Published online September 29, 2008
doi:10.1084/jem.20080789
The Journal of Experimental Medicine, Vol. 205, No. 11, 2465-2472
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Péron et al.
Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination
Sophie Péron1,2,
Ayse Metin3,
Pauline Gardès1,2,
Marie-Alexandra Alyanakian4,
Eamonn Sheridan5,
Christian Peter Kratz6,
Alain Fischer1,2,7, and
Anne Durandy1,2,7
1 Institut National de la Santé et de la Recherche Médicale, U768, 75015 Paris, France
2 Université Paris Descartes, Faculté de Médecine René Descartes, Site Necker, Institut Fédératif de Recherche, 75015 Paris, France
3 Division of Pediatric Immunology, SB Ankara Diskapi Children's Hospital, 06110 Ankara, Turkey
4 Université Paris Descartes, Assistance Publique–Hôpitaux de Paris, Laboratoire d'Immunologie, Hôpital Necker, 75015 Paris, France
5 Leeds Institute of Molecular Medicine, University of Leeds and Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds, LS9 7TF, England, UK
6 Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, 79106 Freiburg, Germany
7 Assistance Publique–Hôpitaux de Paris, Hôpital Necker Enfants Malades, Service d'Immunologie et d'Hématologie Pédiatrique, 75015 Paris, France
CORRESPONDENCE Anne Durandy: anne.durandy{at}inserm.fr
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.
© Péron et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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