title: Human MSH6 deficiency is associated with impaired antibody maturation.
abstract: Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of γH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions.
authors.affiliation: INSERM U768, Hôpital Necker Enfants Malades, F-75015 Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gardès
authors.forename: Monique
authors.initials: M
authors.lastname: Forveille
authors.forename: Marie-Alexandra
authors.initials: MA
authors.lastname: Alyanakian
authors.forename: Pierre
authors.initials: P
authors.lastname: Aucouturier
authors.forename: Denisa
authors.initials: D
authors.lastname: Ilencikova
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mazerolles
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005260:Female; D006657:Histones / Q000235:genetics; D006801:Humans; D017099:IgG Deficiency / Q000235:genetics; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000097:blood; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C468783:H2AX protein, human; D006657:Histones; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region