Biallelic PAX5 mutations cause hypogammaglobulinemia,sensorimotor deficits and autism spectrum disorder
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA759253 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15680431.fastq.gz | Fastqsanger.gz | |||
| SRR15680432.fastq.gz | Fastqsanger.gz | |||
| SRR15680433.fastq.gz | Fastqsanger.gz | |||
| SRR15680434.fastq.gz | Fastqsanger.gz | |||
| SRR15680435.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the molecular basis for the B cell developmental arrest in Pax5R31Q/– mice, we performed RNA-sequencing (RNA-seq) with ex vivo sorted Pax5+/+ and Pax5R31Q/– pro-B cells. We identified Pax5-activated and Pax5-repressed genes that were no longer properly regulated by the Pax5-R31Q protein in Pax5R31Q/– pro-B cells. Notably, these genes were only a subset of the activated and repressed genes identified by comparing Pax5+/+ and Pax5–/– pro-B cells, which raised the question whether binding of the Pax5-R31Q protein may be selectively lost at the subset of deregulated genes in Pax5R31Q/– pro-B cells. By using a Pax5 paired domain antibody for chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) of short-term cultured Pax5+/+ and Pax5R31Q/– pro-B cells, we identified all associated Pax5 binding sites. Common Pax5 peaks had a similar Pax5-binding density in contrast to the strong binding difference observed at the unique peaks present in Pax5+/+ pro-B cells. To investigate a correlation between the loss of Pax5 binding and gene expression, we focused our analysis on Pax5 peaks in the TSS region of activated genes. We systematically investigated the correlation between loss of Pax5 binding at the TSS and down-regulation of gene expression in Pax5R31Q/– pro-B cells. The ratio of Pax5 binding between Pax5R31Q/– and Pax5+/+ pro-B cells at the TSS of these activated genes was significantly reduced compared to that of expressed non-regulated genes. We next explored whether the Pax5-binding difference at the TSS also correlated with the magnitude of gene expression difference. The loss of Pax5 binding at the TSS also correlated with the degree of expression change in Pax5R31Q/– pro-B cells compared to Pax5+/+ pro-B cells. We conclude therefore that the selective DNA-binding of Pax5-R31Q is responsible for the observed gene expression differences in Pax5R31Q/– pro-B cells.
2022-07-06 | GSE182463 | GEO
Project description:The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.
| S-EPMC9372349 | biostudies-literature
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 40 samples comprising sevenfold replicates of transductions with empty vector, wild type PAX5 and 4 mutant PAX5 constructs
2013-08-01 | E-GEOD-45260 | biostudies-arrayexpress
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 10 samples of J558 murine myeloma cells infected with MSCV-Puro-IRES-GFP (PIG) empty vector (EV; three independent replicates), MSCV-PIG Pax5 WT (WT; three independent replicates), and MSCV-PIG Pax5 G183S (Mut; four independent replicates). Cells were selected with puromycin after infection for 5-7 days, subsequently cells were sorted for GFP and IgM expression by FACS.
2014-04-06 | E-GEOD-45834 | biostudies-arrayexpress
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia.
2013-08-01 | GSE45260 | GEO
Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia.
2014-04-06 | GSE45834 | GEO
Project description:Biallelic RNU12 noncoding variants cause CDAGS syndrome
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Project description:PAX5 transduction of Pax5-/- pro-B cells
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Project description:Pax5 controls B-cell commitment, development and immunity by repressing B-lineage-inappropriate genes and activating B-cell-specific genes. In addition to the N-terminal DNA-binding paired domain, Pax5 contains a conserved octapeptide, partial homeodomain and C-terminal sequences with transactivating and inhibitory potential. To understand how the C-terminal domains of Pax5 contribute to the repression and activation function of Pax5, we performed Pax5 pulldown combined with mass spectrometry to identify coactivator or corepressor complexes that bind to the C-terminal regions of Pax5.
2023-08-24 | PXD040424 | Pride
Project description:B lymphopoiesis is a key developmental event orchestrated by a complex combinatorial action of lineage-specific transcription factors. In early B cell progenitors, lineage commitment is directly mediated by the master regulator PAX5, whose deficiency is commonly associated with B cell Acute Lymphoblastic Leukemia (B-ALL). Despite its essential role in mammalian immunity, the regulatory mechanisms that control PAX5 function remain largely unknown. Here we show that NAD+-dependent enzyme SIRT7 coordinates B cell development progression through PAX5. We have identified a SIRT7-dependent regulatory switch based on dynamic deacetylation of a single PAX5 residue, which controls its activity and thereby B cell fate. While a PAX5K198 acetylated mimic is incapable of inducing both B cell development and identity due to reduced protein stability and impaired binding to chromatin, deacetylation of this residue boosts PAX5 activity, leading to massive gene repression and in vivo restoration of B cell commitment but not differentiation. These findings suggest an unexpected uncoupling of hematopoietic differentiation and lineage commitment. Further supporting the functional relevance of the SIRT7-PAX5 axis, the interplay between both factors is conserved in human B-ALL, where high SIRT7 expression is an independent good prognostic factor. Our findings unveil a crucial mechanism in the regulation of B cell production based on the control of PAX5 function and underscore the key role of Sirtuins in the regulation of the immune system.
2024-09-20 | PXD046457 | Pride