Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24...Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24,CDCA7,or HELLS.While progress has been made in elucidating the roles of these genes in regulating DNA methylation,little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype.Here,we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome.Specifically,Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM,IgG1,and IgA.Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens,respectively,and marginal zone B-cell activation is impaired.Mechanistically,Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra(interleukin-5 receptor subunit alpha),and Il5ra derepression leads to elevated CD19 phosphorylation.Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice.Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.展开更多
基金supported by a grant(1R01AI12140301A1)from the National Institutes of Health(NIH)in the USA.
文摘Immunodeficiency,centromeric instability,and facial anomalies(ICF)syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency.It is caused by mutations in DNMT3B,ZBTB24,CDCA7,or HELLS.While progress has been made in elucidating the roles of these genes in regulating DNA methylation,little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype.Here,we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome.Specifically,Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM,IgG1,and IgA.Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens,respectively,and marginal zone B-cell activation is impaired.Mechanistically,Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra(interleukin-5 receptor subunit alpha),and Il5ra derepression leads to elevated CD19 phosphorylation.Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice.Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.
