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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.

SUBMITTER: Peron S 

PROVIDER: S-EPMC2571921 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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

Péron Sophie S   Metin Ayse A   Gardès Pauline P   Alyanakian Marie-Alexandra MA   Sheridan Eamonn E   Kratz Christian Peter CP   Fischer Alain A   Durandy Anne A  

The Journal of experimental medicine 20080929 11


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-  ...[more]

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