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Project description:The DNA methylome and transcriptome of hyper-IgM syndrome type 2 B cells
| PRJNA721695 | ENA
Project description:BackgroundX-linked hyper-IgM (X-HIGM), which results from mutations in the CD40LG gene located on chromosome Xq26.3, is the most common form of HIGM. To date, more than 130 variants of the CD40L gene have been reported. We described a patient with novel de novo nuclear mitochondrial DNA sequences (NUMTs) in the CD40LG gene that have resulted in X-HIGM.MethodsWhole-exome sequencing (WES) analysis was used to screen for causal variants in the genome, and the candidate breakpoint was confirmed by Sanger sequencing.ResultsA new mutation of CD40LG, which deletes A at position 17 followed by a 147-nucleotide from mitochondrial DNA copies insertion in exon 1, was detected in a 20-month-old boy harbouring an X-HIGM combined with immunodeficiency syndrome.ConclusionThis is one of the few cases of a human genetic disease caused by nuclear mitochondrial DNA sequences (NUMTs). The presented data serve to demonstrate that de novo NUMT transfer of nucleic acid is a novel mechanism of X-HIGM.
| S-EPMC8172197 | biostudies-literature
Project description: Not available
| S-EPMC6030472 | biostudies-literature
Project description:PurposeThe United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM).MethodsThe USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality.ResultsFifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years).ConclusionsAnalysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.
| S-EPMC5039943 | biostudies-literature
Project description:Inactivating mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although there is evidence both to support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation defects. For genes that undergo demethylation in the transition from naïve to memory B cells but not in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns without involvement of its cytosine deaminase activity.
2020-12-31 | GSE134664 | GEO
Project description:Hyper-IgM syndrome (HIGM) is a heterogeneous condition characterized by impaired Ig class-switch recombination (CSR). The molecular defects that have so far been associated with this syndrome - which affect the CD40 ligand in HIGM type 1 (HIGM1), CD40 in HIGM3, and activation-induced cytidine deaminase (AID) in HIGM2 - do not account for all cases. We investigated the clinical and immunological characteristics of 15 patients with an unidentified form of HIGM. Although the clinical manifestations were similar to those observed in HIGM2, these patients exhibited a slightly milder HIGM syndrome with residual IgG production. We found that B cell CSR was intrinsically impaired. However, the generation of somatic hypermutations was observed in the variable region of the Ig heavy chain gene, as in control B lymphocytes. In vitro studies showed that the molecular defect responsible for this new HIGM entity (HIGM4) occurs downstream of the AID activity, as the AID gene was induced normally and AID-induced DNA double-strand breaks in the switch micro region of the Ig heavy chain locus were detected during CSR as normal. Thus, HIGM4 is probably the consequence of a selective defect either in a CSR-specific factor of the DNA repair machinery or in survival signals delivered to switched B cells.
| S-EPMC162294 | biostudies-literature
Project description:B cell maturation depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers costimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class switch. Mutations affecting CD40-CD40L interactions cause abnormal antibody responses in immunodeficiencies known as X-linked hyper-IgM syndrome (X-HIgM). Here, we study the CD40-mediated mechanotransduction in B cells, which likely occurs during their physical contacts with T cells. We found that CD40 forms catch bond with CD40L that lasts longer at larger forces, both B and T cells exert tension on CD40-CD40L bonds, and force enhances CD40 signaling and antibody class switch. X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the role of mechanotransduction in CD40 function and provide insights into the mechanisms underlying X-HIgM syndrome.
| S-EPMC11566996 | biostudies-literature
Project description:Background: Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease. Reports of rare cases of PAP due to Pneumocystis jirovecii (P. jirovecii) exist in infants with immunodeficiency diseases, but no cases have been reported to date in pediatric patients with type 1 hyper-IgM syndrome (HIGM1). Case Presentation: Herein, we present a case of PAP secondary to P. jirovecii on an infant with HIGM1. He was admitted to our unit because of cough and tachypnea. Lung biopsy confirmed the diagnosis of PAP, whereas hexamine-silver staining of the bronchoalveolar lavage fluid identified P. jirovecii infection. No other probable cause of PAP was observed. Whole exome sequencing indicated a novel c.511dupA (p.I171N*30) hemizygous mutation in the CD40 ligand (CD40LG) gene. He was cured with bronchoalveolar lavage and compound sulfamethoxazole tablets. Conclusions: To our knowledge, this is the first reported case of P. jirovecii infection as a reversible cause of PAP in an infant with HIGM1.
| S-EPMC7301693 | biostudies-literature
Project description:Targeted gene editing to restore CD40L expression via homology-directed repair (HDR) in CD34+ hematopoietic stem and progenitor cells (HSPCs) represents a potential long-term therapy for X-linked hyper IgM syndrome. However, clinical translation of HSPC editing is limited by inefficient long-term engraftment of HDR-edited HSPCs. Here, we ameliorate this issue by employing a small-molecule inhibitor of DNA-PKcs, AZD7648, to bias DNA repair mechanisms to facilitate HDR upon CRISPR SpCas9-based gene editing. Using AZD7648 treatment and a clinically relevant HSPC source, mobilized peripheral blood CD34+ cells, we achieve ∼60% HDR efficiency at the CD40LG locus and enhanced engraftment of HDR-edited HSPCs in primary and secondary xenotransplants. Specifically, we observed a 1.6-fold increase of HDR-edited long-term HSPCs in primary transplant recipients without disturbing chimerism levels or differentiation capacity. As CD40L is primarily expressed in T cells, we demonstrate T cell differentiation from HDR-edited HSPCs in vivo and in artificial thymic organoid cultures, and endogenously regulated CD40L expression following activation of in-vivo-derived CD4+ T cells. Our combined findings demonstrate HDR editing at the CD40LG locus at potentially clinically beneficial levels. More broadly, these data support using DNA-PKcs inhibition with AZD7648 as a simple and efficacious addition to HSPC editing platforms.
| S-EPMC11863497 | biostudies-literature
Project description:Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T>C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P<0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P<0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.
| S-EPMC5027683 | biostudies-literature