vaccines. Our understanding of immunity is often derived from animal models. However, analysis of individuals with monogenic defects that disrupt immune cell function are unprecedented models to link genotypes to clinical phenotypes, establish mechanisms of disease pathogenesis, and elucidate critical pathways for immune cell development and differentiation. Here, we review fundamental breakthroughs in unraveling the complexities of humoral immunity in humans that have come from the discovery of inborn errors disrupting B cell function.

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“…Following up on the demonstration that the ErasmusLadder enables the differentiation between cerebellar mutants in cross sectional studies (Van Der Giessen et al, 2008; Renier et al, 2010; Schonewille et al, 2011; van der Vaart et al, 2011; Baudouin et al, 2012; Saab et al, 2012; Vinueza Veloz et al, 2012; Galliano et al, 2013; Marques et al, 2015; Vinueza Veloz et al, 2015; Ha et al, 2016; Peter et al, 2016; Rahmati et al, 2016; French et al, 2018; Prekop et al, 2018; Sathyanesan et al, 2018; Sayed-Zahid et al, 2019; Wu et al, 2019; Almeida et al, 2020; Grasselli et al, 2020; Haify et al, 2020; Namdar et al, 2020; Peter et al, 2020; Blot et al, 2021; Lang-Ouellette et al, 2021; Vacher et al, 2021; White et al, 2021; Kaiser et al, 2022; Klomp et al, 2022; Lauffer et al, 2022; Ottenhoff et al, 2022; Birkisdóttir et al, 2023a; Fang et al, 2023) (Table S1), in this study we aimed to probe the ErasmusLadder as a tool for quantifying disease onset and progression in cerebellar disease models. We examined two mouse lines displaying progressive Purkinje cell degeneration, and followed their behavioral performance from early to severe symptomatic stages.…”

Section: Introductionmentioning

confidence: 99%

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

Jaarsma,

Birkisdóttir,

van Vossen

et al. 2023

Preprint

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Background Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. Objectives We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice and whether two different mechanisms that both lead to Purkinje cell degeneration caused different patterns in the development of gait ataxia. Methods Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a physically challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Results Both mouse models showed increasingly stronger gaiting deficits, but the sequence with which gaiting parameters deteriorated depended on the specific mutation. Conclusions Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and our findings will facilitate the study of therapeutic interventions in mice, as very subtle changes in locomotor abilities can be quantified by our methods.

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Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Cited by 15 publications

References 100 publications

Enhancers of the PAIR4 regulatory module promote distal V_H gene recombination at the Igh locus

Enhancers of the PAIR4 regulatory module promote distal V_H gene recombination at the Igh locus

Inborn errors of human B cell development, differentiation, and function

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

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Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Cited by 15 publications

References 100 publications

Enhancers of the PAIR4 regulatory module promote distal VH gene recombination at the Igh locus

Enhancers of the PAIR4 regulatory module promote distal VH gene recombination at the Igh locus

Inborn errors of human B cell development, differentiation, and function

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

Contact Info

Product

Resources

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Enhancers of the PAIR4 regulatory module promote distal V_H gene recombination at the Igh locus

Enhancers of the PAIR4 regulatory module promote distal V_H gene recombination at the Igh locus