Human MSH6 deficiency is associated with impaired antibody maturation.

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.

Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair.

Ig class-switch recombination (CSR) is a region-specific process that exchanges the constant Ig heavy-chain region and thus modifies an antibody's effector function. DNA lesions in switch (S) regions are induced by activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2), subsequently processed to DNA breaks, and resolved by either the classical nonhomologous end-joining pathway or the alternative end-joining pathway (XRCC4/DNA ligase 4- and/or Ku70/Ku80-independent and prone to increased microhomology usage). We examined whether the induction of DNA lesions influences DNA end-joining during CSR by analyzing Sμ-Sα recombination junctions in various human Ig CSR defects of DNA lesion induction.

Inherited defects of immunoglobulin class switch recombination.

The investigation of an inherited primary immunodeficiency, the immunoglobulin class switch recombination deficiency, has allowed the delineation of complex molecular events that underlie antibody maturation in humans. The Activation-induced cytidine deaminase (AID)-deficiency, characterized by a defect in Class Switch Recombination (CSR) and somatic hypermutation, has revealed the master role of this molecule in the induction of DNA damage, the first step required for these two processes. The description that mutations in the gene encoding the Uracil-DNA glycosylase (UNG) lead to defective CSR has been essential for defining the DNA-editing activity of AID.

Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.

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.