title: Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.
abstract: Immunoglobulin (Ig) class switch recombination (CSR) deficiencies are rare primary immunodeficiencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation. Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase. We report a new form of B cell-intrinsic CSR deficiency found in three patients with deleterious, homozygous mutations in the gene encoding the PMS2 component of the mismatch repair machinery. CSR was found partially defective in vivo and markedly impaired in vitro. It is characterized by the defective occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. This observation strongly suggests a role for PMS2 in CSR-induced DSB generation.
authors.affiliation: Institut National de Santé et de Recherche Médicale, U768, 75015 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Péron
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Pauline
authors.initials: P
authors.lastname: Gardès
authors.forename: Marie-Alexandra
authors.initials: MA
authors.lastname: Alyanakian
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.forename: Christian Peter
authors.initials: CP
authors.lastname: Kratz
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D015153:Blotting, Western; D002648:Child; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes