A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair.
Immunoglobulin class switch recombination (CSR) deficiencies are rare primary immunodeficiencies, characterized by a lack of switched isotype (IgG, IgA, or IgE) production, variably associated with abnormal somatic hypermutation (SHM). Deficiencies in CD40 ligand, CD40, activation-induced cytidine deaminase, and uracil-N-glycosylase may account for this syndrome. We previously described another Ig CSR deficiency condition, characterized by a defect in CSR downstream of the generation of double-stranded DNA breaks in switch (S) mu regions. Further analysis performed with the cells of five affected patients showed that the Ig CSR deficiency was associated with an abnormal formation of the S junctions characterized by microhomology and with increased cell radiosensitivity. In addition, SHM was skewed toward transitions at G/C residues. Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events.
Péron
Sophie
S
Institut National de la Santé et de la Recherche Médicale, U768, Paris, France.
Pan-Hammarström
Qiang
Q
Imai
Kohsuke
K
Du
Likun
L
Taubenheim
Nadine
N
Sanal
Ozden
O
Marodi
Laszlo
L
Bergelin-Besançon
Anne
A
Benkerrou
Malika
M
de Villartay
Jean-Pierre
JP
Fischer
Alain
A
Revy
Patrick
P
Durandy
Anne
A
D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology; D020029:Base Pairing; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D011995:Recombination, Genetic / Q000235:genetics* / Q000276:immunology; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics* / Q000502:physiology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
D018941:Antigens, CD19; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; C508551:NHEJ1 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D045643:DNA Repair Enzymes