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

Péron S, Metin A, Gardès P, Alyanakian MA, Sheridan E, Kratz CP, Fischer A, Durandy A - J. Exp. Med. (2008)

Bottom Line: 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.CSR was found partially defective in vivo and markedly impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Institut National de Santé et de Recherche Médicale, U768, 75015 Paris, France.

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.

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Induction of RNA transcripts in control, P1, and P2 lymphocytes undergoing in vitro CSR. RNA transcripts of the genes encoding CD19, AID, UNG2, PMS2, MLH1, PMS1, MSH2, MSH6, and IgE (germline and functional) were analyzed using RT-PCR in PBLs from controls (n = 5), and P1 and P2 (n = 1) both before and after a 5-d activation with sCD40L plus IL-4. As is the case for AID and UNG2, MMR transcripts were induced during CSR activation. Germline IgE transcripts were normally expressed after activation, in contrast to the lack of functional transcripts in P1 and low level in P2. (D0, day 0; D5, day 5).
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fig1: Induction of RNA transcripts in control, P1, and P2 lymphocytes undergoing in vitro CSR. RNA transcripts of the genes encoding CD19, AID, UNG2, PMS2, MLH1, PMS1, MSH2, MSH6, and IgE (germline and functional) were analyzed using RT-PCR in PBLs from controls (n = 5), and P1 and P2 (n = 1) both before and after a 5-d activation with sCD40L plus IL-4. As is the case for AID and UNG2, MMR transcripts were induced during CSR activation. Germline IgE transcripts were normally expressed after activation, in contrast to the lack of functional transcripts in P1 and low level in P2. (D0, day 0; D5, day 5).

Mentions: Three patients with Ig-CSR deficiency (see the following paragraph) were found to carry homozygous mutations in the PMS2 gene. Recurrent infections and café-au-lait skin spots observed in patient 1 (P1) were evocative of MMR defect. First-degree consanguinity enabled us to perform a genome scan using polymorphic markers flanking the MLH1, PMS1, PMS2, MSH2, and MSH6 genes. A large, homozygous, 107-bp region including the PMS2 gene was observed on chromosome 7p22. The PMS2 gene was thus sequenced on genomic DNA, and a homozygous deletion of exons 11–14 was observed (p.N412DfsX6). All other exons and their flanking regions had a normal sequence. Parents were found to be heterozygous for the deletion, whereas the healthy sister had a wild-type homozygous PMS2 sequence. The homozygous deletion of exons 11–14 was confirmed on the patient's cDNA, with an 18-nucleotide frameshift insertion and a stop codon at the very beginning of exon 15. This abnormality was found in cDNA from both fibroblasts and PBLs before and after CSR induction by sCD40L/IL-4 co-stimulation (Fig. 1).


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

Péron S, Metin A, Gardès P, Alyanakian MA, Sheridan E, Kratz CP, Fischer A, Durandy A - J. Exp. Med. (2008)

Induction of RNA transcripts in control, P1, and P2 lymphocytes undergoing in vitro CSR. RNA transcripts of the genes encoding CD19, AID, UNG2, PMS2, MLH1, PMS1, MSH2, MSH6, and IgE (germline and functional) were analyzed using RT-PCR in PBLs from controls (n = 5), and P1 and P2 (n = 1) both before and after a 5-d activation with sCD40L plus IL-4. As is the case for AID and UNG2, MMR transcripts were induced during CSR activation. Germline IgE transcripts were normally expressed after activation, in contrast to the lack of functional transcripts in P1 and low level in P2. (D0, day 0; D5, day 5).
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571921&req=5

fig1: Induction of RNA transcripts in control, P1, and P2 lymphocytes undergoing in vitro CSR. RNA transcripts of the genes encoding CD19, AID, UNG2, PMS2, MLH1, PMS1, MSH2, MSH6, and IgE (germline and functional) were analyzed using RT-PCR in PBLs from controls (n = 5), and P1 and P2 (n = 1) both before and after a 5-d activation with sCD40L plus IL-4. As is the case for AID and UNG2, MMR transcripts were induced during CSR activation. Germline IgE transcripts were normally expressed after activation, in contrast to the lack of functional transcripts in P1 and low level in P2. (D0, day 0; D5, day 5).
Mentions: Three patients with Ig-CSR deficiency (see the following paragraph) were found to carry homozygous mutations in the PMS2 gene. Recurrent infections and café-au-lait skin spots observed in patient 1 (P1) were evocative of MMR defect. First-degree consanguinity enabled us to perform a genome scan using polymorphic markers flanking the MLH1, PMS1, PMS2, MSH2, and MSH6 genes. A large, homozygous, 107-bp region including the PMS2 gene was observed on chromosome 7p22. The PMS2 gene was thus sequenced on genomic DNA, and a homozygous deletion of exons 11–14 was observed (p.N412DfsX6). All other exons and their flanking regions had a normal sequence. Parents were found to be heterozygous for the deletion, whereas the healthy sister had a wild-type homozygous PMS2 sequence. The homozygous deletion of exons 11–14 was confirmed on the patient's cDNA, with an 18-nucleotide frameshift insertion and a stop codon at the very beginning of exon 15. This abnormality was found in cDNA from both fibroblasts and PBLs before and after CSR induction by sCD40L/IL-4 co-stimulation (Fig. 1).

Bottom Line: 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.CSR was found partially defective in vivo and markedly impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Institut National de Santé et de Recherche Médicale, U768, 75015 Paris, France.

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.

Show MeSH
Related in: MedlinePlus